Molecular discovery has potential to solve the billion-dollar global cost of poorly managed wound healing Medical Xpress
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Molecular discovery has potential to solve the billion-dollar global cost of poorly managed wound healing - Medical Xpress
Biotherapeutics
January 29, 2022
2021 has been a year of significant innovation across the field of regenerative medicine at Mayo Clinic. Important advancements in preclinical research, as well as new regenerative treatments for patients, further are solidifying Mayo Clinics reputation as a world-class leader in regenerative medicine.
Regenerative medicine is still a relatively new field of practice, representing a paradigm shift from the traditional focus of health care of fighting disease to rebuilding health. Mayo Clinic's Center for Regenerative Medicine is leveraging its unique expertise, resources and capabilities to create the worlds most advanced and innovative ecosystem for the development, manufacture and delivery of novel regenerative biotherapeutics.
New directions in biomanufacturing
Mayo Clinic is focused on a newly refreshed strategy in regenerative medicine this year one that emphasizes an enhanced capability for biomanufacturing, with technology platforms supporting the development of new therapeutics known as biologics. Biologics are a new type of "drug" derived from living organisms that have the potential for targeted healing with fewer side effects. Many of these next-generation therapeutics can be scaled and mass produced for patients at Mayo Clinic and around the world. The Center for Regenerative Medicine is leading Mayos enterprise biomanufacturing strategy in close collaboration with Research, Practice and Education leaders and key stakeholders, including theCancer Center,Center for Individualized Medicine,Department of Laboratory Medicine and Pathology,Mayo Clinic Ventures, Mayo ClinicPlatform,Center for Digital Healthand Mayo ClinicInternational.
In August, Mayo welcomed Julie Allickson, Ph.D., as the Michael S. and Mary Sue Shannon Family Director of Mayo Clinic's Center for Regenerative Medicine and the Otto Bremer Trust director of Biomanufacturing and Product Development in the Center for Regenerative Medicine, and she will lead the execution of Mayos biomanufacturing strategy. Dr. Allickson joined Mayo Clinic from the Institute for Regenerative Medicine at Wake Forest School of Medicine in North Carolina.
"This is an exciting time in regenerative medicine, a new era with great promise for the impact that these new therapies and procedures can have for patients," says Dr. Allickson. "I am looking forward to working collaboratively with colleagues across the enterprise to position Mayo Clinic as the global leader in scientific discovery and clinical practice advancement in regenerative medicine."
Significant investments in biomanufacturing facilities continued this year with the buildout of current Good Manufacturing Practices facilities on all three Mayo campuses.These facilities meet strict quality controls and regulatory guidelines that are required for manufacturing new biologics. The long-term goal is to have these new types of healing solutions on-site where they can be used immediately for patients with unmet needs. Mayo will focus on biomanufacturing across seven prioritized technology platforms:
Research that advances the practice
From helping establish common terminology for regenerative medicine to discovering new ways of manufacturing cardiopoietic stem cells with heart healing potential for select patients with advanced heart failure, Mayo Clinic physicians and scientists have made significant advancements in the discovery-translation-application continuum in regenerative medicine. Examples include:
Difficult-to-treat, chronic wounds healed with normal scar-free skin in preclinical models after treatment with an acellular product discovered at Mayo Clinic. Derived from platelets, the purified exosomal product, known as PEP, was used to deliver healing messages into cells of animal models of ischemic wounds. In a groundbreaking study published in Theranostics, the Mayo Clinic research team documented restoration of skin integrity, hair follicles, sweat glands, skin oils and normal hydration.
A Mayo Clinic collaborative study documented a remote-controlled bronchoscope functioned like a GPS system, tracking hard-to-find lung masses and accurately biopsying them. This multisite research, published in Annals of Thoracic Surgery, lays the foundation for precisely finding early stage cancer when it is most treatable, and targeting it with regenerative biotherapeutics needed to stimulate healing.
"In the past, we didn't have a reliable way of reaching these nodules in the lungs from within the airway. This is a very small catheter that gets almost anywhere, and is able to access and biopsy lung nodules," says Janani Reisenauer, M.D., first author on the study and a Mayo Clinic thoracic surgeon. "It's very similar to driving a car and having your normal street view with the aid of the GPS in your car telling you in real-time where to turn right and left to arrive at your destination."
