StemCell Therapy

Cancer stem cells (CSCs) are cancer cells (found within tumors or hematological cancers) that possess characteristics associated with normal stem cells, specifically the ability to give rise to all cell types found in a particular cancer sample. CSCs are therefore tumorigenic (tumor-forming), perhaps in contrast to other non-tumorigenic cancer cells. CSCs may generate tumors through the stem cell processes of self-renewal and differentiation into multiple cell types. Such cells are hypothesized to persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors. Therefore, development of specific therapies targeted at CSCs holds hope for improvement of survival and quality of life of cancer patients, especially for patients with metastatic disease.

Existing cancer treatments have mostly been developed based on animal models, where therapies able to promote tumor shrinkage were deemed effective. However, animals do not provide a complete model of human disease. In particular, in mice, whose life spans do not exceed two years, tumor relapse is difficult to study.

The efficacy of cancer treatments is, in the initial stages of testing, often measured by the ablation fraction of tumor mass (fractional kill). As CSCs form a small proportion of the tumor, this may not necessarily select for drugs that act specifically on the stem cells. The theory suggests that conventional chemotherapies kill differentiated or differentiating cells, which form the bulk of the tumor but do not generate new cells. A population of CSCs, which gave rise to it, could remain untouched and cause relapse.

Cancer stem cells were first identified by John Dick in acute myeloid leukemia in the late 1990s. Since the early 2000s they have been an intense cancer research focus.[1]

In different tumor subtypes, cells within the tumor population exhibit functional heterogeneity and tumors are formed from cells with various proliferative and differentiation capacities.[2] This functional heterogeneity among cancer cells has led to the creation of multiple propagation models to account for heterogeneity and differences in tumor-regenerative capacity: the cancer stem cell (CSC) and stochastic model.

The Cancer Stem Cell Model, also known as the Hierarchical Model proposes that tumors are hierarchically organized (CSCs lying at the apex[3] (Fig. 3).) Within the cancer population of the tumors there are cancer stem cells (CSC) that are tumorigenic cells and are biologically distinct from other subpopulations[4] They have two defining features: their long-term ability to self-renew and their capacity to differentiate into progeny that is non-tumorigenic but still contributes to the growth of the tumor. This model suggests that only certain subpopulations of cancer stem cells have the ability to drive the progression of cancer, meaning that there are specific (intrinsic) characteristics that can be identified and then targeted to destroy a tumor long-term without the need to battle the whole tumor [5]

In order for a cell to become cancerous it must undergo a significant number of alterations to its DNA sequence. This cell model suggests these mutations could occur to any cell in the body resulting in a cancer. Essentially this theory proposes that all cells have the ability to be tumorigenic making all tumor cells equipotent with the ability to self-renew or differentiate, leading to tumor heterogeneity while others can differentiate into non-CSCs [4][6] The cell's potential can be influenced by unpredicted genetic or epigenetic factors, resulting in phenotypically diverse cells in both the tumorigenic and non-tumorigenic cells that compose the tumor.[7]

These mutations could progressively accumulate and enhance the resistance and fitness of cells that allow them to outcompete other tumor cells, better known as the somatic evolution model.[4] The clonal evolution model, which occurs in both the CSC model and stochastic model, postulates that mutant tumor cells with a growth advantage outproliferate others. Cells in the dominant population have a similar potential for initiating tumor growth[8] (Fig. 4).

[9] These two models are not mutually exclusive, as CSCs themselves undergo clonal evolution. Thus, the secondary more dominant CSCs may emerge, if a mutation confers more aggressive properties[10] (Fig. 5).

A study in 2014 argues the gap between these two controversial models can be bridged by providing an alternative explanation of tumor heterogeneity. They demonstrate a model that includes aspects of both the Stochastic and CSC models.[6] They examined cancer stem cell plasticity in which cancer stem cells can transition between non-cancer stem cells (Non-CSC) and CSC via in situ supporting a more Stochastic model.[6][11] But the existence of both biologically distinct non-CSC and CSC populations supports a more CSC model, proposing that both models may play a vital role in tumor heterogeneity.[6]

The existence of CSCs is under debate, because many studies found no cells with their specific characteristics.[12] Cancer cells must be capable of continuous proliferation and self-renewal to retain the many mutations required for carcinogenesis and to sustain the growth of a tumor, since differentiated cells (constrained by the Hayflick Limit[13]) cannot divide indefinitely. If most tumor cells are endowed with stem cell properties, targeting tumor size directly is a valid strategy. If they are a small minority, targeting them may be more effective. Another debate is over the origin of CSCs - whether from disregulation of normal stem cells or from a more specialized population that acquired the ability to self-renew (which is related to the issue of stem cell plasticity).

The first conclusive evidence for CSCs came in 1997. Bonnet and Dick isolated a subpopulation of leukemia cells that expressed surface marker CD34, but not CD38.[14] The authors established that the CD34+/CD38 subpopulation is capable of initiating tumors in NOD/SCID mice that were histologically similar to the donor. The first evidence of a solid tumor cancer stem-like cell followed in 2002 with the discovery of a clonogenic, sphere-forming cell isolated and characterized from human brain gliomas. Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro.[15]

In cancer research experiments, tumor cells are sometimes injected into an experimental animal to establish a tumor. Disease progression is then followed in time and novel drugs can be tested for their efficacy. Tumor formation requires thousands or tens of thousands of cells to be introduced. Classically, this was explained by poor methodology (i.e., the tumor cells lose their viability during transfer) or the critical importance of the microenvironment, the particular biochemical surroundings of the injected cells. Supporters of the CSC paradigm argue that only a small fraction of the injected cells, the CSCs, have the potential to generate a tumor. In human acute myeloid leukemia the frequency of these cells is less than 1 in 10,000.[14]

Further evidence comes from histology. Many tumors are heterogeneous and contain multiple cell types native to the host organ. Heterogeneity is commonly retained by tumor metastases. This suggests that the cell that produced them had the capacity to generate multiple cell types, a classical hallmark of stem cells.[14]

The existence of leukemia stem cells prompted research into other cancers. CSCs have recently been identified in several solid tumors, including:

Once the pathways to cancer are hypothesized, it is possible to develop predictive mathematical models,[33] e.g., based on the cell compartment method. For instance, the growths of abnormal cells can be denoted with specific mutation probabilities. Such a model predicted that repeated insult to mature cells increases the formation of abnormal progeny and the risk of cancer.[34] The clinical efficacy of such models[35] remains unestablished.

The origin of CSCs is an active research area. The answer may depend on the tumor type and phenotype. So far the hypothesis that tumors originate from a single "cell of origin" has not been demonstrated using the cancer stem cell model. This is because cancer stem cells are not present in end-stage tumors.

Origin hypotheses include mutants in developing stem or progenitor cells, mutants in adult stem cells or adult progenitor cells and mutant, differentiated cells that acquire stem-like attributes. These theories often focus on a tumor's "cell of origin".

The "mutation in stem cell niche populations during development" hypothesis claims that these developing stem populations are mutated and then reproduce so that the mutation is shared by many descendants. These daughter cells are much closer to becoming tumors and their numbers increase the chance of a cancerous mutation.[36]

Another theory associates adult stem cells (ASC) with tumor formation. This is most often associated with tissues with a high rate of cell turnover (such as the skin or gut). In these tissues, ASCs are candidates because of their frequent cell divisions (compared to most ASCs) in conjunction with the long lifespan of ASCs. This combination creates the ideal set of circumstances for mutations to accumulate: mutation accumulation is the primary factor that drives cancer initiation. Evidence shows that the association represents an actual phenomenon, although specific cancers have been linked to a specific cause.[37][38]

De-differentiation of mutated cells may create stem cell-like characteristics, suggesting that any cell might become a cancer stem cell. In other words, a fully differentiated cell undergoes several mutations that drive it back to a stem-like state.

The concept of tumor hierarchy claims that a tumor is a heterogeneous population of mutant cells, all of which share some mutations, but vary in specific phenotype. A tumor hosts several types of stem cells, one optimal to the specific environment and other less successful lines. These secondary lines may be more successful in other environments, allowing the tumor to adapt, including adaptation to therapeutic intervention. If correct, this concept impacts cancer stem cell-specific treatment regimes.[39] Such a hierarchy would complicate attempts to pinpoint the origin.

CSCs, now reported in most human tumors, are commonly identified and enriched using strategies for identifying normal stem cells that are similar across studies.[40] These procedures include fluorescence-activated cell sorting (FACS), with antibodies directed at cell-surface markers and functional approaches including side population assay or Aldefluor assay.[41] The CSC-enriched result is then implanted, at various doses, in immune-deficient mice to assess its tumor development capacity. This in vivo assay is called a limiting dilution assay. The tumor cell subsets that can initiate tumor development at low cell numbers are further tested for self-renewal capacity in serial tumor studies.[42]

CSC can also be identified by efflux of incorporated Hoechst dyes via multidrug resistance (MDR) and ATP-binding cassette (ABC) Transporters.[41]

Another approach is sphere-forming assays. Many normal stem cells such as hematopoietics or stem cells from tissues, under special culture conditions, form three-dimensional spheres that can differentiate. As with normal stem cells, the CSCs isolated from brain or prostate tumors also have the ability to form anchor-independent spheres.[43]

CSCs have been identified in various solid tumors. Markers specific for normal stem cells are commonly used for isolating CSCs from solid and hematological tumors. Cell surface markers have proved useful for isolation of CSC-enriched populations including CD133 (also known as PROM1), CD44, CD24, EpCAM (epithelial cell adhesion molecule, also known as epithelial specific antigen, ESA), THY1, ATP-binding cassette B5 (ABCB5),[44] and CD200.

CD133 (prominin 1) is a five-transmembrane domain glycoprotein expressed on CD34+ stem and progenitor cells, in endothelial precursors and fetal neural stem cells. It has been detected using its glycosylated epitope known as AC133.

EpCAM (epithelial cell adhesion molecule, ESA, TROP1) is hemophilic Ca2+-independent cell adhesion molecule expressed on the basolateral surface of most epithelial cells.

CD90 (THY1) is a glycosylphosphatidylinositol glycoprotein anchored in the plasma membrane and involved in signal transduction. It may also mediate adhesion between thymocytes and thymic stroma.

CD44 (PGP1) is an adhesion molecule that has pleiotropic roles in cell signaling, migration and homing. It has multiple isoforms, including CD44H, which exhibits high affinity for hyaluronate and CD44V which has metastatic properties.

CD24 (HSA) is a glycosylated glycosylphosphatidylinositol-anchored adhesion molecule, which has co-stimulatory role in B and T cells.

CD200 (OX-2) is a type 1 membrane glycoprotein, which delivers an inhibitory signal to immune cells including T cells, natural killer cells and macrophages.

ALDH is a ubiquitous aldehyde dehydrogenase family of enzymes, which catalyzes the oxidation of aromatic aldehydes to carboxyl acids. For instance, it has a role in conversion of retinol to retinoic acid, which is essential for survival.[45][46]

The first solid malignancy from which CSCs were isolated and identified was breast cancer and they are the most intensely studied. Breast CSCs have been enriched in CD44+CD24/low,[44] SP[47] and ALDH+ subpopulations.[48][49] Breast CSCs are apparently phenotypically diverse. CSC marker expression in breast cancer cells is apparently heterogeneous and breast CSC populations vary across tumors.[50] Both CD44+CD24 and CD44+CD24+ cell populations are tumor initiating cells; however, CSC are most highly enriched using the marker profile CD44+CD49fhiCD133/2hi.[51]

CSCs have been reported in many brain tumors. Stem-like tumor cells have been identified using cell surface markers including CD133,[52] SSEA-1 (stage-specific embryonic antigen-1),[53]EGFR[54] and CD44.[55] The use of CD133 for identification of brain tumor stem-like cells may be problematic because tumorigenic cells are found in both CD133+ and CD133 cells in some gliomas and some CD133+ brain tumor cells may not possess tumor-initiating capacity.[54]

CSCs were reported in human colon cancer.[56] For their identification, cell surface markers such as CD133,[56] CD44[57] and ABCB5,[58] functional analysis including clonal analysis [59] and Aldefluor assay were used.[60] Using CD133 as a positive marker for colon CSCs generated conflicting results. The AC133 epitope, but not the CD133 protein, is specifically expressed in colon CSCs and its expression is lost upon differentiation.[61] In addition, CD44+ colon cancer cells and additional sub-fractionation of CD44+EpCAM+ cell population with CD166 enhance the success of tumor engraftments.[57]

Multiple CSCs have been reported in prostate,[62]lung and many other organs, including liver, pancreas, kidney or ovary.[45][63] In prostate cancer, the tumor-initiating cells have been identified in CD44+[64] cell subset as CD44+21+,[65] TRA-1-60+CD151+CD166+[66] or ALDH+[67] cell populations. Putative markers for lung CSCs have been reported, including CD133+,[68] ALDH+,[69] CD44+[70] and oncofetal protein 5T4+.[71]

Metastasis is the major cause of tumor lethality. However, not every tumor cell can metastasize. This potential depends on factors that determine growth, angiogenesis, invasion and other basic processes.

In epithelial tumors, the epithelial-mesenchymal transition (EMT) is considered to be a crucial event.[72] EMT and the reverse transition from mesenchymal to an epithelial phenotype (MET) are involved in embryonic development, which involves disruption of epithelial cell homeostasis and the acquisition of a migratory mesenchymal phenotype.[73] EMT appears to be controlled by canonical pathways such as WNT and transforming growth factor .[74]

EMT's important feature is the loss of membrane E-cadherin in adherens junctions, where -catenin may play a significant role. Translocation of -catenin from adherens junctions to the nucleus may lead to a loss of E-cadherin and subsequently to EMT. Nuclear -catenin apparently can directly, transcriptionally activate EMT-associated target genes, such as the E-cadherin gene repressor SLUG (also known as SNAI2).[75] Mechanical properties of the tumor microenvironment, such as hypoxia, can contribute to CSC survival and metastatic potential through stabilization of hypoxia inducible factors through interactions with ROS (reactive oxygen species).[76][77]

Tumor cells undergoing an EMT may be precursors for metastatic cancer cells, or even metastatic CSCs.[78] In the invasive edge of pancreatic carcinoma, a subset of CD133+CXCR4+ (receptor for CXCL12 chemokine also known as a SDF1 ligand) cells was defined. These cells exhibited significantly stronger migratory activity than their counterpart CD133+CXCR4 cells, but both showed similar tumor development capacity.[79] Moreover, inhibition of the CXCR4 receptor reduced metastatic potential without altering tumorigenic capacity.[80]

In breast cancer CD44+CD24/low cells are detectable in metastatic pleural effusions.[44] By contrast, an increased number of CD24+ cells have been identified in distant metastases in breast cancer patients.[81] It is possible that CD44+CD24/low cells initially metastasize and in the new site change their phenotype and undergo limited differentiation.[82] The two-phase expression pattern hypothesis proposes two forms of cancer stem cells - stationary (SCS) and mobile (MCS). SCS are embedded in tissue and persist in differentiated areas throughout tumor progression. MCS are located at the tumor-host interface. These cells are apparently derived from SCS through the acquisition of transient EMT (Figure 7).[83]

CSCs have implications for cancer therapy, including for disease identification, selective drug targets, prevention of metastasis and intervention strategies.

Somatic stem cells are naturally resistant to chemotherapeutic agents. They produce various pumps (such as MDR[citation needed]) that pump out drugs and DNA repair proteins. They have a slow rate of cell turnover (chemotherapeutic agents naturally target rapidly replicating cells).[citation needed] CSCs that develop from normal stem cells may also produce these proteins, which could increase their resistance towards chemotherapy. The surviving CSCs then repopulate the tumor, causing a relapse.[84]

Selectively targeting CSCs may allow treatment of aggressive, non-resectable tumors, as well as prevent metastasis and relapse.[84] The hypothesis suggests that upon CSC elimination, cancer could regress due to differentiation and/or cell death.[citation needed] The fraction of tumor cells that are CSCs and therefore need to be eliminated is unclear.[85]

Studies looked for specific markers[17] and for proteomic and genomic tumor signatures that distinguish CSCs from others.[86] In 2009, scientists identified the compound salinomycin, which selectively reduces the proportion of breast CSCs in mice by more than 100-fold relative to Paclitaxel, a commonly used chemotherapeutic agent.[87] Some types of cancer cells can survive treatment with salinomycin through autophagy,[88] whereby cells use acidic organelles such as lysosomes to degrade and recycle certain types of proteins. The use of autophagy inhibitors can kill cancer stem cells that survive by autophagy.[89]

The cell surface receptor interleukin-3 receptor-alpha (CD123) is overexpressed on CD34+CD38- leukemic stem cells (LSCs) in acute myelogenous leukemia (AML) but not on normal CD34+CD38- bone marrow cells.[90] Treating AML-engrafted NOD/SCID mice with a CD123-specific monoclonal antibody impaired LSCs homing to the bone marrow and reduced overall AML cell repopulation including the proportion of LSCs in secondary mouse recipients.[91]

A 2015 study packaged nanoparticles with miR-34a and ammonium bicarbonate and delivered them to prostate CSCs in a mouse model. Then they irradiated the area with near-infrared laser light. This caused the nanoparticles to swell three times or more in size bursting the endosomes and dispersing the RNA in the cell. miR-34a can lower the levels of CD44.[92][93]

The design of new drugs for targeting CSCs requires understanding the cellular mechanisms that regulate cell proliferation. The first advances in this area were made with hematopoietic stem cells (HSCs) and their transformed counterparts in leukemia, the disease for which the origin of CSCs is best understood. Stem cells of many organs share the same cellular pathways as leukemia-derived HSCs.

A normal stem cell may be transformed into a CSC through disregulation of the proliferation and differentiation pathways controlling it or by inducing oncoprotein activity.

The Polycomb group transcriptional repressor Bmi-1 was discovered as a common oncogene activated in lymphoma[94] and later shown to regulate HSCs.[95] The role of Bmi-1 has been illustrated in neural stem cells.[96] The pathway appears to be active in CSCs of pediatric brain tumors.[97]

The Notch pathway plays a role in controlling stem cell proliferation for several cell types including hematopoietic, neural and mammary[98] SCs. Components of this pathway have been proposed to act as oncogenes in mammary[99] and other tumors.

A branch of the Notch signaling pathway that involves the transcription factor Hes3 regulates a number of cultured cells with CSC characteristics obtained from glioblastoma patients.[100]

These developmental pathways are SC regulators.[101] Both Sonic hedgehog (SHH) and Wnt pathways are commonly hyperactivated in tumors and are necessary to sustain tumor growth. However, the Gli transcription factors that are regulated by SHH take their name from gliomas, where they are highly expressed. A degree of crosstalk exists between the two pathways and they are commonly activated together.[102] By contrast, in colon cancer hedgehog signalling appears to antagonise Wnt.[103]

Sonic hedgehog blockers are available, such as cyclopamine. A water-soluble cyclopamine may be more effective in cancer treatment. DMAPT, a water-soluble derivative of parthenolide, induces oxidative stress and inhibits NF-B signaling[104] for AML (leukemia) and possibly myeloma and prostate cancer. Telomerase is a study subject in CSC physiology.[105] GRN163L (Imetelstat) was recently started in trials to target myeloma stem cells.

Wnt signaling can become independent of regular stimuli, through mutations in downstream oncogenes and tumor suppressor genes that become permanently activated even though the normal receptor has not received a signal. -catenin binds to transcription factors such as the protein TCF4 and in combination the molecules activate the necessary genes. LF3 strongly inhibits this binding in vitro, in cell lines and reduced tumor growth in mouse models. It prevented replication and reduced their ability to migrate, all without affecting healthy cells. No cancer stem cells remained after treatment. The discovery was the product of "rational drug design", involving AlphaScreens and ELISA technologies.[106]

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Cancer stem cell - Wikipedia

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Study: Strong link between sense of smell and death wwlp.com Dr. Sprehe says the olfactory system depends on stem cell turnover and when it loses function, it could be a warning sign for degenerative diseases like Parkinson's, Alzheimer's, dementia, even certain viral illnesses. It appears to be a degeneration ... and more »

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Study: Strong link between sense of smell and death - wwlp.com

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A new study claims life remains in the human body - even 48 hours after the person has been scientifically declared dead.

The Open Biology report said genetic activity actually increases after death - a bizarre discovery.

Senior author Peter Noble said: Not all cells are 'dead' when an organism dies. Different cell types have different life spans, generation times and resilience to extreme stress.

It is likely that some cells remain alive and are attempting to repair themselves, specifically stem cells.

Life is not simply extinguished after death, like a flame or lightbulb, but instead lives on in stages, like a computer slowly shutting down, the scientists said.

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Death is probably more like turning a computer off and much less like turning a light bulb of

Arne Traulsen

Arne Traulsen of the Max Planck Institute for Evolutionary Biology said: In spirit, death is probably more like turning a computer off and much less like turning a light bulb off.

Mr Nobles, of the University of Washington and Alabama State University, agreed with this interpretation.

He likened it to the Twin Towers collapsing floor by floor during the September 11 terror attacks in New York.

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He said: Like the Twin Towers on 9-11, we can get a lot of information on how a system collapses by studying the sequence of events as they unfold through time.

"In the case of the twin towers, we saw a systematic collapse of one floor at a time that affected the floors underneath it. This gives us an idea of the structural foundations supporting the building and we see a similar pattern in the shutdown of animals."

Death is a time-dependent process. We have framed our discussion of death in reference to 'postmortem time' because on the one hand, there is no reason to suspect that minutes after an animal dies, gene transcription will abruptly stop.

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On the other hand we know that within hours to days, the animal's body will eventually decompose by natural processes and gene transcription will end."

This was described by the reports authors as the twilight of death - when gene expression occurs but not all the cells are dead yet.

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LIFE AFTER DEATH? Scientists claim dying is 'NOT like turning off a lightbulb' - Express.co.uk

Sacramento Bee

To fulfill stem cell agency's promise, consider winding it down Sacramento Bee The stem cell agency, in fact, recently failed to raise just $75 million in new funds from private investors. Even if all stem cell clinical trials resulted in drug candidates, they would still come up against the so-called Valley of Death the term ...

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To fulfill stem cell agency's promise, consider winding it down - Sacramento Bee

Some cancer cells have a trick up their sleeve to avoid cell death: boosting maintenance of telomeres, the protective "end caps" on chromosomes, and a research team led by Jackson Laboratory (JAX) Professor Roel Verhaak reports in Nature Genetics on a newly discovered telomere maintenance mechanism.

The findings open avenues for functional studies that may yield insight into how to steer cancer cells away from immortalizing and back to normal death programming. Moreover, harnessing telomere maintenance mechanisms could be a potential approach to selectively retarding aging. The 2009 Nobel Prize in Physiology or Medicine to Elizabeth Blackburn, Carol Greider and Jack Szostak established the roles of telomeres and telomerase in the aging of cells and organisms.

In most cells, telomeres shorten over time to the point where cell division is no longer possible, leading to cell death. Certain cells, such as stem cells and germ cells, are capable of ongoing division because they contain active telomerase, an enzyme that lengthens telomeres.

It has been long known to researchers that cancer cells reactivate telomerase through telomerase reverse transcriptase (TERT) transcription, but the mechanisms behind this remain elusive.

"These cancer cells are hijacking a mechanism to maintain telomeres, enabling them to continue to divide," Verhaak says.

The researchers scanned 18,430 samples from cancerous and non-neoplastic tissues to determine and compare their telomere lengths and query them for telomerase activity. The analysis, which included samples from 31 different cancer types, showed that telomeres were generally shorter in tumors than in healthy tissues, and longer in soft tissue tumors and brain tumors compared to other cancers.

They found that the majority -- 73 percent -- of cancers expressed TERT (which in turn drives reactivation of telomerase). In addition to the expected mutations and genomic rearrangements driving TERT expression, the researchers discovered an important new mechanism: TERT promoter methylation.

In methylation, clumps of molecules called methyl groups attach to a segment of DNA and can change the activity of that segment without changing its genetic sequence.

Methylation in DNA sequences known as promoters, as the researchers found in most of the cancer samples, typically acts to repress gene transcription, the process of making an RNA copy of a gene sequence. Counterintuitively, Verhaak says, "we found that TERT DNA promoter methylation resulted in TERT expression. We think that because of the DNA methylation, mRNA transcription-repressing proteins are no longer able to bind."

About 22 percent of the tumor cells lacked detectable TERT expression. "There could be a number of reasons for this," says Floris Barthel, a JAX postdoctoral associate and first author of the study. "Maybe not all tumors harbor immortalized cells with a telomere maintenance mechanism, or there are alternative mechanisms at play, or perhaps TERT expression that falls below the detection threshold we used is still sufficient to maintain telomeres." Future studies are needed to elucidate the telomere maintenance mechanisms, or lack thereof, in these tumors, he notes.

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Materials provided by Jackson Laboratory. Original written by Joyce Dall'Acqua Peterson. Note: Content may be edited for style and length.

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KXAN.com

Study: Death likely within 5 years of loss of smell | KXAN.com KXAN.com If you think you are losing your sense of smell, or have a family member who is, doctors say it needs to be checked out. and more »

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by David M. Panchision*

Diseases of the nervous system, including congenital disorders, cancers, and degenerative diseases, affect millions of people of all ages. Congenital disorders occur when the brain or spinal cord does not form correctly during development. Cancers of the nervous system result from the uncontrolled spread of aberrant cells. Degenerative diseases occur when the nervous system loses functioning of nerve cells. Most of the advances in stem cell research have been directed at treating degenerative diseases. While many treatments aim to limit the damage of these diseases, in some cases scientists believe that damage can be reversed by replacing lost cells with new ones derived from cells that can mature into nerve cells, called neural stem cells. Research that uses stem cells to treat nervous system disorders remains an area of great promise and challenge to demonstrate that cell-replacement therapy can restore lost function.

The nervous system is a complex organ made up of nerve cells (also called neurons) and glial cells, which surround and support neurons (see Figure 3.1). Neurons send signals that affect numerous functions including thought processes and movement. One type of glial cell, the oligodendrocyte, acts to speed up the signals of neurons that extend over long distances, such as in the spinal cord. The loss of any of these cell types may have catastrophic results on brain function.

Although reports dating back as early as the 1960s pointed towards the possibility that new nerve cells are formed in adult mammalian brains, this knowledge was not applied in the context of curing devastating brain diseases until the 1990s. While earlier medical research focused on limiting damage once it had occurred, in recent years researchers have been working hard to find out if the cells that can give rise to new neurons can be coaxed to restore brain function. New neurons in the adult brain arise from slowly-dividing cells that appear to be the remnants of stem cells that existed during fetal brain development. Since some of these adult cells still retain the ability to generate both neurons and glia, they are referred to as adult neural stem cells.

These findings are exciting because they suggest that the brain may contain a built-in mechanism to repair itself. Unfortunately, these new neurons are only generated in a few sites in the brain and turn into only a few specialized types of nerve cells. Although there are many different neuronal cell types in the brain, we now know that these new neurons can quot;plug inquot; correctly to assist brain function.1 The discovery of these cells has spurred further research into the characteristics of neural stem cells from the fetus and the adult, mostly using rodents and primates as model species. The hope is that these cells may be able to replenish those that are functionally lost in human degenerative diseases such as Parkinson's Disease, Huntington's Disease, and amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease), as well as from brain and spinal cord injuries that result from stroke or trauma.

Scientists are applying these new stem cell discoveries in two ways in their experiments. First, they are using current knowledge of normal brain development to modulate stem cells that are harvested and grown in culture. Researchers can then transplant these cultured cells into the brain of an animal model and allow the brain's own signals to differentiate the stem cells into neurons or glia. Alternatively, the stem cells can be induced to differentiate into neurons and glia while in the culture dish, before being transplanted into the brain. Much progress has been made the last several years with human embryonic stem (ES) cells that can differentiate into all cell types in the body. While ES cells can be maintained in culture for relatively long periods of time without differentiating, they usually must be coaxed through many more steps of differentiation to produce the desired cell types. Recent studies, however, suggest that ES cells may differentiate into neurons in a more straightforward manner than may other cell types.

Figure 3.1. The Neuron When sufficient neurotransmitters cross synapses and bind receptors on the neuronal cell body and dendrites, the neuron sends an electrical signal down its axon to synaptic terminals, which in turn release neurotransmitters into the synapse that affects the following neuron. The brain neurons that die in Parkinson's Disease release the transmitter dopamine. Oligodendrocytes supply the axon with an insulating myelin sheath.

2001 Terese Winslow

Second, scientists are identifying growth (trophic) factors that are normally produced and used by the developing and adult brain. They are using these factors to minimize damage to the brain and to activate the patient's own stem cells to repair damage that has occurred. Each of these strategies is being aggressively pursued to identify the most effective treatments for degenerative diseases. Most of these studies have been carried out initially with animal stem cells and recipients to determine their likelihood of success. Still, much more research is necessary to develop stem cell therapies that will be useful for treating brain and spinal cord disease in the same way that hematopoietic stem cell therapies are routinely used for immune system replacement (see Chapter 2).

The majority of stem cell studies of neurological disease have used rats and mice, since these models are convenient to use and are well-characterized biologically. If preliminary studies with rodent stem cells are successful, scientists will attempt to transplant human stem cells into rodents. Studies may then be carried out in primates (e.g., monkeys) to offer insight into how humans might respond to neurological treatment. Human studies are rarely undertaken until these other experiments have shown promising results. While human transplant studies have been carried out for decades in the case of Parkinson's disease, animal research continues to provide improved strategies to generate an abundant supply of transplantable cells.

The intensive research aiming at curing Parkinson's disease with stem cells is a good example for the various strategies, successful results, and remaining challenges of stem cell-based brain repair. Parkinson's disease is a progressive disorder of motor control that affects roughly 2% of persons 65 years and older. Triggered by the death of neurons in a brain region called the substantia nigra, Parkinson's disease begins with minor tremors that progress to limb and bodily rigidity and difficulty initiating movement. These neurons connect via long axons to another region called the striatum, composed of subregions called the caudate nucleus and the putamen. These neurons that reach from the substantia nigra to the striatum release the chemical transmitter dopamine onto their target neurons in the striatum. One of dopamine's major roles is to regulate the nerves that control body movement. As these cells die, less dopamine is produced, leading to the movement difficulties characteristic of Parkinson's disease. Currently, the causes of death of these neurons are not well understood.

For many years, doctors have treated Parkinson's disease patients with the drug levodopa (L-dopa), which the brain converts into dopamine. Although the drug works well initially, levodopa eventually loses its effectiveness, and side-effects increase. Ultimately, many doctors and patients find themselves fighting a losing battle. For this reason, a huge effort is underway to develop new treatments, including growth factors that help the remaining dopamine neurons survive and transplantation procedures to replace those that have died.

The strategy to use new cells to replace lost ones is not new. Surgeons first attempted to transplant dopamine-releasing cells from a patient's own adrenal glands in the 1980s.2,3 Although one of these studies reported a dramatic improvement in the patients' conditions, U.S. surgeons were only able to achieve modest and temporary improvement, insufficient to outweigh the risks of such a procedure. As a result, these human studies were not pursued further.

Another strategy was attempted in the 1970s, in which cells derived from fetal tissue from the mouse substantia nigra was transplanted into the adult rat eye and found to develop into mature dopamine neurons.4 In the 1980s, several groups showed that transplantation of this type of tissue could reverse Parkinson's-like symptoms in rats and monkeys when placed in the damaged areas.The success of the animal studies led to several human trials beginning in the mid-1980s.5,6 In some cases, patients showed a lessening of their symptoms. Also, researchers could measure an increase in dopamine neuron function in the striatum of these patients by using a brain-imaging method called positron emission tomography (PET) (see Figure 3.2).7

The NIH has funded two large and well-controlled clinical trials in the past 15 years in which researchers transplanted tissue from aborted fetuses into the striatum of patients with Parkinson's disease.7,8 These studies, performed in Colorado and New York, included controls where patients received quot;shamquot; surgery (no tissue was implanted), and neither the patients nor the scientists who evaluated their progress knew which patients received the implants. The patients' progress was followed for up to eight years. Unfortunately, both studies showed that the transplants offered little benefit to the patients as a group. While some patients showed improvement, others began to suffer from dyskinesias, jerky involuntary movements that are often side effects of long-term L-dopa treatment. This effect occurred in 15% of the patients in the Colorado study.7 and more than half of the patients in the New York study.8 Additionally, the New York study showed evidence that some patients' immune systems were attacking the grafts.

However, promising findings emerged from these studies as well. Younger and milder Parkinson's patients responded relatively well to the grafts, and PET scans of patients showed that some of the transplanted dopamine neurons survived and matured. Additionally, autopsies on three patients who died of unrelated causes, years after the surgeries, indicated the presence of dopamine neurons from the graft. These cells appeared to have matured in the same way as normal dopamine neurons, which suggested that they were acting normally in the brain.

Figure 3.2. Positron Emission Tomography (PET) images from a Parkinson's patient before and after fetal tissue transplantation. The image taken before surgery (left) shows uptake of a radioactive form of dopamine (red) only in the caudate nucleus, indicating that dopamine neurons have degenerated. Twelve months after surgery, an image from the same patient (right) reveals increased dopamine function, especially in the putamen. (Reprinted with permission from N Eng J Med 2001;344(10) p. 710.)

Researchers in Sweden followed the severity of dyskinesia in patients for eleven years after neural transplantation and found that the severity was typically mild or moderate. These results suggested that dyskinesias were due to effects that were distinct from the beneficial effects of the grafts.9 Dyskinesias may therefore be related to the ways that transplantation disturbs other cells in the brain and so may be minimized by future improvements in therapy. Another study that involved the grafting of cells both into the striatum (the target of dopamine neurons) and the substantia nigra (where dopamine neurons normally reside) of three patients showed no adverse effects and some modest improvement in patient movement.10 To determine the full extent of therapeutic benefits from such a procedure and confirm the reliability of these results, this study will need to be repeated with a larger patient population that includes the appropriate controls.

The limited success of these studies may reflect variations in the fetal tissue used for transplantation, which is of limited quantity and can not be standardized or well-characterized. The full complement of cells in these fetal tissue samples is not known at present. As a result, the tissue remains the greatest source of uncertainty in patient outcome following transplantation.

The major goal for Parkinson's investigators is to generate a source of cells that can be grown in large supply, maintained indefinitely in the laboratory, and differentiated efficiently into dopamine neurons that work when transplanted into the brain of a Parkinson's patient. Scientists have investigated the behavior of stem cells in culture and the mechanisms that govern dopamine neuron production during development in their attempts to identify optimal culture conditions that allow stem cells to turn into dopamine-producing neurons.

Preliminary studies have been carried out using immature stem cell-like precursors from the rodent ventral midbrain, the region that normally gives rise to these dopamine neurons. In one study these precursors were turned into functional dopamine neurons, which were then grafted into rats previously treated with 6-hydroxy-dopamine (6-OHDA) to kill the dopamine neurons in their substantia nigra and induce Parkinson's-like symptoms. Even though the percentage of surviving dopamine neurons was low following transplantation, it was sufficient to relieve the Parkinson's-like symptoms.11 Unfortunately, these fetal cells cannot be maintained in culture for very long before they lose the ability to differentiate into dopamine neurons.

Cells with features of neural stem cells have been derived from ES-cells, fetal brain tissue, brain tissue from neurosurgery, and brain tissue that was obtained after a person's death. There is controversy about whether other organ stem cell populations, such as hematopoietic stem cells, either contain or give rise to neural stem cells

Many researchers believe that the more primitive ES cells may be an excellent source of dopamine neurons because ES-cells can be grown indefinitely in a laboratory dish and can differentiate into any cell type, even after long periods in culture. Mouse ES cells injected directly into 6-OHDA-treated rat brains led to relief of Parkinson-like symptoms. Further investigation showed that these ES cells had differentiated into both dopamine and serotonin neurons.12 This latter type of neuron is generated in an adjacent region of the brain and may complicate the response to transplantation. Since ES cells can generate all cell types in the body, unwanted cell types such as muscle or bone could theoretically also be introduced into the brain. As a result, a great deal of effort is being currently put into finding the right quot;recipequot; for turning ES cells into dopamine neuronsand only this cell typeto treat Parkinson's disease. Researchers strive to learn more about normal brain development to help emulate the natural progression of ES cells toward dopamine neurons in the culture dish.

The recent availability of human ES cells has led to further studies to examine their potential for differentiation into dopamine neurons. Recently, dopamine neurons from human embryonic stem cells have been generated.13 One research group used a special type of companion cell, along with specific growth factors, to promote the differentiation of the ES cells through several stages into dopamine neurons. These neurons showed many of the characteristic properties of normal dopamine neurons.13 Furthermore, recent evidence of more direct neuronal differentiation methods from mouse ES cells fuels hope that scientists can refine and streamline the production of transplantable human dopamine neurons.

One method with great therapeutic potential is nuclear transfer. This method fuses the genetic material from one individual donor with a recipient egg cell that has had its nucleus removed. The early embryo that develops from this fusion is a genetic match for the donor. This process is sometimes called quot;therapeutic cloningquot; and is regarded by some to be ethically questionable. However, mouse ES cells have been differentiated successfully in this way into dopamine neurons that corrected Parkinsonian symptoms when transplanted into 6-OHDA-treated rats.14 Similar results have been obtained using parthenogenetic primate stem cells, which are cells that are genetic matches from a female donor with no contribution from a male donor.15 These approaches may offer the possibility of treating patients with genetically-matched cells, thereby eliminating the possibility of graft rejection.

Scientists are also studying the possibility that the brain may be able to repair itself with therapeutic support. This avenue of study is in its early stages but may involve administering drugs that stimulate the birth of new neurons from the brain's own stem cells. The concept is based on research showing that new nerve cells are born in the adult brains of humans. The phenomenon occurs in a brain region called the dentate gyrus of the hippocampus. While it is not yet clear how these new neurons contribute to normal brain function, their presence suggests that stem cells in the adult brain may have the potential to re-wire dysfunctional neuronal circuitry.

The adult brain's capacity for self-repair has been studied by investigating how the adult rat brain responds to transforming growth factor alpha (TGF), a protein important for early brain development that is expressed in limited quantities in adults.16 Injection of TGF into a healthy rat brain causes stem cells to divide for several days before ceasing division. In 6-OHDAtreated (Parkinsonian) rats, however, the cells proliferated and migrated to the damaged areas. Surprisingly, the TGF-treated rats showed few of the behavioral problems associated with untreated Parkinsonian rats.16 Additionally, in 2002 and 2003, two research groups isolated small numbers of dividing cells in the substantia nigra of adult rodents.17,18

These findings suggest that the brain can repair itself, as long as the repair process is triggered sufficiently. It is not clear, though, whether stem cells are responsible for this repair or if the TGF activates a different repair mechanism.

Many other diseases that affect the nervous system hold the potential for being treated with stem cells. Experimental therapies for chronic diseases of the nervous system, such as Alzheimer's disease, Lou Gehrig's disease, or Huntington's disease, and for acute injuries, such as spinal cord and brain trauma or stoke, are being currently developed and tested. These diverse disorders must be investigated within the contexts of their unique disease processes and treated accordingly with highly adapted cell-based approaches.

Although severe spinal cord injury is an area of intense research, the therapeutic targets are not as clear-cut as in Parkinson's disease. Spinal cord trauma destroys numerous cell types, including the neurons that carry messages between the brain and the rest of the body. In many spinal injuries, the cord is not actually severed, and at least some of the signal-carrying neuronal axons remain intact. However, the surviving axons no longer carry messages because oligodendrocytes, which make the axons' insulating myelin sheath, are lost. Researchers have recently made progress to replenish these lost myelin-producing cells. In one study, scientists cultured human ES cells through several steps to make mixed cultures that contained oligodendrocytes. When they injected these cells into the spinal cords of chemically-demyelinated rats, the treated rats regained limited use of their hind limbs compared with un-grafted rats.19 Researchers are not certain, however, whether the limited increase in function observed in rats is actually due to the remyelination or to an unidentified trophic effect of the treatment.

Getting neurons to grow new axons through the injury site to reconnect with their targets is even more challenging. While myelin promotes normal neuronal function, it also inhibits the growth of new axons following spinal injury. In a recent study to attempt post-trauma axonal growth, Harper and colleagues treated ES cells with a combination of factors that are known to promote motor neuron differentiation.20 The researchers then transplanted these cells into adult rats that had received spinal cord injuries. While many of these cells survived and differentiated into neurons, they did not send out axons unless the researchers also added drugs that interfered with the inhibitory effects of myelin. The growth effect was modest, and the researchers have not yet seen evidence of functional neuron connections. However, their results raise the possibility that signals can be turned on and off in the correct order to allow neurons to reconnect and function properly. Spinal injury researchers emphasize that additional basic and preclinical research must be completed before attempting human trials using stem cell therapies to repair the trauma-damaged nervous system.

Since myelin loss is at the heart of many other degenerative diseases, oligodendrocytes made from ES cells may be useful to treat these conditions as well. For example, scientists recently cultured human ES cells with a combination of growth factors to generate a highly enriched population of myelinating oligodendrocyte precursors.21,22 The researchers then tested these cells in a genetically-mutated mouse that does not produce myelin properly. When the growth factor-cultured ES cells were transplanted into affected mice, the cells migrated and differentiated into mature oligodendrocytes that made myelin sheaths around neighboring axons. These researchers subsequently showed that these cells matured and improved movement when grafted in rats with spinal cord injury.23 Improved movement only occurred when grafting was completed soon after injury, suggesting that some post-injury responses may interfere with the grafted cells. However, these results are sufficiently encouraging to plan clinical trials to test whether replacement of myelinating glia can treat spinal cord injury.

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is characterized by a progressive destruction of motor neurons in the spinal cord. Patients with ALS develop increasing muscle weakness over time, which ultimately leads to paralysis and death. The cause of ALS is largely unknown, and there are no effective treatments. Researchers recently have used different sources of stem cells to test in rat models of ALS to test for possible nerve cell-restoring properties. In one study, researchers injected cell clusters made from embryonic germ (EG) cells into the spinal cord fluid of the partially-paralyzed rats.24 Three months after the injections, many of the treated rats were able to move their hind limbs and walk with difficulty, while the rats that did not receive cell injections remained paralyzed. Moreover, the transplanted cells had migrated throughout the spinal fluid and developed into cells that displayed molecular characteristics of mature motor neurons. However, too few cells matured in this way to account for the recovery, and there was no evidence that the transplanted cells formed functional connections with muscles. The researchers suggest that the transplanted cells may be promoting recovery in some other way, such as by producing trophic factors.

This possibility was addressed in a second study in which scientists grew human fetal CNS stem cells in culture and genetically modified them to produce a trophic factor that promotes the survival of cells that are lost in ALS. When grafted into the spinal cords of the ALS-like rats, these cells secreted the desired growth factor and promoted the survival of the neurons that are normally lost in the ALS-like rats.25 While promising, these results highlight the need for additional basic research into functional recovery in ALS disease models.

Stroke affects about 750,000 patients per year in the

U.S. and is the most common cause of disability in adults. A stroke occurs when blood flow to the brain is disrupted. As a consequence, cells in affected brain regions die from insufficient amounts of oxygen. The treatment of stroke with anti-clotting drugs has dramatically improved the odds of patient recovery. However, in many patients the damage cannot be prevented, and the patient may permanently lose the functions of affected areas of the brain. For these patients, researchers are now considering stem cells as a way to repair the damaged brain regions. This problem is made more challenging because the damage in stroke may be widespread and may affect many cell types and connections.

However, researchers from Sweden recently observed that strokes in rats cause the brain's own stem cells to divide and give rise to new neurons.26 However, these neurons, which survived only a couple of weeks, are few in number compared to the extent of damage caused. A group from the University of Tokyo added a growth factor, bFGF, into the brains of rats after stroke and showed that the hippocampus was able to generate large numbers of new neurons.27 The researchers found evidence that these new neurons were actually making connections with other neurons. These and other results suggest that future stroke treatments may be able to coax the brain's own stem cells to make replacement neurons.

Taking an alternative approach, another group attempted transplantation as a means to treat the loss of brain mass after a severe stroke. By adding stem cells onto a polymer scaffold that they implanted into the stroke-damaged brains of mice, the researchers demonstrated that the seeded stem cells differentiated into neurons and that the polymer scaffold reduced scarring.28 Two groups transplanted human fetal stem cells in independent studies into the brains of stroke-affected rodents; these stem cells not only survived but migrated to the damaged areas of the brain.29,30 These studies increase our knowledge of how stem cells are attracted to diseased areas of the brain.

There is also increasing evidence from numerous animal disease models that stem cells are actively drawn to brain damage. Once they reach these damaged areas, they have been shown to exert beneficial effects such as reducing brain inflammation or supporting nerve cells. It is hoped that, once these mechanisms are better understood, this stem cell recruitment can potentially be exploited to mobilize a patient's own stem cells.

Similar lines of research are being considered with other disorders such as Huntington's Disease and certain congenital defects. While much attention has been called to the treatment of Alzheimer's Disease, it is still not clear if stem cells hold the key to its treatment. But despite the fact that much basic work remains and many fundamental questions are yet to be answered, researchers are hopeful that repair for once-incurable nervous system disorders may be amenable to stem cell based therapies.

Considerable progress has been made the last few years in our understanding of stem cell biology and devising sources of cells for transplantation. New methods are also being developed for cell delivery and targeting to affected areas of the body. These advances have fueled optimism that new treatments will come for millions of persons who suffer from neurological disorders. But it is the current task of scientists to bring these methods from the laboratory bench to the clinic in a scientifically sound and ethically acceptable fashion.

Notes:

* Chief, Developmental Neurobiology Program, Molecular, Cellular & Genomic Neuroscience Research Branch, Division of Neuroscience and Basic Behavioral Science, National Institute of Mental Health, National Institutes of Health, Email: panchisiond@mail.nih.gov

Chapter 2|Table of Contents|Chapter 4

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Repairing the Nervous System with Stem Cells | stemcells ...