Mayo Clinic researchers biomanufactured chimeric antigen receptor-T cell therapy (CAR-T cell therapy) in a new way to track the cells' cancer fighting journey and predict toxic side effects. This Mayo Clinic breakthrough, published in Cancer Immunology Research, could make this immunotherapy easier for patients to tolerate. Perhaps more importantly, it could unravel the mystery of how to expand CAR-T cell therapy to more types of cancers.
"This new technology allows us to image CAR-T cells after they are given to patients and study their fate," says Saad Kenderian, M.B., Ch.B., a Mayo Clinic hematologist and researcher, and lead author. "This allows us to investigate strategies that could improve CAR-T cell trafficking and penetration into the tumor cells, and thus canimprove tumor killing."
Mayo Clinic is applying regenerative medicine to cosmetic services aimed at resetting the body's clock to a time of more youthful function and appearance. Regenerative procedures, such as platelet-rich plasma to rejuvenate aging skin and stimulate hair growth for people with alopecia or baldness, are offered on all three campuses. Many regenerative services go beyond cosmetics to facial reconstruction after disease, cancer or traumatic injury. For example, The Multidisciplinary Cosmetic Center at Mayo Clinic in Arizona pairs general and facial plastic surgery with dermatologists, gynecologists, vascular surgeons, urologists and aestheticists to deliver services grounded in scientific evidence and the latest regenerative technologies.
Training the emerging regenerative sciences workforce
A well-trained regenerative science workforce is needed to apply the newest discoveries to clinical care. Mayo Clinic has made significant strides this past year in educating future physicians, scientists and allied health staff in regenerative medicine.
Mayo Clinic achieved an important milestone when it admitted its first five students as inaugural scholars in the newly established Regenerative Sciences Track within the Ph.D. program in the Mayo Clinic Graduate School of Biomedical Sciences. The new doctoral program that began this fall fulfills Mayo's objective of providing first-of-its-kind education in the evolving field of regenerative science and medicine
Taught by regenerative science and medicine experts, the curriculum embraces a training paradigm that includes fundamental cellular and molecular science principles, and transdisciplinary education in regulatory issues, quality control, bio-business and entrepreneurial pathways, data science, medical sciences, ethics, and emerging technologies.
Throughout the four-day symposium, experts at Mayo Clinic and around the world shared regenerative medicine applications to aging, musculoskeletal conditions, lung diseases, organ transplantation and cancer. The symposium featured presentations on promising research, navigating regulatory pathways and seeking opportunities for commercialization.
Peter Marks, M.D., Ph.D.,director of the Food and Drug Administration (FDA) Center for Biologics Evaluation made a virtual presentation where he pledged FDA support for regenerative technologies that offer new solutions for unmet patient needs.
Another promising year in 2022
Mayo Clinic in Arizona is among the first to offer larynx transplantation and is currently evaluating patients for this landmark surgery. In addition, Center for Regenerative Medicine continues to support initiatives, such as expanding of CAR-T therapy and making organ transplantation more available and successful for patients.
New advanced biomanufacturing facilities will be operational in One Discovery Square in Rochester and in the Discovery & Innovation Building in Florida. Biomanufacturing expansion on the Phoenix campus will be strategically assessed as the buildout of Arizona "Bold. Forward" continues. The Center for Regenerative Medicine continues to spur innovation to rapidly advance novel regenerative therapies into the clinic to support Mayo Clinic's 2030 Vision to cure, connect and transform care.
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Science Saturday: A year of new directions and advancements for ...
Biotherapeutics
January 13, 2021
Regenerative medicine has contributed to patient care in 2020 more than ever before, bolstered by synergies in research, practice and education. Mayo Clinic's Center for Regenerative Medicine is at the forefront of a biotherapy revolution in which health care advances from treating disease to restoring health.
"The centrality of the body to regenerate itself is paving the way for new horizons in regenerative care. The triad of protecting against disease, preventing disease progression and promoting healing is at the core of the regenerative vision," says Andre Terzic, M.D., Ph.D., director of Mayo Clinic's Center for Regenerative Medicine. "To this end, the regenerative toolkit has grown more robust over the past year with new technologies now available to boost the body's ability to repair and restore health of an organ and importantly of the patient as a whole."