Everyone knows that the heart is a vital organ. We cannot live without our heart. However, when you get right down to it, the heart is just a pump. A complex and important one, yes, but still just a pump. As with all other pumps it can become clogged, break down and need repair. This is why it is critical that we know how the heart works. With a little knowledge about your heart and what is good or bad for it, you can significantly reduce your risk for heart disease.

Heart disease is the leading cause of death in the United States. Almost 2,000 Americans die of heart disease each day. That is one death every 44 seconds. The good news is that the death rate from heart disease has been steadily decreasing. Unfortunately, heart disease still causes sudden death and many people die before even reaching the hospital.

The heart holds a special place in our collective psyche as well. Of course the heart is synonymous with love. It has many other associations, too. Here are just a few examples:

Certainly no other bodily organ elicits this kind of response. When was the last time you had a heavy pancreas?

In this article, we will look at this important organ so that you can understand exactly what makes your heart tick.

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How Your Heart Works | HowStuffWorks

Neural stem cells (NSCs) are self-renewing, multipotent cells that generate the neurons and glia of the nervous system of all animals during embryonic development. Some neural stem cells persist in the adult vertebrate brain and continue to produce neurons throughout life. Stem cells are characterized by their capacity to differentiate into multiple cell types.[1] They undergo symmetric or asymmetric cell division into two daughter cells. In symmetric cell division, both daughter cells are also stem cells. In asymmetric division, a stem cells produces one stem cell and one specialized cell.[2] NSCs primarily differentiate into neurons, astrocytes, and oligodendrocytes.[3]

In 1989, Sally Temple described multipotent, self-renewing progenitor and stem cells in the subventricular zone (SVZ) of the mouse brain.[4] In 1992, Brent A. Reynolds and Samuel Weiss were the first to isolate neural progenitor and stem cells from the adult striatal tissue, including the SVZ one of the neurogenic areas of adult mice brain tissue.[5] In the same year the team of Constance Cepko and Evan Y. Snyder were the first to isolate multipotent cells from the mouse cerebellum and stably transfected them with the oncogene v-myc.[6] Interestingly, this molecule is one of the genes widely used now to reprogram adult non-stem cells into pluripotent stem cells. Since then, neural progenitor and stem cells have been isolated from various areas of the adult brain, including non-neurogenic areas, such as the spinal cord, and from various species including humans.[7][8]

There are two basic types of stem cell: adult stem cells, which are limited in their ability to differentiate, and embryonic stem cells (ESCs), which are pluripotent. ESCs are not limited to a particular cell fate; rather they have the capability to differentiate into any cell type.[1] ESCs are derived from the inner cell mass of the blastocyst with the potential to self-replicate.[3]

Neural stem cells are more specialized than ESCs because they generate only neural cells (neurons or glial cells).[9] During embryonic development of vertebrates, NSCs of the central nervous system (CNS) are called radial glial cells (RGCs), and reside in a transient zone called the ventricular zone (VZ).[10] Neurons are generated in large numbers by NSCs during a specific period of embryonic development through the process of neurogenesis, and continue to be generated in adult life in restricted regions of the adult brain.[11] Adult NSCs differentiate into new neurons within the adult subventricular zone (SVZ), a remnant of the embryonic germinal neuroepithelium, as well as the dentate gyrus of the hippocampus.[11] NSCs can be extracted, cultured in a laboratory, and experimentally differentiated using specific culture conditions to replace lost or injured neurons or in many cases even glial cells.[3]

Adult NSCs were first isolated from mouse striatum in the early 1990s. They are capable of forming multipotent neurospheres when cultured in vitro. Neurospheres can produce self-renewing and proliferating specialized cells. These neurospheres can differentiate to form the specified neurons, glial cells, and oligodendrocytes.[3][11] In previous studies, cultured neurospheres have been transplanted into the brains of immunodeficient neonatal mice and have shown engraftment, proliferation, and neural differentiation.[11]

NSCs are stimulated to begin differentiation via exogenous cues from the microenvironment, or stem cell niche. This capability of the NSCs to replace lost or damaged neural cells is called neurogenesis.[3] Some neural cells are migrated from the SVZ along the rostral migratory stream which contains a marrow-like structure with ependymal cells and astrocytes when stimulated. The ependymal cells and astrocytes form glial tubes used by migrating neuroblasts. The astrocytes in the tubes provide support for the migrating cells as well as insulation from electrical and chemical signals released from surrounding cells. The astrocytes are the primary precursors for rapid cell amplification. The neuroblasts form tight chains and migrate towards the specified site of cell damage to repair or replace neural cells. One example is a neuroblast migrating towards the olfactory bulb to differentiate into periglomercular or granule neurons which have a radial migration pattern rather than a tangential one.[12]

On the other hand, the dentate gyrus neural stem cells produce excitatory granule neurons which are involved in learning and memory. One example of learning and memory is pattern separation, a cognitive process used to distinguish similar inputs.[3]

Neural stem cell proliferation declines as a consequence of aging.[13] Various approaches have been taken to counteract this age-related decline.[14] Because FOXO proteins regulate neural stem cell homeostasis,[15] FOXO proteins have been used to protect neural stem cells by inhibiting Wnt signaling.[16]

Epidermal growth factor (EGF) and fibroblast growth factor (FGF) are mitogens that promote neural progenitor and stem cell growth in vitro, though other factors synthesized by the neural progenitor and stem cell populations are also required for optimal growth.[17] It is hypothesized that neurogenesis in the adult brain originates from NSCs. The origin and identity of NSCs in the adult brain remain to be defined.

The most widely accepted model of an adult NSC is a radial, astrocytes-like, GFAP-positive cell. Quiescent stem cells are Type B that are able to remain in the quiescent state due to the renewable tissue provided by the specific niches composed of blood vessels, astrocytes, microglia, ependymal cells, and extracellular matrix present within the brain. These niches provide nourishment, structural support, and protection for the stem cells until they are activated by external stimuli. Once activated, the Type B cells develop into Type C cells, active proliferating intermediate cells, which then divide into neuroblasts consisting of Type A cells. The undifferentiated neuroblasts form chains that migrate and develop into mature neurons. In the olfactory bulb, they mature into GABAergic granule neurons, while in the hippocampus they mature into dentate granule cells.[18]

NSCs have an important role during development producing the enormous diversity of neurons, astrocytes and oligodendrocytes in the developing CNS. They also have important role in adult animals, for instance in learning and hippocampal plasticity in the adult mice in addition to supplying neurons to the olfactory bulb in mice.[11]

Notably the role of NSCs during diseases is now being elucidated by several research groups around the world. The responses during stroke, multiple sclerosis, and Parkinson's disease in animal models and humans is part of the current investigation. The results of this ongoing investigation may have future applications to treat human neurological diseases.[11]

Neural stem cells have been shown to engage in migration and replacement of dying neurons in classical experiments performed by Sanjay Magavi and Jeffrey Macklis.[19] Using a laser-induced damage of cortical layers, Magavi showed that SVZ neural progenitors expressing Doublecortin, a critical molecule for migration of neuroblasts, migrated long distances to the area of damage and differentiated into mature neurons expressing NeuN marker. In addition Masato Nakafuku's group from Japan showed for the first time the role of hippocampal stem cells during stroke in mice.[20] These results demonstrated that NSCs can engage in the adult brain as a result of injury. Furthermore, in 2004 Evan Y. Snyder's group showed that NSCs migrate to brain tumors in a directed fashion. Jaime Imitola, M.D and colleagues from Harvard demonstrated for the first time, a molecular mechanism for the responses of NSCs to injury. They showed that chemokines released during injury such as SDF-1a were responsible for the directed migration of human and mouse NSCs to areas of injury in mice.[21] Since then other molecules have been found to participate in the responses of NSCs to injury. All these results have been widely reproduced and expanded by other investigators joining the classical work of Richard L. Sidman in autoradiography to visualize neurogenesis during development, and neurogenesis in the adult by Joseph Altman in the 1960s, as evidence of the responses of adult NSCs activities and neurogenesis during homeostasis and injury.

The search for additional mechanisms that operate in the injury environment and how they influence the responses of NSCs during acute and chronic disease is matter of intense research.[22]

Cell death is a characteristic of acute CNS disorders as well as neurodegenerative disease. The loss of cells is amplified by the lack of regenerative abilities for cell replacement and repair in the CNS. One way to circumvent this is to use cell replacement therapy via regenerative NSCs. NSCs can be cultured in vitro as neurospheres. These neurospheres are composed of neural stem cells and progenitors (NSPCs) with growth factors such as EGF and FGF. The withdrawal of these growth factors activate differentiation into neurons, astrocytes, or oligodendrocytes which can be transplanted within the brain at the site of injury. The benefits of this therapeutic approach have been examined in Parkinson's disease, Huntington's disease, and multiple sclerosis. NSPCs induce neural repair via intrinsic properties of neuroprotection and immunomodulation. Some possible routes of transplantation include intracerebral transplantation and xenotransplantation.[23][24]

An alternative therapeutic approach to the transplantation of NSPCs is the pharmacological activation of endogenous NSPCs (eNSPCs). Activated eNSPCs produce neurotrophic factors,several treatments that activate a pathway that involves the phosphorylation of STAT3 on the serine residue and subsequent elevation of Hes3 expression (STAT3-Ser/Hes3 Signaling Axis) oppose neuronal death and disease progression in models of neurological disorder.[25][26]

Human midbrain-derived neural progenitor cells (hmNPCs) have the ability to differentiate down multiple neural cell lineages that lead to neurospheres as well as multiple neural phenotypes. The hmNPC can be used to develop a 3D in vitro model of the human CNS. There are two ways to culture the hmNPCs, the adherent monolayer and the neurosphere culture systems. The neurosphere culture system has previously been used to isolate and expand CNS stem cells by its ability to aggregate and proliferate hmNPCs under serum-free media conditions as well as with the presence of epidermal growth factor (EGF) and fibroblast growth factor-2 (FGF2). Initially, the hmNPCs were isolated and expanded before performing a 2D differentiation which was used to produce a single-cell suspension. This single-cell suspension helped achieve a homogenous 3D structure of uniform aggregate size. The 3D aggregation formed neurospheres which was used to form an in vitro 3D CNS model.[27]

Traumatic brain injury (TBI) can deform the brain tissue, leading to necrosis primary damage which can then cascade and activate secondary damage such as excitotoxicity, inflammation, ischemia, and the breakdown of the blood-brain-barrier. Damage can escalate and eventually lead to apoptosis or cell death. Current treatments focus on preventing further damage by stabilizing bleeding, decreasing intracranial pressure and inflammation, and inhibiting pro-apoptoic cascades. In order to repair TBI damage, an upcoming therapeutic option involves the use of NSCs derived from the embryonic peri-ventricular region. Stem cells can be cultured in a favorable 3-dimensional, low cytotoxic environment, a hydrogel, that will increase NSC survival when injected into TBI patients. The intracerebrally injected, primed NSCs were seen to migrate to damaged tissue and differentiate into oligodendrocytes or neuronal cells that secreted neuroprotective factors.[28][29]

Galectin-1 is expressed in adult NSCs and has been shown to have a physiological role in the treatment of neurological disorders in animal models. There are two approaches to using NSCs as a therapeutic treatment: (1) stimulate intrinsic NSCs to promote proliferation in order to replace injured tissue, and (2) transplant NSCs into the damaged brain area in order to allow the NSCs to restore the tissue. Lentivirus vectors were used to infect human NSCs (hNSCs) with Galectin-1 which were later transplanted into the damaged tissue. The hGal-1-hNSCs induced better and faster brain recovery of the injured tissue as well as a reduction in motor and sensory deficits as compared to only hNSC transplantation.[12]

Neural stem cells are routinely studied in vitro using a method referred to as the Neurosphere Assay (or Neurosphere culture system), first developed by Reynolds and Weiss.[5] Neurospheres are intrinsically heterogeneous cellular entities almost entirely formed by a small fraction (1 to 5%) of slowly dividing neural stem cells and by their progeny, a population of fast-dividing nestin-positive progenitor cells.[5][30][31] The total number of these progenitors determines the size of a neurosphere and, as a result, disparities in sphere size within different neurosphere populations may reflect alterations in the proliferation, survival and/or differentiation status of their neural progenitors. Indeed, it has been reported that loss of 1-integrin in a neurosphere culture does not significantly affect the capacity of 1-integrin deficient stem cells to form new neurospheres, but it influences the size of the neurosphere: 1-integrin deficient neurospheres were overall smaller due to increased cell death and reduced proliferation.[32]

While the Neurosphere Assay has been the method of choice for isolation, expansion and even the enumeration of neural stem and progenitor cells, several recent publications have highlighted some of the limitations of the neurosphere culture system as a method for determining neural stem cell frequencies.[33] In collaboration with Reynolds, STEMCELL Technologies has developed a collagen-based assay, called the Neural Colony-Forming Cell (NCFC) Assay, for the quantification of neural stem cells. Importantly, this assay allows discrimination between neural stem and progenitor cells.[34]

The damaged CNS tissue has very limited regenerative and repair capacity so that loss of neurological function is often chronic and progressive. Cell replacement from stem cells is being actively pursued as a therapeutic option. In 2009, a research institute dedicated solely to translating neural stem research into therapies for patients was created outside of Albany, New York, The Neural Stem Cell Institute.

Intensity-modulated radiation to spare neural stem cells in brain tumors: a computational platform for evaluation of physical and biological dose metrics. Jaganathan A, Tiwari M, Phansekar R, Panta R, Huilgol N.

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Neural stem cell - Wikipedia

Brain stem death is a clinical syndrome defined by the absence of reflexes with pathways through the brain stem - the stalk of the brain, which connects the spinal cord to the mid-brain, cerebellum and cerebral hemispheres - in a deeply comatose, ventilator-dependent patient. Identification of this state carries a very grave prognosis for survival; cessation of heartbeat often occurs within a few days although it may continue for weeks or even months if intensive support is maintained.[1]

In the United Kingdom, the formal diagnosis of brain stem death by the procedure laid down in the official Code of Practice[1] permits the diagnosis and certification of death on the premise that a person is dead when consciousness and the ability to breathe are permanently lost, regardless of continuing life in the body and parts of the brain, and that death of the brain stem alone is sufficient to produce this state.[2]

This concept of brain stem death is also accepted as grounds for pronouncing death for legal purposes in India[3] and Trinidad & Tobago.[4] Elsewhere in the world the concept upon which the certification of death on neurological grounds is based is that of permanent cessation of all function in all parts of the brain - whole brain death - with which the reductionist United Kingdom concept should not be confused. The United States' President's Council on Bioethics made it clear, in its White Paper of December 2008, that the United Kingdom concept and clinical criteria are not considered sufficient for the diagnosis of death in the United States of America.[5]

The United Kingdom (UK) criteria were first published by the Conference of Medical Royal Colleges (with advice from the Transplant Advisory Panel) in 1976, as prognostic guidelines.[6] They were drafted in response to a perceived need for guidance in the management of deeply comatose patients with severe brain damage who were being kept alive by mechanical ventilators but showing no signs of recovery. The Conference sought to establish diagnostic criteria of such rigour that on their fulfilment the mechanical ventilator can be switched off, in the secure knowledge that there is no possible chance of recovery. The published criteria negative responses to bedside tests of some reflexes with pathways through the brain stem and a specified challenge to the brain stem respiratory centre, with caveats about exclusion of endocrine influences, metabolic factors and drug effects were held to be sufficient to distinguish between those patients who retain the functional capacity to have a chance of even partial recovery and those where no such possibility exists. Recognition of that state required the withdrawal of fruitless further artificial support so that death might be allowed to occur, thus sparing relatives from the further emotional trauma of sterile hope.[6]

In 1979, the Conference of Medical Royal Colleges promulgated its conclusion that identification of the state defined by those same criteria then thought sufficient for a diagnosis of brain death means that the patient is dead [7]Death certification on those criteria has continued in the United Kingdom (where there is no statutory legal definition of death) since that time, particularly for organ transplantation purposes, although the conceptual basis for that use has changed.

In 1995, after a review by a Working Group of the Royal College of Physicians of London, the Conference of Medical Royal Colleges [2] formally adopted the more correct term for the syndrome, "brain stem death" - championed by Pallis in a set of 1982 articles in the British Medical Journal [8] and advanced a new definition of human death as the basis for equating this syndrome with the death of the person. The suggested new definition of death was the irreversible loss of the capacity for consciousness, combined with irreversible loss of the capacity to breathe. It was stated that the irreversible cessation of brain stem function will produce this state and therefore brain stem death is equivalent to the death of the individual.[2]

In the UK, the formal rules for the diagnosis of brain stem death have undergone only minor modifications since they were first published [6] in 1976. The most recent revision of the UK's Department of Health Code of Practice governing use of that procedure for the diagnosis of death [1] reaffirms the preconditions for its consideration. These are:

With these pre-conditions satisfied, the definitive criteria are:

Two doctors, of specified status and experience, are required to act together to diagnose death on these criteria and the tests must be repeated after a short period of time ... to allow return of the patients arterial blood gases and baseline parameters to the pre-test state. These criteria for the diagnosis of death are not applicable to infants below the age of two months.

With due regard for the cause of the coma, and the rapidity of its onset, testing for the purpose of diagnosing death on brain stem death grounds may be delayed beyond the stage where brain stem reflexes may be absent only temporarily because the cerebral blood flow is inadequate to support synaptic function although there is still sufficient blood flow to keep brain cells alive [9] and capable of recovery. There has recently been renewed interest in the possibility of neuronal protection during this phase by use of moderate hypothermia and by correction of the neuroendocrine abnormalities commonly seen in this early stage.[13]

Published studies of patients meeting the criteria for brain stem death or whole brain death the American standard which includes brain stem death diagnosed by similar means record that even if ventilation is continued after diagnosis, the heart stops beating within only a few hours or days.[14] However, there have been some very long-term survivals[15] and it is noteworthy that expert management can maintain the bodily functions of pregnant brain dead women for long enough to bring them to term.[16]

The management of patients pronounced dead on meeting the brain stem death criteria depends upon the reason for diagnosing death on that basis. If the intent is to take organs from the body for transplantation, the ventilator is reconnected and life-support measures are continued, perhaps intensified, with the addition of procedures designed to protect the wanted organs until they can be removed. Otherwise, the ventilator is left disconnected on confirmation of the lack of respiratory centre response.

The diagnostic criteria were originally published for the purpose of identifying a clinical state associated with a fatal prognosis (see above). The change of use, in the UK, to criteria for the diagnosis of death itself was protested from the first.[17][18] The initial basis for the change of use was the claim that satisfaction of the criteria sufficed for the diagnosis of the death of the brain as a whole, despite the persistence of demonstrable activity in parts of the brain.[19] In 1995, that claim was abandoned[7] and the diagnosis of death (acceptable for legal purposes in the UK in the context of organ procurement for transplantation) by the specified testing of brain stem functions was based on a new definition of death, viz. the permanent loss of the capacity for consciousness and spontaneous breathing. There are doubts that this concept is generally understood and accepted and that the specified testing is stringent enough to determine that state. It is, however, associated with substantial risk of exacerbating the brain damage and even causing the death of the apparently dying patient so tested (see "the apnoea test" above). This raises ethical problems which seem not to have been addressed.

It has been argued that sound scientific support is lacking for the claim that the specified purely bedside tests have the power to diagnose true and total death of the brain stem, the necessary condition for the assumption of permanent loss of the intrinsically untestable consciousness-arousal function of those elements of the reticular formation which lie within the brain stem (there are elements also within the higher brain).[19] Knowledge of this arousal system is based upon the findings from animal experiments[20][21][22] as illuminated by pathological studies in humans.[23] The current neurological consensus is that the arousal of consciousness depends upon reticular components which reside in the midbrain, diencephalon and pons.[24][25] It is said that the midbrain reticular formation may be viewed as a driving centre for the higher structures, loss of which produces a state in which the cortex appears, on the basis of electroencephalographic (EEG) studies, to be awaiting the command or ability to function. The role of diencephalic (higher brain) involvement is stated to be uncertain and we are reminded that the arousal system is best regarded as a physiological rather than a precise anatomical entity. There should, perhaps, also be a caveat about possible arousal mechanisms involving the first and second cranial nerves (serving sight and smell) which are not tested when diagnosing brain stem death but which were described in cats in 1935 and 1938.[20] In humans, light flashes have been observed to disturb the sleep-like EEG activity persisting after the loss of all brain stem reflexes and of spontaneous respiration.[26]

There is also concern about the permanence of consciousness loss, based on studies in cats, dogs and monkeys which recovered consciousness days or weeks after being rendered comatose by brain stem ablation and on human studies of brain stem stroke raising thoughts about the plasticity of the nervous system.[23] Other theories of consciousness place more stress on the thalamocortical system.[27] Perhaps the most objective statement to be made is that consciousness is not currently understood. That being so, proper caution must be exercised in accepting a diagnosis of its permanent loss before all cerebral blood flow has permanently ceased.

The ability to breathe spontaneously depends upon functioning elements in the medulla the respiratory centre. In the UK, establishing a neurological diagnosis of death involves challenging this centre with the strong stimulus offered by an unusually high concentration of carbon dioxide in the arterial blood, but it is not challenged by the more powerful drive stimulus provided by anoxia although the effect of that ultimate stimulus is sometimes seen after final disconnection of the ventilator in the form of agonal gasps.

No testing of testable brain stem functions such as oesophageal and cardiovascular regulation is specified in the UK Code of Practice for the diagnosis of death on neurological grounds. There is published evidence[28][29][30] strongly suggestive of the persistence of brain stem blood pressure control in organ donors.

A small minority of medical practitioners working in the UK have argued that neither requirement of the UK Health Department's Code of Practice basis for the equation of brain stem death with death is satisfied by its current diagnostic protocol[1] and that in terms of its ability to diagnose de facto brain stem death it falls far short.

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Brain stem death - Wikipedia

A bone marrow transplant poses many risks of complications, some potentially fatal.

The risk can depend on many factors, including the type of disease or condition, the type of transplant, and the age and health of the person receiving the transplant.

Although some people experience minimal problems with a bone marrow transplant, others may develop complications that may require treatment or hospitalization. Some complications could even be life-threatening.

Complications that can arise with a bone marrow transplant include:

Your doctor can explain your risk of complications from a bone marrow transplant. Together you can weigh the risks and benefits to decide whether a bone marrow transplant is right for you.

If you receive a transplant that uses stem cells from a donor (allogeneic transplant), you may be at risk of developing graft-versus-host disease (GVHD). This condition occurs when the donor stem cells that make up your new immune system see your body's tissues and organs as something foreign and attack them.

Many people who have an allogeneic transplant get GVHD at some point. The risk of GVHD is a bit greater if the stem cells come from an unrelated donor, but it can happen to anyone who gets a bone marrow transplant from a donor.

GVHD may happen at any time after your transplant. However, it's more common after your bone marrow has started to make healthy cells.

There are two kinds of GVHD: acute and chronic. Acute GVHD usually happens earlier, during the first months after your transplant. It typically affects your skin, digestive tract or liver. Chronic GVHD typically develops later and can affect many organs.

Chronic GVHD signs and symptoms include:

Oct. 13, 2016

Read more:
Risks - Bone marrow transplant - Mayo Clinic

OBJECTIVES:

This study explored the novel strategy of hypoxic preconditioning of bone marrow mesenchymal stem cells before transplantation into the infarcted heart to promote their survival and therapeutic potential of mesenchymal stem cell transplantation after myocardial ischemia.

Mesenchymal stem cells from green fluorescent protein transgenic mice were cultured under normoxic or hypoxic (0.5% oxygen for 24 hours) conditions. Expression of growth factors and anti-apoptotic genes were examined by immunoblot. Normoxic or hypoxic stem cells were intramyocardially injected into the peri-infarct region of rats 30 minutes after permanent myocardial infarction. Death of mesenchymal stem cells was assessed in vitro and in vivo after transplantation. Angiogenesis, infarct size, and heart function were measured 6 weeks after transplantation.

Hypoxic preconditioning increased expression of pro-survival and pro-angiogenic factors including hypoxia-inducible factor 1, angiopoietin-1, vascular endothelial growth factor and its receptor, Flk-1, erythropoietin, Bcl-2, and Bcl-xL. Cell death of hypoxic stem cells and caspase-3 activation in these cells were significantly lower compared with that in normoxic stem cells both in vitro and in vivo. Transplantation of hypoxic versus normoxic mesenchymal stem cells after myocardial infarction resulted in an increase in angiogenesis, as well as enhanced morphologic and functional benefits of stem cell therapy.

Hypoxic preconditioning enhances the capacity of mesenchymal stem cells to repair infarcted myocardium, attributable to reduced cell death and apoptosis of implanted cells, increased angiogenesis/vascularization, and paracrine effects.

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Transplantation of Hypoxia-preconditioned Mesenchymal Stem ...

Hematopoietic progenitor cell antigen CD34 also known as CD34 antigen is a protein that in humans is encoded by the CD34 gene.[3][4][5]

CD34 is a cluster of differentiation first described independently by Civin et al. and Tindle et al.[6][7][8][9] in a cell surface glycoprotein and functions as a cell-cell adhesion factor. It may also mediate the attachment of stem cells to bone marrow extracellular matrix or directly to stromal cells.

The CD34 protein is a member of a family of single-pass transmembrane sialomucin proteins that show expression on early hematopoietic and vascular-associated tissue.[10] However, little is known about its exact function.[11]

CD34 is also an important adhesion molecule and is required for T cells to enter lymph nodes. It is expressed on lymph node endothelia, whereas the L-selectin to which it binds is on the T cell.[12][13] Conversely, under other circumstances CD34 has been shown to act as molecular "Teflon" and block mast cell, eosinophil and dendritic cell precursor adhesion, and to facilitate opening of vascular lumens.[14][15] Finally, recent data suggest CD34 may also play a more selective role in chemokine-dependent migration of eosinophils and dendritic cell precursors.[16][17] Regardless of its mode of action, under all circumstances CD34, and its relatives podocalyxin and endoglycan, facilitates cell migration.[10][16]

Cells expressing CD34 (CD34+ cell) are normally found in the umbilical cord and bone marrow as hematopoietic cells, a subset of mesenchymal stem cells, endothelial progenitor cells, endothelial cells of blood vessels but not lymphatics (except pleural lymphatics), mast cells, a sub-population dendritic cells (which are factor XIIIa-negative) in the interstitium and around the adnexa of dermis of skin, as well as cells in soft tissue tumors like DFSP, GIST, SFT, HPC, and to some degree in MPNSTs, etc. The presence of CD34 on non-hematopoietic cells in various tissues has been linked to progenitor and adult stem cell phenotypes.[18]

It is important to mention that Long-Term Hematopoietic Stem Cells [LT-HSCs] in mice and humans are the hematopoietic cells with the greatest self-renewal capacity.[citation needed] Human HSCs express CD34 marker.[citation needed]

CD34 is expressed in roughly 20% of murine hematopoietic stem cells,[19] and can be stimulated and reversed.[20]

CD34+ cells may be isolated from blood samples using immunomagnetic or immunofluorescent methods.

Antibodies are used to quantify and purify hematopoietic progenitor stem cells for research and for clinical bone marrow transplantation. However, counting CD34+ mononuclear cells may overestimate myeloid blasts in bone marrow smears due to hematogones (B lymphocyte precursors) and CD34+ megakaryocytes.

Cells observed as CD34+ and CD38- are of an undifferentiated, primitive form; i.e., they are multipotential hemopoietic stem cells. Thus, because of their CD34+ expression, such undifferentiated cells can be sorted out.

In tumors, CD34 is found in alveolar soft part sarcoma, preB-ALL (positive in 75%), AML (40%), AML-M7 (most), dermatofibrosarcoma protuberans, gastrointestinal stromal tumors, giant cell fibroblastoma, granulocytic sarcoma, Kaposis sarcoma, liposarcoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumors, mengingeal hemangiopericytomas, meningiomas, neurofibromas, schwannomas, and papillary thyroid carcinoma.

A negative CD34 may exclude Ewing's sarcoma/PNET, myofibrosarcoma of the breast, and inflammatory myofibroblastic tumors of the stomach.

Injection of CD34+ hematopoietic Stem Cells has been clinically applied to treat various diseases including Spinal Cord Injury,[21] Liver Cirrhosis[22] and Peripheral Vascular disease.[23] Research has shown that CD34+ cells are relatively more in men than in women in the reproductive age among Spinal Cord Injury victims.[24]

CD34 has been shown to interact with CRKL.[25] It also interacts with L-selectin, important in inflammation.

More:
CD34 - Wikipedia

Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body.[1][2] Not all tumors are cancerous; benign tumors do not spread to other parts of the body.[2] Possible signs and symptoms include a lump, abnormal bleeding, prolonged cough, unexplained weight loss and a change in bowel movements.[3] While these symptoms may indicate cancer, they may have other causes.[3] Over 100 cancers affect humans.[2]

Tobacco use is the cause of about 22% of cancer deaths.[1] Another 10% is due to obesity, poor diet, lack of physical activity and drinking alcohol.[1][4] Other factors include certain infections, exposure to ionizing radiation and environmental pollutants.[5] In the developing world nearly 20% of cancers are due to infections such as hepatitis B, hepatitis C and human papillomavirus (HPV).[1] These factors act, at least partly, by changing the genes of a cell.[6] Typically many genetic changes are required before cancer develops.[6] Approximately 510% of cancers are due to inherited genetic defects from a person's parents.[7] Cancer can be detected by certain signs and symptoms or screening tests.[1] It is then typically further investigated by medical imaging and confirmed by biopsy.[8]

Many cancers can be prevented by not smoking, maintaining a healthy weight, not drinking too much alcohol, eating plenty of vegetables, fruits and whole grains, vaccination against certain infectious diseases, not eating too much processed and red meat, and avoiding too much sunlight exposure.[9][10] Early detection through screening is useful for cervical and colorectal cancer.[11] The benefits of screening in breast cancer are controversial.[11][12] Cancer is often treated with some combination of radiation therapy, surgery, chemotherapy, and targeted therapy.[1][13] Pain and symptom management are an important part of care. Palliative care is particularly important in people with advanced disease.[1] The chance of survival depends on the type of cancer and extent of disease at the start of treatment.[6] In children under 15 at diagnosis the five-year survival rate in the developed world is on average 80%.[14] For cancer in the United States the average five-year survival rate is 66%.[15]

In 2012 about 14.1 million new cases of cancer occurred globally (not including skin cancer other than melanoma).[6] It caused about 8.2 million deaths or 14.6% of human deaths.[6][16] The most common types of cancer in males are lung cancer, prostate cancer, colorectal cancer and stomach cancer. In females, the most common types are breast cancer, colorectal cancer, lung cancer and cervical cancer.[6] If skin cancer other than melanoma were included in total new cancers each year it would account for around 40% of cases.[17][18] In children, acute lymphoblastic leukaemia and brain tumors are most common except in Africa where non-Hodgkin lymphoma occurs more often.[14] In 2012, about 165,000 children under 15 years of age were diagnosed with cancer. The risk of cancer increases significantly with age and many cancers occur more commonly in developed countries.[6] Rates are increasing as more people live to an old age and as lifestyle changes occur in the developing world.[19] The financial costs of cancer were estimated at $1.16 trillion US dollars per year as of 2010.[20]

Cancers are a large family of diseases that involve abnormal cell growth with the potential to invade or spread to other parts of the body.[1][2] They form a subset of neoplasms. A neoplasm or tumor is a group of cells that have undergone unregulated growth and will often form a mass or lump, but may be distributed diffusely.[21][22]

All tumor cells show the six hallmarks of cancer. These characteristics are required to produce a malignant tumor. They include:[23]

The progression from normal cells to cells that can form a detectable mass to outright cancer involves multiple steps known as malignant progression.[24][25]

When cancer begins, it produces no symptoms. Signs and symptoms appear as the mass grows or ulcerates. The findings that result depend on the cancer's type and location. Few symptoms are specific. Many frequently occur in individuals who have other conditions. Cancer is a "great imitator". Thus, it is common for people diagnosed with cancer to have been treated for other diseases, which were hypothesized to be causing their symptoms.[26]

Local symptoms may occur due to the mass of the tumor or its ulceration. For example, mass effects from lung cancer can block the bronchus resulting in cough or pneumonia; esophageal cancer can cause narrowing of the esophagus, making it difficult or painful to swallow; and colorectal cancer may lead to narrowing or blockages in the bowel, affecting bowel habits. Masses in breasts or testicles may produce observable lumps. Ulceration can cause bleeding that, if it occurs in the lung, will lead to coughing up blood, in the bowels to anemia or rectal bleeding, in the bladder to blood in the urine and in the uterus to vaginal bleeding. Although localized pain may occur in advanced cancer, the initial swelling is usually painless. Some cancers can cause a buildup of fluid within the chest or abdomen.[26]

General symptoms occur due to effects that are not related to direct or metastatic spread. These may include: unintentional weight loss, fever, excessive fatigue and changes to the skin.[27]Hodgkin disease, leukemias and cancers of the liver or kidney can cause a persistent fever.[26]

Some cancers may cause specific groups of systemic symptoms, termed paraneoplastic phenomena. Examples include the appearance of myasthenia gravis in thymoma and clubbing in lung cancer.[26]

Cancer can spread from its original site by local spread, lymphatic spread to regional lymph nodes or by haematogenous spread via the blood to distant sites, known as metastasis. When cancer spreads by a haematogenous route, it usually spreads all over the body. However, cancer 'seeds' grow in certain selected site only ('soil') as hypothesized in the soil and seed hypothesis of cancer metastasis. The symptoms of metastatic cancers depend on the tumor location and can include enlarged lymph nodes (which can be felt or sometimes seen under the skin and are typically hard), enlarged liver or enlarged spleen, which can be felt in the abdomen, pain or fracture of affected bones and neurological symptoms.[26]

The majority of cancers, some 9095% of cases, are due to environmental factors. The remaining 510% are due to inherited genetics.[5]Environmental, as used by cancer researchers, means any cause that is not inherited genetically, such as lifestyle, economic and behavioral factors and not merely pollution.[28] Common environmental factors that contribute to cancer death include tobacco (2530%), diet and obesity (3035%), infections (1520%), radiation (both ionizing and non-ionizing, up to 10%), stress, lack of physical activity and environmental pollutants.[5]

It is not generally possible to prove what caused a particular cancer, because the various causes do not have specific fingerprints. For example, if a person who uses tobacco heavily develops lung cancer, then it was probably caused by the tobacco use, but since everyone has a small chance of developing lung cancer as a result of air pollution or radiation, the cancer may have developed for one of those reasons. Excepting the rare transmissions that occur with pregnancies and occasional organ donors, cancer is generally not a transmissible disease.[29]

Exposure to particular substances have been linked to specific types of cancer. These substances are called carcinogens.

Tobacco smoke, for example, causes 90% of lung cancer.[30] It also causes cancer in the larynx, head, neck, stomach, bladder, kidney, esophagus and pancreas.[31] Tobacco smoke contains over fifty known carcinogens, including nitrosamines and polycyclic aromatic hydrocarbons.[32]

Tobacco is responsible about one in five cancer deaths worldwide[32] and about one in three in the developed world[33]Lung cancer death rates in the United States have mirrored smoking patterns, with increases in smoking followed by dramatic increases in lung cancer death rates and, more recently, decreases in smoking rates since the 1950s followed by decreases in lung cancer death rates in men since 1990.[34][35]

In Western Europe, 10% of cancers in males and 3% of cancers in females are attributed to alcohol exposure, especially liver and digestive tract cancers.[36] Cancer from work-related substance exposures may cause between 220% of cases,[37] causing at least 200,000 deaths.[38] Cancers such as lung cancer and mesothelioma can come from inhaling tobacco smoke or asbestos fibers, or leukemia from exposure to benzene.[38]

Diet, physical inactivity and obesity are related to up to 3035% of cancer deaths.[5][39] In the United States excess body weight is associated with the development of many types of cancer and is a factor in 1420% of cancer deaths.[39] A UK study including data on over 5 million people showed higher body mass index to be related to at least 10 types of cancer and responsible for around 12,000 cases each year in that country.[40] Physical inactivity is believed to contribute to cancer risk, not only through its effect on body weight but also through negative effects on the immune system and endocrine system.[39] More than half of the effect from diet is due to overnutrition (eating too much), rather than from eating too few vegetables or other healthful foods.

Some specific foods are linked to specific cancers. A high-salt diet is linked to gastric cancer.[41]Aflatoxin B1, a frequent food contaminant, causes liver cancer.[41]Betel nut chewing can cause oral cancer.[41] National differences in dietary practices may partly explain differences in cancer incidence. For example, gastric cancer is more common in Japan due to its high-salt diet[42] while colon cancer is more common in the United States. Immigrant cancer profiles develop mirror that of their new country, often within one generation.[43]

Worldwide approximately 18% of cancer deaths are related to infectious diseases.[5] This proportion ranges from a high of 25% in Africa to less than 10% in the developed world.[5]Viruses are the usual infectious agents that cause cancer but cancer bacteria and parasites may also play a role.

Oncoviruses (viruses that can cause cancer) include human papillomavirus (cervical cancer), EpsteinBarr virus (B-cell lymphoproliferative disease and nasopharyngeal carcinoma), Kaposi's sarcoma herpesvirus (Kaposi's sarcoma and primary effusion lymphomas), hepatitis B and hepatitis C viruses (hepatocellular carcinoma) and human T-cell leukemia virus-1 (T-cell leukemias). Bacterial infection may also increase the risk of cancer, as seen in Helicobacter pylori-induced gastric carcinoma.[44][45] Parasitic infections associated with cancer include Schistosoma haematobium (squamous cell carcinoma of the bladder) and the liver flukes, Opisthorchis viverrini and Clonorchis sinensis (cholangiocarcinoma).[46]

Up to 10% of invasive cancers are related to radiation exposure, including both ionizing radiation and non-ionizing ultraviolet radiation.[5] Additionally, the majority of non-invasive cancers are non-melanoma skin cancers caused by non-ionizing ultraviolet radiation, mostly from sunlight. Sources of ionizing radiation include medical imaging and radon gas.

Ionizing radiation is not a particularly strong mutagen.[47] Residential exposure to radon gas, for example, has similar cancer risks as passive smoking.[47] Radiation is a more potent source of cancer when combined with other cancer-causing agents, such as radon plus tobacco smoke.[47] Radiation can cause cancer in most parts of the body, in all animals and at any age. Children and adolescents are twice as likely to develop radiation-induced leukemia as adults; radiation exposure before birth has ten times the effect.[47]

Medical use of ionizing radiation is a small but growing source of radiation-induced cancers. Ionizing radiation may be used to treat other cancers, but this may, in some cases, induce a second form of cancer.[47] It is also used in some kinds of medical imaging.[48]

Prolonged exposure to ultraviolet radiation from the sun can lead to melanoma and other skin malignancies.[49] Clear evidence establishes ultraviolet radiation, especially the non-ionizing medium wave UVB, as the cause of most non-melanoma skin cancers, which are the most common forms of cancer in the world.[49]

Non-ionizing radio frequency radiation from mobile phones, electric power transmission and other similar sources have been described as a possible carcinogen by the World Health Organization's International Agency for Research on Cancer.[50] However, studies have not found a consistent link between mobile phone radiation and cancer risk.[51]

The vast majority of cancers are non-hereditary ("sporadic"). Hereditary cancers are primarily caused by an inherited genetic defect. Less than 0.3% of the population are carriers of a genetic mutation that has a large effect on cancer risk and these cause less than 310% of cancer.[52] Some of these syndromes include: certain inherited mutations in the genes BRCA1 and BRCA2 with a more than 75% risk of breast cancer and ovarian cancer,[52] and hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome), which is present in about 3% of people with colorectal cancer,[53] among others.

Some substances cause cancer primarily through their physical, rather than chemical, effects.[54] A prominent example of this is prolonged exposure to asbestos, naturally occurring mineral fibers that are a major cause of mesothelioma (cancer of the serous membrane) usually the serous membrane surrounding the lungs.[54] Other substances in this category, including both naturally occurring and synthetic asbestos-like fibers, such as wollastonite, attapulgite, glass wool and rock wool, are believed to have similar effects.[54] Non-fibrous particulate materials that cause cancer include powdered metallic cobalt and nickel and crystalline silica (quartz, cristobalite and tridymite).[54] Usually, physical carcinogens must get inside the body (such as through inhalation) and require years of exposure to produce cancer.[54]

Physical trauma resulting in cancer is relatively rare.[55] Claims that breaking bones resulted in bone cancer, for example, have not been proven.[55] Similarly, physical trauma is not accepted as a cause for cervical cancer, breast cancer or brain cancer.[55] One accepted source is frequent, long-term application of hot objects to the body. It is possible that repeated burns on the same part of the body, such as those produced by kanger and kairo heaters (charcoal hand warmers), may produce skin cancer, especially if carcinogenic chemicals are also present.[55] Frequent consumption of scalding hot tea may produce esophageal cancer.[55] Generally, it is believed that the cancer arises, or a pre-existing cancer is encouraged, during the process of healing, rather than directly by the trauma.[55] However, repeated injuries to the same tissues might promote excessive cell proliferation, which could then increase the odds of a cancerous mutation.

Chronic inflammation has been hypothesized to directly cause mutation.[55][56] Inflammation can contribute to proliferation, survival, angiogenesis and migration of cancer cells by influencing the tumor microenvironment.[57][58]Oncogenes build up an inflammatory pro-tumorigenic microenvironment.[59]

Some hormones play a role in the development of cancer by promoting cell proliferation.[60]Insulin-like growth factors and their binding proteins play a key role in cancer cell proliferation, differentiation and apoptosis, suggesting possible involvement in carcinogenesis.[61]

Hormones are important agents in sex-related cancers, such as cancer of the breast, endometrium, prostate, ovary and testis and also of thyroid cancer and bone cancer.[60] For example, the daughters of women who have breast cancer have significantly higher levels of estrogen and progesterone than the daughters of women without breast cancer. These higher hormone levels may explain their higher risk of breast cancer, even in the absence of a breast-cancer gene.[60] Similarly, men of African ancestry have significantly higher levels of testosterone than men of European ancestry and have a correspondingly higher level of prostate cancer.[60] Men of Asian ancestry, with the lowest levels of testosterone-activating androstanediol glucuronide, have the lowest levels of prostate cancer.[60]

Other factors are relevant: obese people have higher levels of some hormones associated with cancer and a higher rate of those cancers.[60] Women who take hormone replacement therapy have a higher risk of developing cancers associated with those hormones.[60] On the other hand, people who exercise far more than average have lower levels of these hormones and lower risk of cancer.[60]Osteosarcoma may be promoted by growth hormones.[60] Some treatments and prevention approaches leverage this cause by artificially reducing hormone levels and thus discouraging hormone-sensitive cancers.[60]

There is an association between celiac disease and an increased risk of all cancers. People with untreated celiac disease have a higher risk, but this risk decreases with time after diagnosis and strict treatment, probably due to the adoption of a gluten-free diet, which seems to have a protective role against development of malignancy in people with celiac disease. However, the delay in diagnosis and initiation of a gluten-free diet seems to increase the risk of malignancies.[62] Rates of gastrointestinal cancers are increased in people with Crohn's disease and ulcerative colitis, due to chronic inflammation. Also, immunomodulators and biologic agents used to treat these diseases may promote developing extra-intestinal malignancies.[63]

Cancer is fundamentally a disease of tissue growth regulation. In order for a normal cell to transform into a cancer cell, the genes that regulate cell growth and differentiation must be altered.[64]

The affected genes are divided into two broad categories. Oncogenes are genes that promote cell growth and reproduction. Tumor suppressor genes are genes that inhibit cell division and survival. Malignant transformation can occur through the formation of novel oncogenes, the inappropriate over-expression of normal oncogenes, or by the under-expression or disabling of tumor suppressor genes. Typically, changes in multiple genes are required to transform a normal cell into a cancer cell.[65]

Genetic changes can occur at different levels and by different mechanisms. The gain or loss of an entire chromosome can occur through errors in mitosis. More common are mutations, which are changes in the nucleotide sequence of genomic DNA.

Large-scale mutations involve the deletion or gain of a portion of a chromosome. Genomic amplification occurs when a cell gains copies (often 20 or more) of a small chromosomal locus, usually containing one or more oncogenes and adjacent genetic material. Translocation occurs when two separate chromosomal regions become abnormally fused, often at a characteristic location. A well-known example of this is the Philadelphia chromosome, or translocation of chromosomes 9 and 22, which occurs in chronic myelogenous leukemia and results in production of the BCR-abl fusion protein, an oncogenic tyrosine kinase.

Small-scale mutations include point mutations, deletions and insertions, which may occur in the promoter region of a gene and affect its expression, or may occur in the gene's coding sequence and alter the function or stability of its protein product. Disruption of a single gene may also result from integration of genomic material from a DNA virus or retrovirus, leading to the expression of viral oncogenes in the affected cell and its descendants.

Replication of the data contained within the DNA of living cells will probabilistically result in some errors (mutations). Complex error correction and prevention is built into the process and safeguards the cell against cancer. If significant error occurs, the damaged cell can self-destruct through programmed cell death, termed apoptosis. If the error control processes fail, then the mutations will survive and be passed along to daughter cells.

Some environments make errors more likely to arise and propagate. Such environments can include the presence of disruptive substances called carcinogens, repeated physical injury, heat, ionising radiation or hypoxia.[66]

The errors that cause cancer are self-amplifying and compounding, for example:

The transformation of a normal cell into cancer is akin to a chain reaction caused by initial errors, which compound into more severe errors, each progressively allowing the cell to escape more controls that limit normal tissue growth. This rebellion-like scenario is an undesirable survival of the fittest, where the driving forces of evolution work against the body's design and enforcement of order. Once cancer has begun to develop, this ongoing process, termed clonal evolution, drives progression towards more invasive stages.[67] Clonal evolution leads to intra-tumour heterogeneity (cancer cells with heterogeneous mutations) that complicates designing effective treatment strategies.