The convergence of research, practice and education, empowered by strong innovation and advanced biomanufacturing, is creating an increased level of readiness for applying validated regenerative science to new areas of health care, Dr. Terzic says.
Practice advancement
A deeper understanding of the biology of health and disease is driving the ongoing regenerative medicine evolution.
"The remarkable progress in science that is advancing our fundamental comprehension of both health and disease has guided the informed and responsible development of patient-ready curative strategies," says Dr. Terzic.
New discoveries at Mayo Clinic that may shape future practice include:
The largest regenerative medicine clinical trial to date for heart failure, spanning 39 medical centers and 315 patients from 10 countries, validated the long-term safety of stem cell therapy. The late-stage research found stem cell therapy shows particular benefit for patients with advanced left ventricular enlargement. This Mayo Clinic-led study offers guidance on which patients are most likely to respond to stem cell therapy for heart failure.
Mayo Clinic researchers uncovered stem cell-activated molecular mechanisms of healing after a heart attack. Stem cells restored the makeup of failing cardiac muscle back to its condition before the heart attack, providing an intimate blueprint of how they may work to heal diseased tissue. This research offers utility to delineate and interpret complex regenerative outcomes.
Mayo Clinic research discovered a molecular switch that turns on a substance that repairs neurological damage. This early research could bolster a therapy approved by the Food and Drug Administration, and that could lead to new strategies for treating diseases of the central nervous system such as multiple sclerosis.
The federal regulatory environment is making it possible to more seamlessly integrate new discoveries into the practice. The 21st Century Cures Act, for example, seeks to create an accelerated path to market for safe, validated procedures that could provide new therapies for patients with serious conditions.
Examples of how that new regulatory environment is accelerating discoveries into regenerative care at Mayo Clinic are:
With FDA permission, Mayo Clinic performs surgery before birth to correct a congenital defect known as spina bifida. Spina bifida is a condition in which the spinal cord does not close properly. Fetal surgery at Mayo Clinic to repair the spinal cord not only closed the spine, but also restored brain structure. Clinical experience to date, published in Mayo Clinic Proceedings, concluded that fetal surgery to treat spina bifida is effective at early healing of neurological structures. Mayo continues to evaluate this regenerative procedure.
Mayo Clinic has FDA permission for investigational new drug use in regenerative surgery aimed at restoring damaged knee cartilage in a single surgical procedure. Bits of a patient's cartilage are recycled and mixed with donor mesenchymal stem cells. Mesenchymal stem cells are adult stem cells derived from sources such as fat tissue or bone marrow. Much like filling potholes in a street, the cellular mixture repairs holes within the cartilage. Mayo Clinic is treating patients with this surgery and hopes to make it available to patients more broadly within the coming year.
Mayo Clinic promotes responsible adoption of validated procedures. An example of this ongoing effort is a regenerative procedure that augments standard surgery for cancer.
Mayo Clinic orthopedic oncologists are teaming with plastic surgeons to restore muscle strength after some cancer surgeries, particularly surgery to remove soft tissue sarcoma. Advancements in microsurgery are making it possible to transfer large muscle to close a surgical wound where it functions like the muscle lost to cancer. This so-called "oncoregenerative" surgery combines free muscle transfers with pain management and lymphatic reconstruction, while preventing damaged nerves and lymph nodes that can cause pain and swelling.
Regenerative medicine know-how is advancing immunotherapy options for cancer patients, including chimeric antigen receptor-T cell therapy (CAR-T cell therapy). CAR-T cell therapy seeks to unleash the power of the immune system by genetically modifying cells, equipping them to go on search-and-destroy missions to kill cancer. These engineered cells act like a living drug, continually working within the body to cure disease.
"On-demand regenerative immunity is being built against blood cancers and is advancing how hemato-oncologists treat lymphomas and leukemias. We hope that regenerative sciences will discover and perfect ways to expand this treatment approach to solid cancers, as well," says Dr. Terzic.