Characteristic abilities developed by cancers are divided into categories, specifically evasion of apoptosis, self-sufficiency in growth signals, insensitivity to anti-growth signals, sustained angiogenesis, limitless replicative potential, metastasis, reprogramming of energy metabolism and evasion of immune destruction.[24][25]

The classical view of cancer is a set of diseases that are driven by progressive genetic abnormalities that include mutations in tumor-suppressor genes and oncogenes and chromosomal abnormalities. Later epigenetic alterations' role was identified.[68]

Epigenetic alterations refer to functionally relevant modifications to the genome that do not change the nucleotide sequence. Examples of such modifications are changes in DNA methylation (hypermethylation and hypomethylation), histone modification[69] and changes in chromosomal architecture (caused by inappropriate expression of proteins such as HMGA2 or HMGA1).[70] Each of these alterations regulates gene expression without altering the underlying DNA sequence. These changes may remain through cell divisions, last for multiple generations and can be considered to be epimutations (equivalent to mutations).

Epigenetic alterations occur frequently in cancers. As an example, one study listed protein coding genes that were frequently altered in their methylation in association with colon cancer. These included 147 hypermethylated and 27 hypomethylated genes. Of the hypermethylated genes, 10 were hypermethylated in 100% of colon cancers and many others were hypermethylated in more than 50% of colon cancers.[71]

While epigenetic alterations are found in cancers, the epigenetic alterations in DNA repair genes, causing reduced expression of DNA repair proteins, may be of particular importance. Such alterations are thought to occur early in progression to cancer and to be a likely cause of the genetic instability characteristic of cancers.[72][73][74][75]

Reduced expression of DNA repair genes disrupts DNA repair. This is shown in the figure at the 4th level from the top. (In the figure, red wording indicates the central role of DNA damage and defects in DNA repair in progression to cancer.) When DNA repair is deficient DNA damage remains in cells at a higher than usual level (5th level) and cause increased frequencies of mutation and/or epimutation (6th level). Mutation rates increase substantially in cells defective in DNA mismatch repair[76][77] or in homologous recombinational repair (HRR).[78] Chromosomal rearrangements and aneuploidy also increase in HRR defective cells.[79]

Higher levels of DNA damage cause increased mutation (right side of figure) and increased epimutation. During repair of DNA double strand breaks, or repair of other DNA damage, incompletely cleared repair sites can cause epigenetic gene silencing.[80][81]

Deficient expression of DNA repair proteins due to an inherited mutation can increase cancer risks. Individuals with an inherited impairment in any of 34 DNA repair genes (see article DNA repair-deficiency disorder) have increased cancer risk, with some defects ensuring a 100% lifetime chance of cancer (e.g. p53 mutations).[82] Germ line DNA repair mutations are noted on the figure's left side. However, such germline mutations (which cause highly penetrant cancer syndromes) are the cause of only about 1 percent of cancers.[83]

In sporadic cancers, deficiencies in DNA repair are occasionally caused by a mutation in a DNA repair gene, but are much more frequently caused by epigenetic alterations that reduce or silence expression of DNA repair genes. This is indicated in the figure at the 3rd level. Many studies of heavy metal-induced carcinogenesis show that such heavy metals cause reduction in expression of DNA repair enzymes, some through epigenetic mechanisms. DNA repair inhibition is proposed to be a predominant mechanism in heavy metal-induced carcinogenicity. In addition, frequent epigenetic alterations of the DNA sequences code for small RNAs called microRNAs (or miRNAs). MiRNAs do not code for proteins, but can "target" protein-coding genes and reduce their expression.

Cancers usually arise from an assemblage of mutations and epimutations that confer a selective advantage leading to clonal expansion (see Field defects in progression to cancer). Mutations, however, may not be as frequent in cancers as epigenetic alterations. An average cancer of the breast or colon can have about 60 to 70 protein-altering mutations, of which about three or four may be "driver" mutations and the remaining ones may be "passenger" mutations.[84]

Metastasis is the spread of cancer to other locations in the body. The dispersed tumors are called metastatic tumors, while the original is called the primary tumor. Almost all cancers can metastasize.[85] Most cancer deaths are due to cancer that has metastasized.[86]

Metastasis is common in the late stages of cancer and it can occur via the blood or the lymphatic system or both. The typical steps in metastasis are local invasion, intravasation into the blood or lymph, circulation through the body, extravasation into the new tissue, proliferation and angiogenesis. Different types of cancers tend to metastasize to particular organs, but overall the most common places for metastases to occur are the lungs, liver, brain and the bones.[85]

Most cancers are initially recognized either because of the appearance of signs or symptoms or through screening. Neither of these lead to a definitive diagnosis, which requires the examination of a tissue sample by a pathologist. People with suspected cancer are investigated with medical tests. These commonly include blood tests, X-rays, CT scans and endoscopy.

People may become extremely anxious and depressed post-diagnosis. The risk of suicide in people with cancer is approximately double the normal risk.[87]

Cancers are classified by the type of cell that the tumor cells resemble and is therefore presumed to be the origin of the tumor. These types include:

Cancers are usually named using -carcinoma, -sarcoma or -blastoma as a suffix, with the Latin or Greek word for the organ or tissue of origin as the root. For example, cancers of the liver parenchyma arising from malignant epithelial cells is called hepatocarcinoma, while a malignancy arising from primitive liver precursor cells is called a hepatoblastoma and a cancer arising from fat cells is called a liposarcoma. For some common cancers, the English organ name is used. For example, the most common type of breast cancer is called ductal carcinoma of the breast. Here, the adjective ductal refers to the appearance of the cancer under the microscope, which suggests that it has originated in the milk ducts.

Benign tumors (which are not cancers) are named using -oma as a suffix with the organ name as the root. For example, a benign tumor of smooth muscle cells is called a leiomyoma (the common name of this frequently occurring benign tumor in the uterus is fibroid). Confusingly, some types of cancer use the -noma suffix, examples including melanoma and seminoma.

Some types of cancer are named for the size and shape of the cells under a microscope, such as giant cell carcinoma, spindle cell carcinoma and small-cell carcinoma.

The tissue diagnosis from the biopsy indicates the type of cell that is proliferating, its histological grade, genetic abnormalities and other features. Together, this information is useful to evaluate the prognosis of the patient and to choose the best treatment. Cytogenetics and immunohistochemistry are other types of tissue tests. These tests may provide information about molecular changes (such as mutations, fusion genes and numerical chromosome changes) and may thus also indicate the prognosis and best treatment.

Cancer prevention is defined as active measures to decrease cancer risk.[89] The vast majority of cancer cases are due to environmental risk factors. Many of these environmental factors are controllable lifestyle choices. Thus, cancer is generally preventable.[90] Between 70% and 90% of common cancers are due to environmental factors and therefore potentially preventable.[91]

Greater than 30% of cancer deaths could be prevented by avoiding risk factors including: tobacco, excess weight/obesity, insufficient diet, physical inactivity, alcohol, sexually transmitted infections and air pollution.[92] Not all environmental causes are controllable, such as naturally occurring background radiation and cancers caused through hereditary genetic disorders and thus are not preventable via personal behavior.

While many dietary recommendations have been proposed to reduce cancer risks, the evidence to support them is not definitive.[9][93] The primary dietary factors that increase risk are obesity and alcohol consumption. Diets low in fruits and vegetables and high in red meat have been implicated but reviews and meta-analyses do not come to a consistent conclusion.[94][95] A 2014 meta-analysis find no relationship between fruits and vegetables and cancer.[96]Coffee is associated with a reduced risk of liver cancer.[97] Studies have linked excess consumption of red or processed meat to an increased risk of breast cancer, colon cancer and pancreatic cancer, a phenomenon that could be due to the presence of carcinogens in meats cooked at high temperatures.[98][99] In 2015 the IARC reported that eating processed meat (e.g., bacon, ham, hot dogs, sausages) and, to a lesser degree, red meat was linked to some cancers.[100][101]

Dietary recommendations for cancer prevention typically include an emphasis on vegetables, fruit, whole grains and fish and an avoidance of processed and red meat (beef, pork, lamb), animal fats and refined carbohydrates.[9][93]

Medications can be used to prevent cancer in a few circumstances.[102] In the general population, NSAIDs reduce the risk of colorectal cancer; however, due to cardiovascular and gastrointestinal side effects, they cause overall harm when used for prevention.[103]Aspirin has been found to reduce the risk of death from cancer by about 7%.[104]COX-2 inhibitors may decrease the rate of polyp formation in people with familial adenomatous polyposis; however, it is associated with the same adverse effects as NSAIDs.[105] Daily use of tamoxifen or raloxifene reduce the risk of breast cancer in high-risk women.[106] The benefit versus harm for 5-alpha-reductase inhibitor such as finasteride is not clear.[107]

Vitamins are not effective at preventing cancer,[108] although low blood levels of vitamin D are correlated with increased cancer risk.[109][110] Whether this relationship is causal and vitamin D supplementation is protective is not determined.[111]Beta-carotene supplementation increases lung cancer rates in those who are high risk.[112]Folic acid supplementation is not effective in preventing colon cancer and may increase colon polyps.[113] It is unclear if selenium supplementation has an effect.[114]

Vaccines have been developed that prevent infection by some carcinogenic viruses.[115]Human papillomavirus vaccine (Gardasil and Cervarix) decrease the risk of developing cervical cancer.[115] The hepatitis B vaccine prevents infection with hepatitis B virus and thus decreases the risk of liver cancer.[115] The administration of human papillomavirus and hepatitis B vaccinations is recommended when resources allow.[116]

Unlike diagnostic efforts prompted by symptoms and medical signs, cancer screening involves efforts to detect cancer after it has formed, but before any noticeable symptoms appear.[117] This may involve physical examination, blood or urine tests or medical imaging.[117]

Cancer screening is not available for many types of cancers. Even when tests are available, they may not be recommended for everyone. Universal screening or mass screening involves screening everyone.[118]Selective screening identifies people who are at higher risk, such as people with a family history.[118] Several factors are considered to determine whether the benefits of screening outweigh the risks and the costs of screening.[117] These factors include:

The U.S. Preventive Services Task Force (USPSTF) issues recommendations for various cancers:

Screens for gastric cancer using photofluorography due to the high incidence there.[19]

Genetic testing for individuals at high-risk of certain cancers is recommended by unofficial groups.[116][132] Carriers of these mutations may then undergo enhanced surveillance, chemoprevention, or preventative surgery to reduce their subsequent risk.[132]

Many treatment options for cancer exist. The primary ones include surgery, chemotherapy, radiation therapy, hormonal therapy, targeted therapy and palliative care. Which treatments are used depends on the type, location and grade of the cancer as well as the patient's health and preferences. The treatment intent may or may not be curative.

Chemotherapy is the treatment of cancer with one or more cytotoxic anti-neoplastic drugs (chemotherapeutic agents) as part of a standardized regimen. The term encompasses a variety of drugs, which are divided into broad categories such as alkylating agents and antimetabolites.[133] Traditional chemotherapeutic agents act by killing cells that divide rapidly, a critical property of most cancer cells.

Targeted therapy is a form of chemotherapy that targets specific molecular differences between cancer and normal cells. The first targeted therapies blocked the estrogen receptor molecule, inhibiting the growth of breast cancer. Another common example is the class of Bcr-Abl inhibitors, which are used to treat chronic myelogenous leukemia (CML).[134] Currently, targeted therapies exist for breast cancer, multiple myeloma, lymphoma, prostate cancer, melanoma and other cancers.[135]

The efficacy of chemotherapy depends on the type of cancer and the stage. In combination with surgery, chemotherapy has proven useful in cancer types including breast cancer, colorectal cancer, pancreatic cancer, osteogenic sarcoma, testicular cancer, ovarian cancer and certain lung cancers.[136] Chemotherapy is curative for some cancers, such as some leukemias,[137][138] ineffective in some brain tumors,[139] and needless in others, such as most non-melanoma skin cancers.[140] The effectiveness of chemotherapy is often limited by its toxicity to other tissues in the body. Even when chemotherapy does not provide a permanent cure, it may be useful to reduce symptoms such as pain or to reduce the size of an inoperable tumor in the hope that surgery will become possible in the future.

Radiation therapy involves the use of ionizing radiation in an attempt to either cure or improve symptoms. It works by damaging the DNA of cancerous tissue, killing it. To spare normal tissues (such as skin or organs, which radiation must pass through to treat the tumor), shaped radiation beams are aimed from multiple exposure angles to intersect at the tumor, providing a much larger dose there than in the surrounding, healthy tissue. As with chemotherapy, cancers vary in their response to radiation therapy.[141][142][143]

Radiation therapy is used in about half of cases. The radiation can be either from internal sources (brachytherapy) or external sources. The radiation is most commonly low energy x-rays for treating skin cancers, while higher energy x-rays are used for cancers within the body.[144] Radiation is typically used in addition to surgery and or chemotherapy. For certain types of cancer, such as early head and neck cancer, it may be used alone.[145] For painful bone metastasis, it has been found to be effective in about 70% of patients.[145]

Surgery is the primary method of treatment for most isolated, solid cancers and may play a role in palliation and prolongation of survival. It is typically an important part of definitive diagnosis and staging of tumors, as biopsies are usually required. In localized cancer, surgery typically attempts to remove the entire mass along with, in certain cases, the lymph nodes in the area. For some types of cancer this is sufficient to eliminate the cancer.[136]

Palliative care refers to treatment that attempts to help the patient feel better and may be combined with an attempt to treat the cancer. Palliative care includes action to reduce physical, emotional, spiritual and psycho-social distress. Unlike treatment that is aimed at directly killing cancer cells, the primary goal of palliative care is to improve quality of life.

People at all stages of cancer treatment typically receive some kind of palliative care. In some cases, medical specialty professional organizations recommend that patients and physicians respond to cancer only with palliative care.[146] This applies to patients who:[147]

Palliative care may be confused with hospice and therefore only indicated when people approach end of life. Like hospice care, palliative care attempts to help the patient cope with their immediate needs and to increase comfort. Unlike hospice care, palliative care does not require people to stop treatment aimed at the cancer.

Multiple national medical guidelines recommend early palliative care for patients whose cancer has produced distressing symptoms or who need help coping with their illness. In patients first diagnosed with metastatic disease, palliative care may be immediately indicated. Palliative care is indicated for patients with a prognosis of less than 12 months of life even given aggressive treatment.[148][149][150]

A variety of therapies using immunotherapy, stimulating or helping the immune system to fight cancer, have come into use since 1997. Approaches include antibodies, checkpoint therapy and adoptive cell transfer.[151]

Complementary and alternative cancer treatments are a diverse group of therapies, practices and products that are not part of conventional medicine.[152] "Complementary medicine" refers to methods and substances used along with conventional medicine, while "alternative medicine" refers to compounds used instead of conventional medicine.[153] Most complementary and alternative medicines for cancer have not been studied or tested using conventional techniques such as clinical trials. Some alternative treatments have been investigated and shown to be ineffective but still continue to be marketed and promoted. Cancer researcher Andrew J. Vickers stated, "The label 'unproven' is inappropriate for such therapies; it is time to assert that many alternative cancer therapies have been 'disproven'."[154]

Survival rates vary by cancer type and by the stage at which it is diagnosed, ranging from majority survival to complete mortality five years after diagnosis. Once a cancer has metastasized, prognosis normally becomes much worse. About half of patients receiving treatment for invasive cancer (excluding carcinoma in situ and non-melanoma skin cancers) die from that cancer or its treatment.[19]

Survival is worse in the developing world,[19] partly because the types of cancer that are most common there are harder to treat than those associated with developed countries.[155]

Those who survive cancer develop a second primary cancer at about twice the rate of those never diagnosed.[156] The increased risk is believed to be primarily due to the same risk factors that produced the first cancer, partly due to treatment of the first cancer and to better compliance with screening.[156]

Predicting short- or long-term survival depends on many factors. The most important are the cancer type and the patient's age and overall health. Those who are frail with other health problems have lower survival rates than otherwise healthy people. Centenarians are unlikely to survive for five years even if treatment is successful. People who report a higher quality of life tend to survive longer.[157] People with lower quality of life may be affected by depression and other complications and/or disease progression that both impairs quality and quantity of life. Additionally, patients with worse prognoses may be depressed or report poorer quality of life because they perceive that their condition is likely to be fatal.

Cancer patients have an increased risk of blood clots in veins. The use of heparin appears to improve survival and decrease the risk of blood clots.[158]

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Cancer - Wikipedia

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Alex Jones' Infowars: There's a war on for your mind!

Induced pluripotent stem cells (iPSCs) are adult cells that have been genetically reprogrammed to an embryonic stem celllike state by being forced to express genes and factors important for maintaining the defining properties of embryonic stem cells. Although these cells meet the defining criteria for pluripotent stem cells, it is not known if iPSCs and embryonic stem cells differ in clinically significant ways. Mouse iPSCs were first reported in 2006, and human iPSCs were first reported in late 2007. Mouse iPSCs demonstrate important characteristics of pluripotent stem cells, including expressing stem cell markers, forming tumors containing cells from all three germ layers, and being able to contribute to many different tissues when injected into mouse embryos at a very early stage in development. Human iPSCs also express stem cell markers and are capable of generating cells characteristic of all three germ layers.

Although additional research is needed, iPSCs are already useful tools for drug development and modeling of diseases, and scientists hope to use them in transplantation medicine. Viruses are currently used to introduce the reprogramming factors into adult cells, and this process must be carefully controlled and tested before the technique can lead to useful treatment for humans. In animal studies, the virus used to introduce the stem cell factors sometimes causes cancers. Researchers are currently investigating non-viral delivery strategies. In any case, this breakthrough discovery has created a powerful new way to "de-differentiate" cells whose developmental fates had been previously assumed to be determined. In addition, tissues derived from iPSCs will be a nearly identical match to the cell donor and thus probably avoid rejection by the immune system. The iPSC strategy creates pluripotent stem cells that, together with studies of other types of pluripotent stem cells, will help researchers learn how to reprogram cells to repair damaged tissues in the human body.

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Stem Cell Basics VI. | stemcells.nih.gov

On behalf of the organizing committee, it is my distinct pleasure to invite you to attend the Stem Cell Congress-2017. After the success of the Cell Science-2011, 2012, 2013, 2014, 2015, Conference series.LLC is proud to announce the 6th World Congress and expo on Cell & Stem Cell Research (Stem Cell Congress-2017) which is going to be held during March 20-22, 2017, Orlando, Florida, USA. The theme of Stem Cell Congress-2017 is Explore and Exploit the Novel Techniques in Cell and Stem Cell Research.

This annual Cell Science conference brings together domain experts, researchers, clinicians, industry representatives, postdoctoral fellows and students from around the world, providing them with the opportunity to report, share, and discuss scientific questions, achievements, and challenges in the field.

Examples of the diverse cell science and stem cell topics that will be covered in this comprehensive conference include Cell differentiation and development, Cell metabolism, Tissue engineering and regenerative medicine, Stem cell therapy, Cell and gene therapy, Novel stem cell technologies, Stem cell and cancer biology, Stem cell treatment, Tendency in cell biology of aging and Apoptosis and cancer disease, Drugs and clinical developments. The meeting will focus on basic cell mechanism studies, clinical research advances, and recent breakthroughs in cell and stem cell research. With the support of many emerging technologies, dramatic progress has been made in these areas. In Stem Cell Congress-2017, you will be able to share experiences and research results, discuss challenges encountered and solutions adopted and have opportunities to establish productive new academic and industry research collaborations.

In association with the Stem Cell Congress-2017 conference, we will invite those selected to present at the meeting to publish a manuscript from their talk in the journal Cell Science with a significantly discounted publication charge. Please join us in Philadelphia for an exciting all-encompassing annual Stem Cell get together with the theme of better understanding from basic cell mechanisms to latest Stem Cell breakthroughs!

Haval Shirwan, Ph.D. Executive Editor, Journal of Clinical & Cellular Immunology Dr. Michael and Joan Hamilton Endowed Chair in Autoimmune Disease Professor, Department of Microbiology and Immunology Director, Molecular Immunomodulation Program, Institute for Cellular Therapeutics, University of Louisville, Louisville, KY

Track01:Stem Cells

The most well-established and widely used stem cell treatment is thetransplantationof blood stem cells to treat diseases and conditions of the blood and immune system, or to restore the blood system after treatments for specific cancers. Since the 1970s,skin stem cellshave been used to grow skin grafts for patients with severe burns on very large areas of the body. Only a few clinical centers are able to carry out this treatment and it is usually reserved for patients with life-threatening burns. It is also not a perfect solution: the new skin has no hair follicles or sweat glands. Research aimed at improving the technique is ongoing.

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Track 02: Stem Cell Banking:

Stem Cell Banking is a facility that preserves stem cells derived from amniotic fluid for future use. Stem cell samples in private or family banks are preserved precisely for use by the individual person from whom such cells have been collected and the banking costs are paid by such person. The sample can later be retrieved only by that individual and for the use by such individual or, in many cases, by his or her first-degree blood relatives.

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Track 03: Stem Cell Therapy:

Autologous cells are obtained from one's own body, just as one may bank his or her own blood for elective surgical procedures. Adult stem cells are frequently used in medical therapies, for example in bone marrow transplantation. Human embryonic stem cells may be grown in vivo and stimulated to produce pancreatic -cells and later transplanted to the patient. Its success depends on response of the patients immune system and ability of the transplanted cells to proliferate, differentiate and integrate with the target tissue.

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Track 04: Novel Stem Cell Technologies:

Stem cell technology is a rapidly developing field that combines the efforts of cell biologists, geneticists, and clinicians and offers hope of effective treatment for a variety of malignant and non-malignant diseases. Stem cells are defined as totipotent progenitor cells capable of self-renewal and multilineage differentiation. Stem cells survive well and show stable division in culture, making them ideal targets for in vitro manipulation. Although early research has focused on haematopoietic stem cells, stem cells have also been recognised in other sites. Research into solid tissue stem cells has not made the same progress as that on haematopoietic stem cells.

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Track 05: Stem Cell Treatment:

Bone marrow transplant is the most extensively used stem-cell treatment, but some treatment derived from umbilical cord blood are also in use. Research is underway to develop various sources for stem cells, and to apply stem-cell treatments for neurodegenerative diseases and conditions, diabetes, heart disease, and other conditions.

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Track 06: Stem cell apoptosis and signal transduction:

Apoptosis is the process of programmed cell death (PCD) that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, chromosomal DNA fragmentation, and global mRNA decay. Most cytotoxic anticancer agents induce apoptosis, raising the intriguing possibility that defects in apoptotic programs contribute to treatment failure. Because the same mutations that suppress apoptosis during tumor development also reduce treatment sensitivity, apoptosis provides a conceptual framework to link cancer genetics with cancer therapy.

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Track 07: Stem Cell Biomarkers:

Molecular biomarkers serve as valuable tools to classify and isolate embryonic stem cells (ESCs) and to monitor their differentiation state by antibody-based techniques. ESCs can give rise to any adult cell type and thus offer enormous potential for regenerative medicine and drug discovery. A number of biomarkers, such as certain cell surface antigens, are used to assign pluripotent ESCs; however, accumulating evidence suggests that ESCs are heterogeneous in morphology, phenotype and function, thereby classified into subpopulations characterized by multiple sets of molecular biomarkers.

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Track 08: Cellular therapies:

Cellular therapy also called Cell therapy is therapy in which cellular material is injected into a patient, this generally means intact, living cells. For example, T cells capable of fighting cancer cells via cell-mediated immunity may be injected in the course of immunotherapy.

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InternationalConference on Genetic Counseling and Genomic MedicineAugust 11-12, 2016 Birmingham, UK;World Congress on Human GeneticsOctober 31- November 02, 2016 Valencia, Spain; InternationalConference on Molecular BiologyOctober 13-15, 2016 Dubai, UAE; 3rd InternationalConference on Genomics & PharmacogenomicsSeptember 21-23, 2015 San Antonio, USA; EuropeanConference on Genomics and Personalized MedicineApril 25-27, 2016 Valencia, Spain;Genomics and Personalized Medicine, Feb 711 2016, Banff, Canada; Drug Discovery for Parasitic Diseases, Jan 2428 2016, Tahoe City, USA; Heart Failure: Genetics,Genomics and Epigenetics, April 37 2016, Snowbird, USA; Understanding the Function ofHuman Genome Variation, May 31 June 4 2016, Uppsala, Sweden; 5thDrug Formulation SummitJan2527,2016,Philadelphia, USA

Track 09: Stem cells and cancer:

Cancer can be defined as a disease in which a group of abnormal cells grow uncontrollably by disregarding the normal rules of cell division. Normal cells are constantly subject to signals that dictate whether the cells should divide, differentiate into another cell or die. Cancer cells develop a degree of anatomy from these signals, resulting in uncontrolled growth and proliferation. If this proliferation is allowed to continue and spread, it can be fatal.

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2ndWorld Congress on Applied MicrobiologyOctober 31-November 02, 2016 Istanbul, Turkey; InternationalConference on Infectious Diseases & Diagnostic MicrobiologyOct 3-5, 2016 Vancouver, Canada;18th International conference on Neuroscience, April 26 2016, Sweden, Austria; 6th Annual Traumatic Brain Injury Conference, May 1112 2016, Washington, D.C., USA; Common Mechanisms of Neurodegeneration, June 1216 2016, Keystone, USA; Neurology Caribbean Cruise, Aug 2128 2016, Fort Lauderdale, USA; Annual Meeting of the German Society ofNeurosurgery(DGNC), June 1215 2016, Frankfurt am Main, Germany

Track 10: Embryonic stem cells:

Embryonic stem cells have a major potential for studying early steps of development and for use in cell therapy. In many situations, however, it will be necessary to genetically engineer these cells. A novel generation of lentivectors which permit easy genetic engineering of mouse and human embryonic stem cells.

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4thCongress on Bacteriology and Infectious DiseasesMay 16-18, 2016 San Antonio, USA; 2ndWorld Congress on Applied MicrobiologyOctober 31-November 02, 2016 Istanbul, Turkey; InternationalConference on Infectious Diseases & Diagnostic MicrobiologyOct 3-5, 2016 Vancouver, Canada; InternationalConference on Water MicrobiologyJuly 18-20, 2016 Chicago, USA; 5th InternationalConference on Clinical MicrobiologyOctober 24-26, 2016 Rome, Italy; Axons: FromCell Biologyto Pathology Conference, 2427 January 2016, Santa Fe, USA; 26th EuropeanCongress of Clinical MicrobiologyApril 912 2016, Istanbul, Turkey;Conference on Gut Microbiota, Metabolic Disorders and Beyond, April 1721 2016, Newport, USA; 7th EuropeanSpores Conference, April 1820 2016, Egham, UK; New Approaches to Vaccines forHuman and Veterinary Tropical Diseases, May 2226 2016, Cape Town, South Africa

Track 11: Cell differentiation and disease modeling:

Cellular differentiation is the progression, whereas a cell changes from one cell type to another. Variation occurs numerous times during the development of a multicellular organism as it changes from a simple zygote to a complex system of tissues and cell types. Differentiation continues in adulthood as adult stem cells divide and create fully differentiated daughter cells during tissue repair and during normal cell turnover. Some differentiation occurs in response to antigen exposure. Differentiation dramatically changes a cell's size, shape, membrane potential, metabolic activity, and responsiveness to signals. These changes are largely due to highly controlled modifications in gene expression and are the study of epigenetics. With a few exceptions, cellular differentiationalmost never involves a change in the DNA sequence itself. Thus, different cells can have very different physical characteristics despite having the same genome.

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4thCongress on Bacteriology and Infectious DiseasesMay 16-18, 2016 San Antonio, USA; 2ndWorld Congress on Applied MicrobiologyOctober 31-November 02, 2016 Istanbul, Turkey; InternationalConference on Infectious Diseases & Diagnostic MicrobiologyOct 3-5, 2016 Vancouver, Canada; InternationalConference on Water MicrobiologyJuly 18-20, 2016 Chicago, USA; 5thInternationalConference on Clinical MicrobiologyOctober 24-26, 2016 Rome, Italy; Axons: FromCell Biologyto Pathology Conference, 2427 January 2016, Santa Fe, USA; 26thEuropeanCongress of Clinical MicrobiologyApril 912 2016, Istanbul, Turkey;Conference on Gut Microbiota, Metabolic Disorders and Beyond, April 1721 2016, Newport, USA; 7thEuropeanSpores Conference, April 1820 2016, Egham, UK; New Approaches toVaccines forHuman and Veterinary Tropical Diseases, May 2226 2016, Cape Town, South Africa

Track 12: Tissue engineering:

Tissue Engineering is the study of the growth of new connective tissues, or organs, from cells and a collagenous scaffold to produce a fully functional organ for implantation back into the donor host. Powerful developments in the multidisciplinary field of tissue engineering have produced a novel set of tissue replacement parts and implementation approaches. Scientific advances in biomaterials, stem cells, growth and differentiation factors, and biomimetic environments have created unique opportunities to fabricate tissues in the laboratory from combinations of engineered extracellular matrices cells, and biologically active molecules.

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4thCongress on Bacteriology and Infectious DiseasesMay 16-18, 2016 San Antonio, USA; 2ndWorld Congress on Applied MicrobiologyOctober 31-November 02, 2016 Istanbul, Turkey; InternationalConference on Infectious Diseases & Diagnostic MicrobiologyOct 3-5, 2016 Vancouver, Canada; InternationalConference on Water MicrobiologyJuly 18-20, 2016 Chicago, USA; 5thInternationalConference on Clinical MicrobiologyOctober 24-26, 2016 Rome, Italy; Axons: FromCell Biologyto Pathology Conference, 2427 January 2016, Santa Fe, USA; 26thEuropeanCongress of Clinical MicrobiologyApril 912 2016, Istanbul, Turkey;Conference on Gut Microbiota, Metabolic Disorders and Beyond, April 1721 2016, Newport, USA; 7thEuropeanSpores Conference, April 1820 2016, Egham, UK; New Approaches toVaccines forHuman and Veterinary Tropical Diseases, May 2226 2016, Cape Town, South Africa

Track 13: Stem cell plasticity and reprogramming:

Stem cell plasticity denotes to the potential of stem cells to give rise to cell types, previously considered outside their normal repertoire of differentiation for the location where they are found. Included under this umbrella title is often the process of transdifferentiation the conversion of one differentiated cell type into another, and metaplasia the conversion of one tissue type into another. From the point of view of this entry, some metaplasias have a clinical significance because they predispose individuals to the development of cancer.

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InternationalConference on Case ReportsMarch 31-April 02, 2016 Valencia, Spain; 2nd International Meeting onClinical Case ReportsApril 18-20, 2016 Dubai, UAE; 3rd Experts Meeting onMedical Case ReportsMay 09-11, 2016 New Orleans, Louisiana, USA; 12thEuro BiotechnologyCongress November 7-9, 2016 Alicante, Spain; 2nd International Conference onTissue preservation and BiobankingSeptember 12-13, 2016 Philadelphia, USA; 11thWorld Conference BioethicsOctober 20-22, 2015 Naples, Italy;Annual Conference Health Law and Bioethics, May 6-7 2016 Cambridge, MA, USA; 27th Maclean Conference on Clinical Medical Ethics, Nov 13-14, 2015, Chicago, USA; CFP: Global Forum on Bioethics in Research, Nov 3-4, 2015, Annecy, France

Track 14: Gene therapy and stem cells

Gene therapy is the therapeutic delivery of nucleic acid polymers into a patient's cells as a drug to treat disease. Gene therapy could be a way to fix a genetic problem at its source. The polymers are either expressed as proteins, interfere with protein expression, or possibly correct genetic mutations. In the future, this technique may allow doctors to treat a disorder by inserting a gene into a patient's cells instead of using drugs or surgery.

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Track 15: Tumour cell science:

An abnormal mass of tissue. Tumors are a classic sign of inflammation, and can be benign or malignant. Tomour usually reflect the kind of tissue they arise in. Treatment is also specific to the location and type of the tumor. Benign tumors can sometimes simply be ignored, cancerous tumors; options include chemotherapy, radiation, and surgery.

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Track 16: Reprogramming stem cells: computational biology

Computational Biology, sometimes referred to as bioinformatics, is the science of using biological data to develop algorithms and relations among various biological systems. Bioinformatics groups use computational methods to explore the molecular mechanisms underpinning stem cells. To accomplish this bioinformaticsdevelop and apply advanced analysis techniques that make it possible to dissect complex collections of data from a wide range of technologies and sources.

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The fields of stem cell biology and regenerative medicine research are fundamentally about understanding dynamic cellular processes such as development, reprogramming, repair, differentiation and the loss, acquisition or maintenance of pluripotency. In order to precisely decipher these processes at a molecular level, it is critical to identify and study key regulatory genes and transcriptional circuits. Modern high-throughput molecular profiling technologies provide a powerful approach to addressing these questions as they allow the profiling of tens of thousands of gene products in a single experiment. Whereas bioinformatics is used to interpret the information produced by such technologies.

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8th World Congress on Cell & Stem Cell Research

The success of the 7 Cell Science conferences series has given us the prospect to bring the gathering one more time for our 8thWorld Congress 2017 meet in Orlando, USA. Since its commencement in 2011 cell science series has perceived around 750 researchers of great potentials and outstanding research presentations around the globe. The awareness of stem cells and its application is increasing among the general population that also in parallel offers hope and add woes to the researchers of cell science due to the potential limitations experienced in the real-time.

Stem Cell Research-2017has the goal to fill the prevailing gaps in the transformation of this science of hope to promptly serve solutions to all in the need.World Congress 2017 will have an anticipated participation of 100-120 delegates from around the world to discuss the conference goal.

History of Stem cells Research

Stem cells have an interesting history, in the mid-1800s it was revealed that cells were basically the building blocks of life and that some cells had the ability to produce other cells. Efforts were made to fertilize mammalian eggs outside of the human body and in the early 1900s, it was discovered that some cells had the capacity to generate blood cells. In 1968, the first bone marrow transplant was achieved successfully to treat two siblings with severe combined immunodeficiency. Other significant events in stem cell research include:

1978: Stem cells were discovered in human cord blood 1981: First in vitro stem cell line developed from mice 1988: Embryonic stem cell lines created from a hamster 1995: First embryonic stem cell line derived from a primate 1997: Cloned lamb from stem cells 1997: Leukaemia origin found as haematopoietic stem cell, indicating possible proof of cancer stem cells

Funding in USA:

No federal law forever did embargo stem cell research in the United States, but only placed restrictions on funding and use, under Congress's power to spend. By executive order on March 9, 2009, President Barack Obama removed certain restrictions on federal funding for research involving new lines of humanembryonic stem cells. Prior to President Obama's executive order, federal funding was limited to non-embryonic stem cell research and embryonic stem cell research based uponembryonic stem celllines in existence prior to August 9, 2001. In 2011, a United States District Court "threw out a lawsuit that challenged the use of federal funds for embryonic stem cell research.

Members Associated with Stem Cell Research:

Discussion on Development, Regeneration, and Stem Cell Biology takes an interdisciplinary approach to understanding the fundamental question of how a single cell, the fertilized egg, ultimately produces a complex fully patterned adult organism, as well as the intimately related question of how adult structures regenerate. Stem cells play critical roles both during embryonic development and in later renewal and repair. More than 65 faculties in Philadelphia from both basic science and clinical departments in the Division of Biological Sciences belong to Development, Regeneration, and Stem Cell Biology. Their research uses traditional model species including nematode worms, fruit-flies, Arabidopsis, zebrafish, amphibians, chick and mouse as well as non-traditional model systems such as lampreys and cephalopods. Areas of research focus include stem cell biology, regeneration, developmental genetics, and cellular basis of development, developmental neurobiology, and evo-devo (Evolutionary developmental biology).

Stem Cell Market Value:

Worldwide many companies are developing and marketing specialized cell culture media, cell separation products, instruments and other reagents for life sciences research. We are providing a unique platform for the discussions between academia and business.

Global Tissue Engineering & Cell Therapy Market, By Region, 2009 2018

$Million

Why to attend???

Stem Cell Research-2017 could be an outstanding event that brings along a novel and International mixture of researchers, doctors, leading universities and stem cell analysis establishments creating the conference an ideal platform to share knowledge, adoptive collaborations across trade and world, and assess rising technologies across the world. World-renowned speakers, the most recent techniques, tactics, and the newest updates in cell science fields are assurances of this conference.

A Unique Opportunity for Advertisers and Sponsors at this International event:

http://stemcell.omicsgroup.com/sponsors.php

UAS Major Universities which deals with Stem Cell Research

University of Washington/Hutchinson Cancer Center

Oregon Stem Cell Center

University of California Davis

University of California San Francisco

University of California Berkeley

Stanford University

Mayo Clinic

Major Stem Cell Organization Worldwide:

Norwegian Center for Stem Cell Research

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Stem Cell Conferences | Cell and Stem Cell Congress | Stem ...

One of the institute's research goals is to explore the potential of using embryonic stem cells to better understand and treat disease. Unlike adult stem cells, embryonic , or pluripotent, stem cells are not restricted to any particular tissue or organ and are capable of producing all cell types. By studying how these cells develop into mature cells, such as those that make up our bone, blood and skin, researchers can learn how those cells function and what goes wrong when they are diseased.

With this understanding, researchers aim to develop new medical strategies capable of extending the capacity for growth and healing present in embryos into later stages of life. Such strategies would regenerate or replenish tissues or specialized cells damaged by Alzheimer's, cancer and other chronic, debilitating and often fatal diseases.

At Stanford, pluripotent stem cells have already been used experimentally to treat mice with diabetes. Researchers found a set of growth factors that induced pluripotent stem cells to develop into insulin-producing cells normally found in the pancreas. When they implanted these cells into diabetic mice that have lost the ability to produce insulin, the implanted cells produced insulin in a biologically normal way and treated the diabetes. This work is still in the early stages of being tested in animals, but could one day lead to new ways of treating diabetes in people.

Pluripotent stem cells, like adult brain stem cells, might also replace nerves damaged in spinal cord injuries or cells lost in neurodegenerative diseases. For any of these treatments to work, researchers have to first learn how to grow the stem cells in a lab so they take on the characteristics of the cells they are meant to replace. At this time it isn't clear whether pluripotent or adult stem cells will be best in this type of therapy.

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Human Embryonic Stem Cells Research Stem Cell Biology

Adult stem cell function declines with age leading to the decline in fitness

The potential therapeutic use of stem cells is a very hot topic these days. Most of the attention has focused on embryonic stem cells and induced Pluripotent Stem cells (iPS cells), which can form every tissue type in the body to regenerate failing organs. The problem is that detailed knowledge is lacking for how to stimulate the embryonic stem cells to form differentiated tissues (e.g. cells that form the heart, pancreas, muscle, and brain). Moreover, because embryonic stem cells are unlimited in their ability to form any type of tissue, the risk of cancer looms large over the therapeutic use of embryonic stem cells. For example, both embryonic and IPS stem cells can form tumors called teratomas when injected into immune-compromised mice. Enter the bodys adult stem cells, which have not generally been associated with cancer and have been used safely as therapeutics in many countries. The problem with adult stem cells is that it is difficult to get enough of them to be effective for most indications or target the harvested adult stem cells to the proper tissue. Moreover, there are scores of different types of adult stem cells in the body, so picking the best type of adult stem cell for a particular therapeutic can be challenging. Thus, adult stem cell therapeutics with all its potential to regenerate damaged organs and tissues is still a work in progress.

But what about the many populations of endogenous adult stem cells that everyone has embedded in every organ system of the body? All the organs and differing tissues of the body appear to have adult stem cells available for regenerating cells in case of injury or disease. It was recently discovered that even brain neurons and heart muscle cells (previously thought to be non-dividing and irreplaceable in adults) have their own reservoirs of adult stem cells for regeneration. Unfortunately, as we age most adult stem cell populations either decline in number and/or lose the ability to differentiate into functional tissue-specific cells. For example, cardiac muscle stem cells exist but old folks have only one half the number of cardiac stem cells found in young people. Thus, adult stem cells become more and more dysfunction with age, which progressively increases organ and tissue dysfunction with age.

There are many examples revealing the role of adult stem cells in aging. First, the outer surface of your skin continuously sloughs off dead cells, so that adult stem cells must continuously replenish the dying skin cells to maintain the skin as an effective protective barrier to the outside world. With age, there are progressively fewer functional skin stem cells, so cell turnover in the skin slows, leading to thinner, dryer skin that loses its elasticity and youthful beauty. Second, hair also thins and goes grey, as functional follicle stem cell decline and the adult stem cells generating hair color also decline. Third, the differing adult stem cells that maintain the tissues composing skeletal muscle, pancreas, heart, bone, liver, kidney, and the immune system lose functional capacity, raising the potential for decline in tissue function or outright failure with age. As a final example, the five senses of sight, hearing, smell, taste, and touch slowly wane with age, as the declining stem cell populations responsible for maintaining these functions are unable to fully replenish the sensory neurons after injury and random cell death.

If your own adult stem cells are a key factor in aging and disease, then one novel way to slow aging and disease is to stimulate your own adult stem cells to maintain their proper numbers and functional capacity to differentiate into the various tissues as needed for repair and regeneration. This makes sense, because in most, if not all, organs of the body, old cells are continually being replaced by new cells coming from the adult stem cell populations. If stem cells are not producing enough new cells, then organs slowly decline in function as you age. Thus, stimulating your own stem cells can be a winning strategy to stave off many of the disorders associated with aging.

In practice, however, stimulating adult stem cell populations in the body is not a simple task. If the proliferation of adult stem cells is over stimulated, then one may get overgrowth of tissues or a potential tumor. Alternatively, one may stimulate the stem cells to proliferate in a balanced and regulated way, but the stem cells lose functionality and cannot differentiate into the desired specialized tissues to replace senescent cells. These twin problems promoting over stimulation or dysfunctional stem cells put real limits on any proposed therapeutic for stimulating stem cells. For example, most current treatments to stimulate immunity or stem cells (nave T cells) rely on complex carbohydrates from mushrooms or microorganisms to provide antigenic material that can stimulate immunity. This will activate the immune system stem cells to make more differentiated non-stem memory T cells directed against the antigenic material, but it does nothing to stimulate more immune stem cells (nave T cells). Indeed, chronic use of such stem cell enhancers may actually lead to stem cell depletion, as more adult stem cells are exhausted from the requirement to respond to the constant presence of the polysaccharide antigen. Indeed, one theory of how the HIV virus causes a defective immune system is that it exhausts the supply of nave T cells by the repeated attacks of the mutating HIV virus.

Stem Cell 100TM is a nutraceutical supplement that improves the function of your existing stem cells rather than over stimulate stem cells to differentiate or divide. By promoting the stability and vitality of adult stem cells they have the capacity to divide when the body signals a need for more stem cells and differentiated cells. When an organ or tissue is damaged, it will send out natural signals that new cells are needed to replace old or damaged cells. Stem Cell 100TM allows the adult stem cells to respond to the damage signal by provided new differentiated cells to replace the old damaged cells and also make more adult stem cells to keep up the stem cell population. Two other compounds in Stem Cell 100TM provide further natural support for stem cells.

(Note that not everyone will experience the same effects, as conditions vary among individuals. The general expectation is that for most health measurements that are in the Normal Range for your age, Stem Cell 100TM will promote readings that you had when some 20 years younger.)

The statements above have not been reviewed by the FDA. Stem Cell 100TM is not meant as a preventive or treatment for any disease.

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Stem Cells and Aging | Life Code

Induced stem cells (iSC) are stem cells artificially derived from somatic, reproductive, pluripotent or other cell types by deliberate epigenetic reprogramming. They are classified as either totipotent (iTC), pluripotent (iPSC) or progenitor (multipotentiMSC, also called an induced multipotent progenitor celliMPC) or unipotent -- (iUSC) according to their developmental potential and degree of dedifferentiation. Progenitors are obtained by so-called direct reprogramming or directed differentiation and are also called induced somatic stem cells.

Three techniques are widely recognized:[1]

In 1895 Thomas Morgan removed one of the two frog blastomeres and found that amphibians are able to form whole embryo from the remaining part. This meant that the cells can change their differentiation pathway. Later, in 1924, Spemann and Mangold demonstrated the key importance of cellcell inductions during animal development.[20] The reversible transformation of cells of one differentiated cell type to another is called metaplasia.[21] This transition can be a part of the normal maturation process, or caused by an inducing stimulus. For example: transformation of iris cells to lens cells in the process of maturation and transformation of retinal pigment epithelium cells into the neural retina during regeneration in adult newt eyes. This process allows the body to replace cells not suitable to new conditions with more suitable new cells. In Drosophila imaginal discs, cells have to choose from a limited number of standard discrete differentiation states. The fact that transdetermination (change of the path of differentiation) often occurs for a group of cells rather than single cells shows that it is induced rather than part of maturation.[22]

The researchers were able to identify the minimal conditions and factors that would be sufficient for starting the cascade of molecular and cellular processes to instruct pluripotent cells to organize the embryo. They showed that opposing gradients of bone morphogenetic protein (BMP) and Nodal, two transforming growth factor family members that act as morphogens, are sufficient to induce molecular and cellular mechanisms required to organize, in vivo or in vitro, uncommitted cells of the zebrafish blastula animal pole into a well-developed embryo.[23]

Some types of mature, specialized adult cells can naturally revert to stem cells. For example, "chief" cells express the stem cell marker Troy. While they normally produce digestive fluids for the stomach, they can revert into stem cells to make temporary repairs to stomach injuries, such as a cut or damage from infection. Moreover, they can make this transition even in the absence of noticeable injuries and are capable of replenishing entire gastric units, in essence serving as quiescent reserve stem cells.[24] Differentiated airway epithelial cells can revert into stable and functional stem cells in vivo.[25]

After injury, mature terminally differentiated kidney cells dedifferentiate into more primordial versions of themselves, and then differentiate into the cell types needing replacement in the damaged tissue[26] Macrophages can self-renew by local proliferation of mature differentiated cells.[27] In newts, muscle tissue is regenerated from specialized muscle cells that dedifferentiate and forget the type of cell they had been. This capacity to regenerate does not decline with age and may be linked to their ability to make new stem cells from muscle cells on demand.[28]

A variety of nontumorigenic stem cells display the ability to generate multiple cell types. For instance, multilineage-differentiating stress-enduring (Muse) cells are stress-tolerant adult human stem cells that can self-renew. They form characteristic cell clusters in suspension culture that express a set of genes associated with pluripotency and can differentiate into endodermal, ectodermal and mesodermal cells both in vitro and in vivo.[29][30][31][32][33]

Other well-documented examples of transdifferentiation and their significance in development and regeneration were described in detail.[34]

Induced totipotent cells can be obtained by reprogramming somatic cells with somatic-cell nuclear transfer (SCNT). The process involves sucking out the nucleus of a somatic (body) cell and injecting it into an oocyte that has had its nucleus removed[3][5][35][36]

Using an approach based on the protocol outlined by Tachibana et al.,[3] hESCs can be generated by SCNT using dermal fibroblasts nuclei from both a middle-aged 35-year-old male and an elderly, 75-year-old male, suggesting that age-associated changes are not necessarily an impediment to SCNT-based nuclear reprogramming of human cells.[37] Such reprogramming of somatic cells to a pluripotent state holds huge potentials for regenerative medicine. Unfortunately, the cells generated by this technology, potentially are not completely protected from the immune system of the patient (donor of nuclei), because they have the same mitochondrial DNA, as a donor of oocytes, instead of the patients mitochondrial DNA. This reduces their value as a source for autologous stem cell transplantation therapy, as for the present, it is not clear whether it can induce an immune response of the patient upon treatment.