Biomanufacturing and supply chain readiness
Mayo Clinic is on the cusp of validating new advanced biomanufacturing facilities where it will engineer the latest cellular, acellular and gene therapies needed for regenerative care. In doing so, Mayo is establishing its in-house supply chain, ensuring quality, and potentially saving time and resources.
Center for Regenerative Medicine has increased supply chain readiness in 2020 in these ways:
Supported by active research and development programs, Mayo Clinic is poised to test acellular healing products known as exosomes in the first clinical trials. Exosomes are extracellular vesicles that are like a delivery service moving cargo from one cell to another, with instructions for healing. It's an example of the emerging field of nanomedicine. Nanodrugs are very small structures that contain enveloped proteins and genetic materials that can be targeted to exact tissues in need of repair.
"Over the past five years, we discovered the healing potential of exosomes, established the science, and ultimately figured out how to manufacture them so that they would meet strict quality standards. Now we are ready to take the important step of introducing them in human safety trials," says Atta Behfar, M.D., Ph.D., deputy director of translation for Mayo Clinic's Center for Regenerative Medicine. "I think the evolution into nanomedicine as a regenerative tool is major milestone. Compared to more traditional living alternatives, these biological messages can be easier to store, ship, analyze and even manufacture."
Exosomes are an example of how Mayo Clinic is manufacturing new healing products that, unlike living stem cells, can be stored at room temperature on-site for immediate use in a hospital or clinic
"Technologies that can be stored at room temperature on the shelf provide the ability to introduce regenerative medicine into new areas of practice such as heart attack and stroke, where therapies need to be delivered on an emergent basis," says Dr. Behfar. "As we move forward, this type of accessibility may help to facilitate adoption of biologics-based therapies and continue to broaden our ability to offer innovative cures to patients in need."
New 3D printing capabilities at Mayo Clinic in Arizona are providing options to improve laryngeal or vocal fold function. For example, 3D printing is providing new ways to close the gap between vocal folds for people with glottic insufficiency a common but difficult-to-treat condition that causes problems with speaking, breathing and swallowing. A 3D implant is printed to fit the exact patient-specific dimensions of the vocal folds and implanted into the voicebox, where it improves voice, swallowing and breathing.
Mayo Clinic in Florida launched the CAR-T Translational Research program that aims to expand regenerative immunotherapy products beyond blood cancers, potentially to neurological and autoimmune disorders. Clinical-grade biotherapies can be manufactured on-site, which potentially will lower the cost and increase patient access to regenerative immunotherapies such as CAR-T cell therapy.
Workforce proficiency
Educating future physicians, scientists and the broader health care workforce to provide the latest, most innovative regenerative medicine technologies is a key objective of the Center for Regenerative Medicine. That strategic priority is reflected in the regenerative curricula that are integrated across each of the five schools of Mayo Clinic College of Medicine and Science.
"We are educating regenerative medicine practitioners who are grounded in scientific knowledge to responsibly translate the latest innovations into patient solutions. They are becoming a trusted source of regenerative care," says Dr. Terzic.
Advancements in training the future workforce in regenerative medicine and science include:
Mayo Clinic graduated the first students in the doctoral research training program known as the Regenerative Sciences Training Program. Established in 2017, this program combines laboratory research with training that covers the complete spectrum of discovery to translation topics.
Mayo Clinic launched one of the first-ever doctoral tracks in regenerative sciences in Mayo Clinic Graduate School of Biomedical Sciences. The curriculum will embrace a training paradigm that includes fundamental cellular and molecular science principles, and transdisciplinary education in regulatory issues, quality control, entrepreneurial pathways, data science, medical sciences, ethics and emerging technologies. Applications opened in the fall, and the first students will be admitted in fall 2021.
In recognition of the scholarly identify of regenerative medicine, Mayo Clinic elevated regenerative medicine to a field of academic rank. Implementing academic ranks paves the way for attracting a new community of dedicated physicians, scientists and engineers focused on advancing regenerative medicine.
"Regenerative medicine touches all medical, surgical, radiology and laboratory medicine specialties across Mayo Clinic. Establishing this new academic rank is like opening a new chapter in medicine. It is a key differentiator for Mayo Clinic," says Dr. Terzic.