Induced androgenetic haploid embryonic stem cells can be used instead of sperm for cloning. These cells, synchronized in M phase and injected into the oocyte can produce viable offspring.[38]

These developments, together with data on the possibility of unlimited oocytes from mitotically active reproductive stem cells,[39] offer the possibility of industrial production of transgenic farm animals. Repeated recloning of viable mice through a SCNT method that includes a histone deacetylase inhibitor, trichostatin, added to the cell culture medium,[40] show that it may be possible to reclone animals indefinitely with no visible accumulation of reprogramming or genomic errors[41] However, research into technologies to develop sperm and egg cells from stem cells raises bioethical issues.[42]

Such technologies may also have far-reaching clinical applications for overcoming cytoplasmic defects in human oocytes.[3][43] For example, the technology could prevent inherited mitochondrial disease from passing to future generations. Mitochondrial genetic material is passed from mother to child. Mutations can cause diabetes, deafness, eye disorders, gastrointestinal disorders, heart disease, dementia and other neurological diseases. The nucleus from one human egg has been transferred to another, including its mitochondria, creating a cell that could be regarded as having two mothers. The eggs were then fertilised, and the resulting embryonic stem cells carried the swapped mitochondrial DNA.[44] As evidence that the technique is safe author of this method points to the existence of the healthy monkeys that are now more than four years old and are the product of mitochondrial transplants across different genetic backgrounds.[45]

In late-generation telomerase-deficient (Terc/) mice, SCNT-mediated reprogramming mitigates telomere dysfunction and mitochondrial defects to a greater extent than iPSC-based reprogramming.[46]

Other cloning and totipotent transformation achievements have been described.[47]

Recently some researchers succeeded to get the totipotent cells without the aid of SCNT. Totipotent cells were obtained using the epigenetic factors such as oocyte germinal isoform of histone.[48] Reprogramming in vivo, by transitory induction of the four factors Oct4, Sox2, Klf4 and c-Myc in mice, confers totipotency features. Intraperitoneal injection of such in vivo iPS cells generates embryo-like structures that express embryonic and extraembryonic (trophectodermal) markers.[49]

iPSc were first obtained in the form of transplantable teratocarcinoma induced by grafts taken from mouse embryos.[50] Teratocarcinoma formed from somatic cells.[51]Genetically mosaic mice were obtained from malignant teratocarcinoma cells, confirming the cells' pluripotency.[52][53][54] It turned out that teratocarcinoma cells are able to maintain a culture of pluripotent embryonic stem cell in an undifferentiated state, by supplying the culture medium with various factors.[55] In the 1980s, it became clear that transplanting pluripotent/embryonic stem cells into the body of adult mammals, usually leads to the formation of teratomas, which can then turn into a malignant tumor teratocarcinoma.[56] However, putting teratocarcinoma cells into the embryo at the blastocyst stage, caused them to become incorporated in the inner cell mass and often produced a normal chimeric (i.e. composed of cells from different organisms) animal.[57][58][59] This indicated that the cause of the teratoma is a dissonance - mutual miscommunication between young donor cells and surrounding adult cells (the recipient's so-called "niche").

In August 2006, Japanese researchers circumvented the need for an oocyte, as in SCNT. By reprograming mouse embryonic fibroblasts into pluripotent stem cells via the ectopic expression of four transcription factors, namely Oct4, Sox2, Klf4 and c-Myc, they proved that the overexpression of a small number of factors can push the cell to transition to a new stable state that is associated with changes in the activity of thousands of genes.[7]

Reprogramming mechanisms are thus linked, rather than independent and are centered on a small number of genes.[60] IPSC properties are very similar to ESCs.[61] iPSCs have been shown to support the development of all-iPSC mice using a tetraploid (4n) embryo,[62] the most stringent assay for developmental potential. However, some genetically normal iPSCs failed to produce all-iPSC mice because of aberrant epigenetic silencing of the imprinted Dlk1-Dio3 gene cluster.[18]

An important advantage of iPSC over ESC is that they can be derived from adult cells, rather than from embryos. Therefore, it became possible to obtain iPSC from adult and even elderly patients.[9][63][64]

Reprogramming somatic cells to iPSC leads to rejuvenation. It was found that reprogramming leads to telomere lengthening and subsequent shortening after their differentiation back into fibroblast-like derivatives.[65] Thus, reprogramming leads to the restoration of embryonic telomere length,[66] and hence increases the potential number of cell divisions otherwise limited by the Hayflick limit.[67]

However, because of the dissonance between rejuvenated cells and the surrounding niche of the recipient's older cells, the injection of his own iPSC usually leads to an immune response,[68] which can be used for medical purposes,[69] or the formation of tumors such as teratoma.[70] The reason has been hypothesized to be that some cells differentiated from ESC and iPSC in vivo continue to synthesize embryonic protein isoforms.[71] So, the immune system might detect and attack cells that are not cooperating properly.

A small molecule called MitoBloCK-6 can force the pluripotent stem cells to die by triggering apoptosis (via cytochrome c release across the mitochondrial outer membrane) in human pluripotent stem cells, but not in differentiated cells. Shortly after differentiation, daughter cells became resistant to death. When MitoBloCK-6 was introduced to differentiated cell lines, the cells remained healthy. The key to their survival, was hypothesized to be due to the changes undergone by pluripotent stem cell mitochondria in the process of cell differentiation. This ability of MitoBloCK-6 to separate the pluripotent and differentiated cell lines has the potential to reduce the risk of teratomas and other problems in regenerative medicine.[72]

In 2012 other small molecules (selective cytotoxic inhibitors of human pluripotent stem cellshPSCs) were identified that prevented human pluripotent stem cells from forming teratomas in mice. The most potent and selective compound of them (PluriSIn #1) inhibits stearoyl-coA desaturase (the key enzyme in oleic acid biosynthesis), which finally results in apoptosis. With the help of this molecule the undifferentiated cells can be selectively removed from culture.[73][74] An efficient strategy to selectively eliminate pluripotent cells with teratoma potential is targeting pluripotent stem cell-specific antiapoptotic factor(s) (i.e., survivin or Bcl10). A single treatment with chemical survivin inhibitors (e.g., quercetin or YM155) can induce selective and complete cell death of undifferentiated hPSCs and is claimed to be sufficient to prevent teratoma formation after transplantation.[75] However, it is unlikely that any kind of preliminary clearance,[76] is able to secure the replanting iPSC or ESC. After the selective removal of pluripotent cells, they re-emerge quickly by reverting differentiated cells into stem cells, which leads to tumors.[77] This may be due to the disorder of let-7 regulation of its target Nr6a1 (also known as Germ cell nuclear factor - GCNF), an embryonic transcriptional repressor of pluripotency genes that regulates gene expression in adult fibroblasts following micro-RNA miRNA loss.[78]

Teratoma formation by pluripotent stem cells may be caused by low activity of PTEN enzyme, reported to promote the survival of a small population (0,1-5% of total population) of highly tumorigenic, aggressive, teratoma-initiating embryonic-like carcinoma cells during differentiation. The survival of these teratoma-initiating cells is associated with failed repression of Nanog as well as a propensity for increased glucose and cholesterol metabolism.[79] These teratoma-initiating cells also expressed a lower ratio of p53/p21 when compared to non-tumorigenic cells.[80] In connection with the above safety problems, the use iPSC for cell therapy is still limited.[81] However, they can be used for a variety of other purposes - including the modeling of disease,[82] screening (selective selection) of drugs, toxicity testing of various drugs.[83]

It is interesting to note that the tissue grown from iPSCs, placed in the "chimeric" embryos in the early stages of mouse development, practically do not cause an immune response (after the embryos have grown into adult mice) and are suitable for autologous transplantation[84] At the same time, full reprogramming of adult cells in vivo within tissues by transitory induction of the four factors Oct4, Sox2, Klf4 and c-Myc in mice results in teratomas emerging from multiple organs.[49] Furthermore, partial reprogramming of cells toward pluripotency in vivo in mice demonstrates that incomplete reprogramming entails epigenetic changes (failed repression of Polycomb targets and altered DNA methylation) in cells that drive cancer development.[85]

By using solely small molecules, Deng Hongkui and colleagues demonstrated that endogenous master genes are enough for cell fate reprogramming. They induced a pluripotent state in adult cells from mice using seven small-molecule compounds.[17] The effectiveness of the method is quite high: it was able to convert 0.02% of the adult tissue cells into iPSCs, which is comparable to the gene insertion conversion rate. The authors note that the mice generated from CiPSCs were "100% viable and apparently healthy for up to 6 months. So, this chemical reprogramming strategy has potential use in generating functional desirable cell types for clinical applications.[87][88]

In 2015th year a robust chemical reprogramming system was established with a yield up to 1,000-fold greater than that of the previously reported protocol. So, chemical reprogramming became a promising approach to manipulate cell fates.[89]

The fact that human iPSCs capable of forming teratomas not only in humans but also in some animal body, in particular in mice or pigs, allowed to develop a method for differentiation of iPSCs in vivo. For this purpose, iPSCs with an agent for inducing differentiation into target cells are injected to genetically modified pig or mouse that has suppressed immune system activation on human cells. The formed after a while teratoma is cut out and used for the isolation of the necessary differentiated human cells[90] by means of monoclonal antibody to tissue-specific markers on the surface of these cells. This method has been successfully used for the production of functional myeloid, erythroid, and lymphoid human cells suitable for transplantation (yet only to mice).[91] Mice engrafted with human iPSC teratoma-derived hematopoietic cells produced human B and T cells capable of functional immune responses. These results offer hope that in vivo generation of patient customized cells is feasible, providing materials that could be useful for transplantation, human antibody generation, and drug screening applications. Using MitoBloCK-6 [72] and / or PluriSIn # 1 the differentiated progenitor cells can be further purified from teratoma forming pluripotent cells. The fact, that the differentiation takes place even in the teratoma niche, offers hope that the resulting cells are sufficiently stable to stimuli able to cause their transition back to the dedifferentiated (pluripotent) state, and therefore safe. A similar in vivo differentiation system, yielding engraftable hematopoietic stem cells from mouse and human iPSCs in teratoma-bearing animals in combination with a maneuver to facilitate hematopoiesis, was described by Suzuki et al.[92] They noted that neither leukemia nor tumors were observed in recipients after intravenous injection of iPSC-derived hematopoietic stem cells into irradiated recipients. Moreover, this injection resulted in multilineage and long-term reconstitution of the hematolymphopoietic system in serial transfers. Such system provides a useful tool for practical application of iPSCs in the treatment of hematologic and immunologic diseases.[93]

For further development of this method animal in which is grown the human cell graft, for example mouse, must have so modified genome that all its cells express and have on its surface human SIRP.[94] To prevent rejection after transplantation to the patient of the allogenic organ or tissue, grown from the pluripotent stem cells in vivo in the animal, these cells should express two molecules: CTLA4-Ig, which disrupts T cell costimulatory pathways, and PD-L1, which activates T cell inhibitory pathway.[95]

See also: US 20130058900 patent.

In the near-future, clinical trials designed to demonstrate the safety of the use of iPSCs for cell therapy of the people with age-related macular degeneration, a disease causing blindness through retina damaging, will begin. There are several articles describing methods for producing retinal cells from iPSCs[96][97] and how to use them for cell therapy.[98][99] Reports of iPSC-derived retinal pigmented epithelium transplantation showed enhanced visual-guided behaviors of experimental animals for 6 weeks after transplantation.[100] However, clinical trials have been successful: ten patients suffering from retinitis pigmentosa have had their eyesight restoredincluding a woman who had only 17 percent of her vision left. [101]

Chronic lung diseases such as idiopathic pulmonary fibrosis and cystic fibrosis or chronic obstructive pulmonary disease and asthma are leading causes of morbidity and mortality worldwide with a considerable human, societal, and financial burden. So there is an urgent need for effective cell therapy and lung tissue engineering.[102][103] Several protocols have been developed for generation of the most cell types of the respiratory system, which may be useful for deriving patient-specific therapeutic cells.[104][105][106][107][108]

Some lines of iPSCs have the potentiality to differentiate into male germ cells and oocyte-like cells in an appropriate niche (by culturing in retinoic acid and porcine follicular fluid differentiation medium or seminiferous tubule transplantation). Moreover, iPSC transplantation make a contribution to repairing the testis of infertile mice, demonstrating the potentiality of gamete derivation from iPSCs in vivo and in vitro.[109]

The risk of cancer and tumors creates the need to develop methods for safer cell lines suitable for clinical use. An alternative approach is so-called "direct reprogramming" - transdifferentiation of cells without passing through the pluripotent state.[110][111][112][113][114][115] The basis for this approach was that 5-azacytidine - a DNA demethylation reagent - can cause the formation of myogenic, chondrogenic and adipogeni clones in the immortal cell line of mouse embryonic fibroblasts[116] and that the activation of a single gene, later named MyoD1, is sufficient for such reprogramming.[117] Compared with iPSC whose reprogramming requires at least two weeks, the formation of induced progenitor cells sometimes occurs within a few days and the efficiency of reprogramming is usually many times higher. This reprogramming does not always require cell division.[118] The cells resulting from such reprogramming are more suitable for cell therapy because they do not form teratomas.[115]

Originally only early embryonic cells could be coaxed into changing their identity. Mature cells are resistant to changing their identity once they've committed to a specific kind. However, brief expression of a single transcription factor, the ELT-7 GATA factor, can convert the identity of fully differentiated, specialized non-endodermal cells of the pharynx into fully differentiated intestinal cells in intact larvae and adult roundworm Caenorhabditis elegans with no requirement for a dedifferentiated intermediate.[119]

Another way of reprogramming is the simulation of the processes that occur during amphibian limb regeneration. In urodele amphibians, an early step in limb regeneration is skeletal muscle fiber dedifferentiation into a cellulate that proliferates into limb tissue. However, sequential small molecule treatment of the muscle fiber with myoseverin, reversine (the aurora B kinase inhibitor) and some other chemicals: BIO (glycogen synthase-3 kinase inhibitor), lysophosphatidic acid (pleiotropic activator of G-protein-coupled receptors), SB203580 (p38 MAP kinase inhibitor), or SQ22536 (adenylyl cyclase inhibitor) causes the formation of new muscle cell types as well as other cell types such as precursors to fat, bone and nervous system cells.[120]

The researchers discovered that GCSF-mimicking antibody can activate a growth-stimulating receptor on marrow cells in a way that induces marrow stem cells that normally develop into white blood cells to become neural progenitor cells. The technique[121] enables researchers to search large libraries of antibodies and quickly select the ones with a desired biological effect.[122]

Schlegel and Liu[123] demonstrated that the combination of feeder cells[124][125][126] and a Rho kinase inhibitor (Y-27632) [127][128] induces normal and tumor epithelial cells from many tissues to proliferate indefinitely in vitro. This process occurs without the need for transduction of exogenous viral or cellular genes. These cells have been termed "Conditionally Reprogrammed Cells (CRC)". The induction of CRCs is rapid and results from reprogramming of the entire cell population. CRCs do not express high levels of proteins characteristic of iPSCs or embryonic stem cells (ESCs) (e.g., Sox2, Oct4, Nanog, or Klf4). This induction of CRCs is reversible and removal of Y-27632 and feeders allows the cells to differentiate normally.[123][129][130] CRC technology can generate 2106 cells in 5 to 6 days from needle biopsies and can generate cultures from cryopreserved tissue and from fewer than four viable cells. CRCs retain a normal karyotype and remain nontumorigenic. This technique also efficiently establishes cell cultures from human and rodent tumors.[123][131][132]

The ability to rapidly generate many tumor cells from small biopsy specimens and frozen tissue provides significant opportunities for cell-based diagnostics and therapeutics (including chemosensitivity testing) and greatly expands the value of biobanking.[123][131][132] Using CRC technology, researchers were able to identify an effective therapy for a patient with a rare type of lung tumor.[133] Engleman's group [134] describes a pharmacogenomic platform that facilitates rapid discovery of drug combinations that can overcome resistance using CRC system. In addition, the CRC method allows for the genetic manipulation of epithelial cells ex vivo and their subsequent evaluation in vivo in the same host. While initial studies revealed that co-culturing epithelial cells with Swiss 3T3 cells J2 was essential for CRC induction, with transwell culture plates, physical contact between feeders and epithelial cells is not required for inducing CRCs, and more importantly that irradiation of the feeder cells is required for this induction. Consistent with the transwell experiments, conditioned medium induces and maintains CRCs, which is accompanied by a concomitant increase of cellular telomerase activity. The activity of the conditioned medium correlates directly with radiation-induced feeder cell apoptosis. Thus, conditional reprogramming of epithelial cells is mediated by a combination of Y-27632 and a soluble factor(s) released by apoptotic feeder cells.[135]

Riegel et al.[136] demonstrate that mouse ME cells isolated from normal mammary glands or from mouse mammary tumor virus (MMTV)-Neuinduced mammary tumors, can be cultured indefinitely as conditionally reprogrammed cells (CRCs). Cell surface progenitor-associated markers are rapidly induced in normal mouse ME-CRCs relative to ME cells. However, the expression of certain mammary progenitor subpopulations, such as CD49f+ ESA+ CD44+, drops significantly in later passages. Nevertheless, mouse ME-CRCs grown in a three-dimensional extracellular matrix gave rise to mammary acinar structures. ME-CRCs isolated from MMTV-Neu transgenic mouse mammary tumors express high levels of HER2/neu, as well as tumor-initiating cell markers, such as CD44+, CD49f+, and ESA+ (EpCam). These patterns of expression are sustained in later CRC passages. Early and late passage ME-CRCs from MMTV-Neu tumors that were implanted in the mammary fat pads of syngeneic or nude mice developed vascular tumors that metastasized within 6 weeks of transplantation. Importantly, the histopathology of these tumors was indistinguishable from that of the parental tumors that develop in the MMTV-Neu mice. Application of the CRC system to mouse mammary epithelial cells provides an attractive model system to study the genetics and phenotype of normal and transformed mouse epithelium in a defined culture environment and in vivo transplant studies.

A different approach to CRC is to inhibit CD47 - a membrane protein that is the thrombospondin-1 receptor. Loss of CD47 permits sustained proliferation of primary murine endothelial cells, increases asymmetric division, and enables these cells to spontaneously reprogram to form multipotent embryoid body-like clusters. CD47 knockdown acutely increases mRNA levels of c-Myc and other stem cell transcription factors in cells in vitro and in vivo. Thrombospondin-1 is a key environmental signal that inhibits stem cell self-renewal via CD47. Thus, CD47 antagonists enable cell self-renewal and reprogramming by overcoming negative regulation of c-Myc and other stem cell transcription factors.[137] In vivo blockade of CD47 using an antisense morpholino increases survival of mice exposed to lethal total body irradiation due to increased proliferative capacity of bone marrow-derived cells and radioprotection of radiosensitive gastrointestinal tissues.[138]

Indirect lineage conversion is a reprogramming methodology in which somatic cells transition through a plastic intermediate state of partially reprogrammed cells (pre-iPSC), induced by brief exposure to reprogramming factors, followed by differentiation in a specially developed chemical environment (artificial niche).[139]

This method could be both more efficient and safer, since it does not seem to produce tumors or other undesirable genetic changes, and results in much greater yield than other methods. However, the safety of these cells remains questionable. Since lineage conversion from pre-iPSC relies on the use of iPSC reprogramming conditions, a fraction of the cells could acquire pluripotent properties if they do not stop the de-differentation process in vitro or due to further de-differentiation in vivo.[140]

A common feature of pluripotent stem cells is the specific nature of protein glycosylation of their outer membrane. That distinguishes them from most nonpluripotent cells, although not white blood cells.[141] The glycans on the stem cell surface respond rapidly to alterations in cellular state and signaling and are therefore ideal for identifying even minor changes in cell populations. Many stem cell markers are based on cell surface glycan epitopes including the widely used markers SSEA-3, SSEA-4, Tra 1-60, and Tra 1-81.[142] Suila Heli et al.[143] speculate that in human stem cells extracellular O-GlcNAc and extracellular O-LacNAc, play a crucial role in the fine tuning of Notch signaling pathway - a highly conserved cell signaling system, that regulates cell fate specification, differentiation, leftright asymmetry, apoptosis, somitogenesis, angiogenesis, and plays a key role in stem cell proliferation (reviewed by Perdigoto and Bardin[144] and Jafar-Nejad et al.[145])

Changes in outer membrane protein glycosylation are markers of cell states connected in some way with pluripotency and differentiation.[146] The glycosylation change is apparently not just the result of the initialization of gene expression, but perform as an important gene regulator involved in the acquisition and maintenance of the undifferentiated state.[147]

For example, activation of glycoprotein ACA,[148] linking glycosylphosphatidylinositol on the surface of the progenitor cells in human peripheral blood, induces increased expression of genes Wnt, Notch-1, BMI1 and HOXB4 through a signaling cascade PI3K/Akt/mTor/PTEN, and promotes the formation of a self-renewing population of hematopoietic stem cells.[149]

Furthermore, dedifferentiation of progenitor cells induced by ACA-dependent signaling pathway leads to ACA-induced pluripotent stem cells, capable of differentiating in vitro into cells of all three germ layers.[150] The study of lectins' ability to maintain a culture of pluripotent human stem cells has led to the discovery of lectin Erythrina crista-galli (ECA), which can serve as a simple and highly effective matrix for the cultivation of human pluripotent stem cells.[151]

Cell adhesion protein E-cadherin is indispensable for a robust pluripotent phenotype.[152] During reprogramming for iPS cell generation, N-cadherin can replace function of E-cadherin.[153] These functions of cadherins are not directly related to adhesion because sphere morphology helps maintaining the "stemness" of stem cells.[154] Moreover, sphere formation, due to forced growth of cells on a low attachment surface, sometimes induces reprogramming. For example, neural progenitor cells can be generated from fibroblasts directly through a physical approach without introducing exogenous reprogramming factors.

Physical cues, in the form of parallel microgrooves on the surface of cell-adhesive substrates, can replace the effects of small-molecule epigenetic modifiers and significantly improve reprogramming efficiency. The mechanism relies on the mechanomodulation of the cells epigenetic state. Specifically, "decreased histone deacetylase activity and upregulation of the expression of WD repeat domain 5 (WDR5)a subunit of H3 methyltranferaseby microgrooved surfaces lead to increased histone H3 acetylation and methylation". Nanofibrous scaffolds with aligned fibre orientation produce effects similar to those produced by microgrooves, suggesting that changes in cell morphology may be responsible for modulation of the epigenetic state.[155]

Substrate rigidity is an important biophysical cue influencing neural induction and subtype specification. For example, soft substrates promote neuroepithelial conversion while inhibiting neural crest differentiation of hESCs in a BMP4-dependent manner. Mechanistic studies revealed a multi-targeted mechanotransductive process involving mechanosensitive Smad phosphorylation and nucleocytoplasmic shuttling, regulated by rigidity-dependent Hippo/YAP activities and actomyosin cytoskeleton integrity and contractility.[156]

Mouse embryonic stem cells (mESCs) undergo self-renewal in the presence of the cytokine leukemia inhibitory factor (LIF). Following LIF withdrawal, mESCs differentiate, accompanied by an increase in cellsubstratum adhesion and cell spreading. Restricted cell spreading in the absence of LIF by either culturing mESCs on chemically defined, weakly adhesive biosubstrates, or by manipulating the cytoskeleton allowed the cells to remain in an undifferentiated and pluripotent state. The effect of restricted cell spreading on mESC self-renewal is not mediated by increased intercellular adhesion, as inhibition of mESC adhesion using a function blocking anti E-cadherin antibody or siRNA does not promote differentiation.[157] Possible mechanisms of stem cell fate predetermination by physical interactions with the extracellular matrix have been described.[158][159]

Cells involved in the reprogramming process change morphologically as the process proceeds. This results in physical difference in adhesive forces among cells. Substantial differences in 'adhesive signature' between pluripotent stem cells, partially reprogrammed cells, differentiated progeny and somatic cells allowed to develop separation process for isolation of pluripotent stem cells in microfluidic devices,[160] which is: fast (separation takes less than 10 minutes); efficient (separation results in a greater than 95 percent pure iPS cell culture); innocuous (cell survival rate is greater than 80 percent and the resulting cells retain normal transcriptional profiles, differentiation potential and karyotype).

Stem cells possess mechanical memory (they remember past physical signals)with the Hippo signaling pathway factors:[161] Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding domain (TAZ) acting as an intracellular mechanical rheostatthat stores information from past physical environments and influences the cells fate.[162][163]

Stroke and many neurodegenerative disorders such as Parkinson's disease, Alzheimers disease, amyotrophic lateral sclerosis need cell replacement therapy. The successful use of converted neural cells (cNs) in transplantations open a new avenue to treat such diseases.[164] Nevertheless, induced neurons (iNs), directly converted from fibroblasts are terminally committed and exhibit very limited proliferative ability that may not provide enough autologous donor cells for transplantation.[165] Self-renewing induced neural stem cells (iNSCs) provide additional advantages over iNs for both basic research and clinical applications.[113][114][115][166][167]

For example, under specific growth conditions, mouse fibroblasts can be reprogrammed with a single factor, Sox2, to form iNSCs that self-renew in culture and after transplantation can survive and integrate without forming tumors in mouse brains.[168] INSCs can be derived from adult human fibroblasts by non-viral techniques, thus offering a safe method for autologous transplantation or for the development of cell-based disease models.[167]

Neural chemically induced progenitor cells (ciNPCs) can be generated from mouse tail-tip fibroblasts and human urinary somatic cells without introducing exogenous factors, but - by a chemical cocktail, namely VCR (V, VPA, an inhibitor of HDACs; C, CHIR99021, an inhibitor of GSK-3 kinases and R, RepSox, an inhibitor of TGF beta signaling pathways), under a physiological hypoxic condition.[169] Alternative cocktails with inhibitors of histone deacetylation, glycogen synthase kinase, and TGF- pathways (where: sodium butyrate (NaB) or Trichostatin A (TSA) could replace VPA, Lithium chloride (LiCl) or lithium carbonate (Li2CO3) could substitute CHIR99021, or Repsox may be replaced with SB-431542 or Tranilast) show similar efficacies for ciNPC induction.[169]

Multiple methods of direct transformation of somatic cells into induced neural stem cells have been described.[170]

Proof of principle experiments demonstrate that it is possible to convert transplanted human fibroblasts and human astrocytes directly in the brain that are engineered to express inducible forms of neural reprogramming genes, into neurons, when reprogramming genes (Ascl1, Brn2a and Myt1l) are activated after transplantation using a drug.[171]

Astrocytesthe most common neuroglial brain cells, which contribute to scar formation in response to injurycan be directly reprogrammed in vivo to become functional neurons that formed networks in mice without the need of cell transplantation.[172] The researchers followed the mice for nearly a year to look for signs of tumor formation and reported finding none. The same researchers have turned scar-forming astrocytes into progenitor cells called neuroblasts that regenerated into neurons in the injured adult spinal cord.[173]

Without myelin to insulate neurons, nerve signals quickly lose power. Diseases that attack myelin, such as multiple sclerosis, result in nerve signals that cannot propagate to nerve endings, and as a consequence lead to cognitive, motor and sensory problems. Transplantation of oligodendrocyte precursor cells (OPCs), which can successfully create myelin sheaths around nerve cells, is a promising potential therapeutic response. Direct lineage conversion of mouse and rat fibroblasts into oligodendroglial cells provides a potential source of OPCs. Conversion by forced expression of both eight[174] or of the three[175] transcription factors Sox10, Olig2 and Zfp536, may provide such cells.

Cell-based in vivo therapies may provide a transformative approach to augment vascular and muscle growth and to prevent non-contractile scar formation by delivering transcription factors[110] or microRNAs[14] to the heart.[176] Cardiac fibroblasts, which represent 50% of the cells in the mammalian heart, can be reprogrammed into cardiomyocyte-like cells in vivo by local delivery of cardiac core transcription factors ( GATA4, MEF2C, TBX5 and for improved reprogramming plus ESRRG, MESP1, Myocardin and ZFPM2) after coronary ligation.[110][177] These results implicated therapies that can directly remuscularize the heart without cell transplantation. However, the efficiency of such reprogramming turned out to be very low and the phenotype of received cardiomyocyte-like cells does not resemble those of a mature normal cardiomyocyte. Furthermore, transplantation of cardiac transcription factors into injured murine hearts resulted in poor cell survival and minimal expression of cardiac genes.[178]

Meanwhile, advances in the methods of obtaining cardiac myocytes in vitro occurred.[179][180] Efficient cardiac differentiation of human iPS cells gave rise to progenitors that were retained within infarcted rat hearts, and reduced remodeling of the heart after ischemic damage.[181]

Furthermore, ischemic cardiomyopathy in the murine infarction model was targeted by iPS cell transplantation. It synchronized failing ventricles, offering a regenerative strategy to achieve resynchronization and protection from decompensation by dint of improved left ventricular conduction and contractility, reduced scarring and reversal of structural remodelling.[182] One protocol generated populations of up to 98% cardiomyocytes from hPSCs simply by modulating the canonical Wnt signaling pathway at defined time points in during differentiation, using readily accessible small molecule compounds.[183]

Discovery of the mechanisms controlling the formation of cardiomyocytes led to the development of the drug ITD-1, which effectively clears the cell surface from TGF- receptor type II and selectively inhibits intracellular TGF- signaling. It thus selectively enhances the differentiation of uncommitted mesoderm to cardiomyocytes, but not to vascular smooth muscle and endothelial cells.[184]

One project seeded decellularized mouse hearts with human iPSC-derived multipotential cardiovascular progenitor cells. The introduced cells migrated, proliferated and differentiated in situ into cardiomyocytes, smooth muscle cells and endothelial cells to reconstruct the hearts. In addition, the heart's extracellular matrix (the substrate of heart scaffold) signalled the human cells into becoming the specialised cells needed for proper heart function. After 20 days of perfusion with growth factors, the engineered heart tissues started to beat again and were responsive to drugs.[185]

See also: review[186]

The elderly often suffer from progressive muscle weakness and regenerative failure owing in part to elevated activity of the p38 and p38 mitogen-activated kinase pathway in senescent skeletal muscle stem cells. Subjecting such stem cells to transient inhibition of p38 and p38 in conjunction with culture on soft hydrogel substrates rapidly expands and rejuvenates them that result in the return of their strength.[187]

In geriatric mice, resting satellite cells lose reversible quiescence by switching to an irreversible pre-senescence state, caused by derepression of p16INK4a (also called Cdkn2a). On injury, these cells fail to activate and expand, even in a youthful environment. p16INK4a silencing in geriatric satellite cells restores quiescence and muscle regenerative functions.[188]

Myogenic progenitors for potential use in disease modeling or cell-based therapies targeting skeletal muscle could also be generated directly from induced pluripotent stem cells using free-floating spherical culture (EZ spheres) in a culture medium supplemented with high concentrations (100ng/ml) of fibroblast growth factor-2 (FGF-2) and epidermal growth factor.[189]

Unlike current protocols for deriving hepatocytes from human fibroblasts, Saiyong Zhu et al., (2014)[190] did not generate iPSCs but, using small molecules, cut short reprogramming to pluripotency to generate an induced multipotent progenitor cell (iMPC) state from which endoderm progenitor cells and subsequently hepatocytes (iMPC-Heps) were efficiently differentiated. After transplantation into an immune-deficient mouse model of human liver failure, iMPC-Heps proliferated extensively and acquired levels of hepatocyte function similar to those of human primary adult hepatocytes. iMPC-Heps did not form tumours, most probably because they never entered a pluripotent state.

These results establish the feasibility of significant liver repopulation of mice with human hepatocytes generated in vitro, which removes a long-standing roadblock on the path to autologous liver cell therapy.

Complications of Diabetes mellitus such as cardiovascular diseases, retinopathy, neuropathy, nephropathy, and peripheral circulatory diseases depend on sugar dysregulation due to lack of insulin from pancreatic beta cells and can be lethal if they are not treated. One of the promising approaches to understand and cure diabetes is to use pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced PCSs (iPSCs).[191] Unfortunately, human PSC-derived insulin-expressing cells resemble human fetal cells rather than adult cells. In contrast to adult cells, fetal cells seem functionally immature, as indicated by increased basal glucose secretion and lack of glucose stimulation and confirmed by RNA-seq of whose transcripts.[192]

An alternative strategy is the conversion of fibroblasts towards distinct endodermal progenitor cell populations and, using cocktails of signalling factors, successful differentiation of these endodermal progenitor cells into functional beta-like cells both in vitro and in vivo.[193]

Overexpression of the three transcription factors, PDX1 (required for pancreatic bud outgrowth and beta-cell maturation), NGN3 (required for endocrine precursor cell formation) and MAFA (for beta-cell maturation) combination (called PNM) can lead to the transformation of some cell types into a beta cell-like state.[194] An accessible and abundant source of functional insulin-producing cells is intestine. PMN expression in human intestinal organoids stimulates the conversion of intestinal epithelial cells into -like cells possibly acceptable for transplantation.[195]

Adult proximal tubule cells were directly transcriptionally reprogrammed to nephron progenitors of the embryonic kidney, using a pool of six genes of instructive transcription factors (SIX1, SIX2, OSR1, Eyes absent homolog 1(EYA1), Homeobox A11 (HOXA11) and Snail homolog 2 (SNAI2)) that activated genes consistent with a cap mesenchyme/nephron progenitor phenotype in the adult proximal tubule cell line.[196] The generation of such cells may lead to cellular therapies for adult renal disease. Embryonic kidney organoids placed into adult rat kidneys can undergo onward development and vascular development.[197]

As blood vessels age, they often become abnormal in structure and function, thereby contributing to numerous age-associated diseases including myocardial infarction, ischemic stroke and atherosclerosis of arteries supplying the heart, brain and lower extremities. So, an important goal is to stimulate vascular growth for the collateral circulation to prevent the exacerbation of these diseases. Induced Vascular Progenitor Cells (iVPCs) are useful for cell-based therapy designed to stimulate coronary collateral growth. They were generated by partially reprogramming endothelial cells.[139] The vascular commitment of iVPCs is related to the epigenetic memory of endothelial cells, which engenders them as cellular components of growing blood vessels. That is why, when iVPCs were implanted into myocardium, they engrafted in blood vessels and increased coronary collateral flow better than iPSCs, mesenchymal stem cells, or native endothelial cells.[198]

Ex vivo genetic modification can be an effective strategy to enhance stem cell function. For example, cellular therapy employing genetic modification with Pim-1 kinase (a downstream effector of Akt, which positively regulates neovasculogenesis) of bone marrowderived cells[199] or human cardiac progenitor cells, isolated from failing myocardium[200] results in durability of repair, together with the improvement of functional parameters of myocardial hemodynamic performance.

Stem cells extracted from fat tissue after liposuction may be coaxed into becoming progenitor smooth muscle cells (iPVSMCs) found in arteries and veins.[201]

The 2D culture system of human iPS cells[202] in conjunction with triple marker selection (CD34 (a surface glycophosphoprotein expressed on developmentally early embryonic fibroblasts), NP1 (receptor - neuropilin 1) and KDR (kinase insert domain-containing receptor)) for the isolation of vasculogenic precursor cells from human iPSC, generated endothelial cells that, after transplantation, formed stable, functional mouse blood vessels in vivo, lasting for 280 days.[203]

To treat infarction, it is important to prevent the formation of fibrotic scar tissue. This can be achieved in vivo by transient application of paracrine factors that redirect native heart progenitor stem cell contributions from scar tissue to cardiovascular tissue. For example, in a mouse myocardial infarction model, a single intramyocardial injection of human vascular endothelial growth factor A mRNA (VEGF-A modRNA), modified to escape the body's normal defense system, results in long-term improvement of heart function due to mobilization and redirection of epicardial progenitor cells toward cardiovascular cell types.[204]

RBC transfusion is necessary for many patients. However, to date the supply of RBCs remains labile. In addition, transfusion risks infectious disease transmission. A large supply of safe RBCs generated in vitro would help to address this issue. Ex vivo erythroid cell generation may provide alternative transfusion products to meet present and future clinical requirements.[205][206] Red blood cells (RBC)s generated in vitro from mobilized CD34 positive cells have normal survival when transfused into an autologous recipient.[207] RBC produced in vitro contained exclusively fetal hemoglobin (HbF), which rescues the functionality of these RBCs. In vivo the switch of fetal to adult hemoglobin was observed after infusion of nucleated erythroid precursors derived from iPSCs.[208] Although RBCs do not have nuclei and therefore can not form a tumor, their immediate erythroblasts precursors have nuclei. The terminal maturation of erythroblasts into functional RBCs requires a complex remodeling process that ends with extrusion of the nucleus and the formation of an enucleated RBC.[209] Cell reprogramming often disrupts enucleation. Transfusion of in vitro-generated RBCs or erythroblasts does not sufficiently protect against tumor formation.

The aryl hydrocarbon receptor (AhR) pathway (which has been shown to be involved in the promotion of cancer cell development) plays an important role in normal blood cell development. AhR activation in human hematopoietic progenitor cells (HPs) drives an unprecedented expansion of HPs, megakaryocyte- and erythroid-lineage cells.[210] See also Concise Review:[211][212]

Platelets help prevent hemorrhage in thrombocytopenic patients and patients with thrombocythemia. A significant problem for multitransfused patients is refractoriness to platelet transfusions. Thus, the ability to generate platelet products ex vivo and platelet products lacking HLA antigens in serum-free media would have clinical value. An RNA interference-based mechanism used a lentiviral vector to express short-hairpin RNAi targeting 2-microglobulin transcripts in CD34-positive cells. Generated platelets demonstrated an 85% reduction in class I HLA antigens. These platelets appeared to have normal function in vitro[213]

One clinically-applicable strategy for the derivation of functional platelets from human iPSC involves the establishment of stable immortalized megakaryocyte progenitor cell lines (imMKCLs) through doxycycline-dependent overexpression of BMI1 and BCL-XL. The resulting imMKCLs can be expanded in culture over extended periods (45 months), even after cryopreservation. Halting the overexpression (by the removal of doxycycline from the medium) of c-MYC, BMI1 and BCL-XL in growing imMKCLs led to the production of CD42b+ platelets with functionality comparable to that of native platelets on the basis of a range of assays in vitro and in vivo.[214]

A specialised type of white blood cell, known as cytotoxic T lymphocytes (CTLs), are produced by the immune system and are able to recognise specific markers on the surface of various infectious or tumour cells, causing them to launch an attack to kill the harmful cells. Thence, immunotherapy with functional antigen-specific T cells has potential as a therapeutic strategy for combating many cancers and viral infections.[215] However, cell sources are limited, because they are produced in small numbers naturally and have a short lifespan.

A potentially efficient approach for generating antigen-specific CTLs is to revert mature immune T cells into iPSCs, which possess indefinite proliferative capacity in vitro, and after their multiplication to coax them to redifferentiate back into T cells.[216][217][218]

Another method combines iPSC and chimeric antigen receptor (CAR) [219] technologies to generate human T cells targeted to CD19, an antigen expressed by malignant B cells, in tissue culture.[220] This approach of generating therapeutic human T cells may be useful for cancer immunotherapy and other medical applications.

Invariant natural killer T (iNKT) cells have great clinical potential as adjuvants for cancer immunotherapy. iNKT cells act as innate T lymphocytes and serve as a bridge between the innate and acquired immune systems. They augment anti-tumor responses by producing interferon-gamma (IFN-).[221] The approach of collection, reprogramming/dedifferentiation, re-differentiation and injection has been proposed for related tumor treatment.[222]

Dendritic cells (DC) are specialized to control T-cell responses. DC with appropriate genetic modifications may survive long enough to stimulate antigen-specific CTL and after that be completely eliminated. DC-like antigen-presenting cells obtained from human induced pluripotent stem cells can serve as a source for vaccination therapy.[223]

CCAAT/enhancer binding protein- (C/EBP) induces transdifferentiation of B cells into macrophages at high efficiencies[224] and enhances reprogramming into iPS cells when co-expressed with transcription factors Oct4, Sox2, Klf4 and Myc.[225] with a 100-fold increase in iPS cell reprogramming efficiency, involving 95% of the population.[226] Furthermore, C/EBPa can convert selected human B cell lymphoma and leukemia cell lines into macrophage-like cells at high efficiencies, impairing the cells tumor-forming capacity.[227]

The thymus is the first organ to deteriorate as people age. This shrinking is one of the main reasons the immune system becomes less effective with age. Diminished expression of the thymic epithelial cell transcription factor FOXN1 has been implicated as a component of the mechanism regulating age-related involution.[228][229]

Clare Blackburn and colleagues show that established age-related thymic involution can be reversed by forced upregulation of just one transcription factor - FOXN1 in the thymic epithelial cells in order to promote rejuvenation, proliferation and differentiation of these cells into fully functional thymic epithelium.[230] This rejuvenation and increased proliferation was accompanied by upregulation of genes that promote cell cycle progression (cyclin D1, Np63, FgfR2IIIb) and that are required in the thymic epithelial cells to promote specific aspects of T cell development (Dll4, Kitl, Ccl25, Cxcl12, Cd40, Cd80, Ctsl, Pax1).

mesenchymal stem/stromal cells (MSCs) are under investigation for applications in cardiac, renal, neural, joint and bone repair, as well as in inflammatory conditions and hemopoietic cotransplantation.[231] This is because of their immunosuppressive properties and ability to differentiate into a wide range of mesenchymal-lineage tissues. MSCs are typically harvested from adult bone marrow or fat, but these require painful invasive procedures and are low-frequency sources, making up only 0.001% 0.01% of bone marrow cells and 0.05% in liposuction aspirates.[232] Of concern for autologous use, in particular in the elderly most in need of tissue repair, MSCs decline in quantity and quality with age.[231][233][234]

IPSCs could be obtained by the cells rejuvenation of even centenarians.[9][37] Because iPSCs can be harvested free of ethical constraints and culture can be expanded indefinitely, they are an advantageous source of MSCs.[235] IPSC treatment with SB-431542 leads to rapid and uniform MSC generation from human iPSCs. (SB-431542 is an inhibitor of activin/TGF- pathways by blocking phosphorylation of ALK4, ALK5, and ALK7 receptors.) These iPS-MSCs may lack teratoma-forming ability, display a normal stable karyotype in culture and exhibit growth and differentiation characteristics that closely resemble those of primary MSCs. It has potential for in vitro scale-up, enabling MSC-based therapies.[236] MSC derived from iPSC have the capacity to aid periodontal regeneration and are a promising source of readily accessible stem cells for use in the clinical treatment of periodontitis.[237][238]

Besides cell therapy in vivo, the culture of human mesenchymal stem cells can be used in vitro for mass-production of exosomes, which are ideal vehicles for drug delivery.[239]

Adipose tissue, because of its abundance and relatively less invasive harvest methods, represents a source of mesenchymal stem cells (MSCs). Unfortunately, liposuction aspirates are only 0.05% MSCs.[232] However, a large amount of mature adipocytes, which in general have lost their proliferative abilities and therefore are typically discarded, can be easily isolated from the adipose cell suspension and dedifferentiated into lipid-free fibroblast-like cells, named dedifferentiated fat (DFAT) cells. DFAT cells re-establish active proliferation ability and express multipotent capacities.[240] Compared with adult stem cells, DFAT cells show unique advantages in abundance, isolation and homogeneity. Under proper induction culture in vitro or proper environment in vivo, DFAT cells could demonstrate adipogenic, osteogenic, chondrogenic, and myogenic potentials. They could also exhibit perivascular characteristics and elicit neovascularization.[241][242][243]

Cartilage is the connective tissue responsible for frictionless joint movement. Its degeneration ultimately results in complete loss of joint function in the late stages of osteoarthritis. As an avascular and hypocellular tissue, cartilage has a limited capacity for self-repair. Chondrocytes are the only cell type in cartilage, in which they are surrounded by the extracellular matrix that they secrete and assemble.

One method of producing cartilage is to induce it from iPS cells.[244] Alternatively, it is possible to convert fibroblasts directly into induced chondrogenic cells (iChon) without an intermediate iPS cell stage, by inserting three reprogramming factors (c-MYC, KLF4, and SOX9).[245] Human iChon cells expressed marker genes for chondrocytes (type II collagen) but not fibroblasts.

Implanted into defects created in the articular cartilage of rats, human iChon cells survived to form cartilaginous tissue for at least four weeks, with no tumors. The method makes use of c-MYC, which is thought to have a major role in tumorigenesis and employs a retrovirus to introduce the reprogramming factors, excluding it from unmodified use in human therapy.[216][218][246]

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