Advancements to watch for in 2021
The opening of two major manufacturing facilities in Rochester and Jacksonville, Florida, will propel Mayo Clinic to a new realm of biomanufacturing and supply chain management of therapeutics for rare and complex medical conditions. The two facilities are cornerstones of a coordinated biomanufacturing strategy that positions Mayo Clinic to deliver first-in-the-world therapeutics produced on-site for use in research and practice. Together with industry partners, Mayo will accelerate these new regenerative products toward the market to benefit Mayo Clinic patients and others around the world.
Here are some specific examples of things to watch for:
The Center for Regenerative Medicine's advanced biomanufacturing facility is nearing completion at One Discovery Square in Rochester. The new facility is equipped with current Good Manufacturing Practices capable of producing clinical-grade regenerative therapies that are easily accessible for clinical trials and patient care. Biomanufacturing will focus on tissue engineering, cellular, acellular and gene therapy products.
Construction is complete on the Center for Regenerative Medicine's advanced biomanufacturing facility in the new Discovery and Innovation Building at Mayo Clinic in Florida. When fully operational, it will deploy current Good Manufacturing Practices facilities where new patient-ready immunotherapies can be manufactured under strict sterile quality control measures that meet FDA guidelines. That could eventually increase patient access to CAR-T cell therapy and other regenerative immunotherapies through clinical trials. On site manufacturing will reduce cost and broaden the access for this curative technology to Mayo patients suffering from lymphoma.
Mayo Clinic will conduct first-in-human safety and dosing studies of exosomes noncellular structures that deliver healing to damaged cells and tissues. After discovering, scaling and manufacturing exosomes, Mayo will evaluate them in the first human trials for wound healing and tissue repair after a heart attack.
Mayo Clinic is on track to launch one of the first-ever living donor cartilage banks. Mayo Clinic orthopedics and sports medicine surgeons, in collaboration with the Center for Regenerative Medicine, have validated methods to collect and store living cartilage tissue that would otherwise be discarded after knee replacement surgery. The donor cartilage bank will dramatically reduce wait times for this valuable tissue used to repair knee damage in younger patients with cartilage and bone damage in their knee.
Regenerative procedures may trigger healing of diseased tissues in some patients, but those therapies may not work for others. One of the key riddles regenerative medicine research seeks to crack is how to target patients who are most likely to benefit from restorative therapies.
"With the assimilation of data sets, we hope to decode the attributes that define regenerative responsiveness. That is the holy grail of regenerative medicine right now," says Dr. Terzic.
As 2020 wraps up and 2021 begins, Mayo Clinic seeks to further its understanding of regenerative medicine, and make new approved therapies accessible and affordable for all patients, particularly those with unmet needs and those in underserved communities.
Dr. Terzic is the Michael S. and Mary Sue Shannon Director, Mayo Clinic Center for Regenerative Medicine, and Marriott Family Professor in Cardiovascular Diseases Research.
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Diverse ways regenerative medicine is advancing health care
Exosomes and Stem Cells Are the Future of Anti-Aging NewBeauty Magazine
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Exosomes and Stem Cells Are the Future of Anti-Aging - NewBeauty Magazine
Global Organoids and Spheroids Market Set for Remarkable Growth, Reaching USD 7.70 Billion by 2034 with a CAGR ... GlobeNewswire
Growth Projections for the Regenerative Medicine Market BioProcess Insider
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Regenerative Medicine - Cell Therapies BioProcess Insider
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Transitioning from traditional surgical methods to the innovative use of stem cells pharmaphorum
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Transitioning from traditional surgical methods to the innovative use of stem cells - pharmaphorum
Stem Cell Investig. 2019; 6: 19.
1Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran;
2Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran;
2Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran;
3Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
1Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran;
2Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran;
3Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
Contributions: (I) Conception and design: E Fathi, R Farahzadi; (II) Administrative support: E Fathi, R Farahzadi; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: R Farahzadi, N Rajabzadeh; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.
#These authors contributed equally to this work.
Received 2018 Nov 11; Accepted 2019 Mar 17.
Recent developments in the stem cell biology provided new hopes in treatment of diseases and disorders that yet cannot be treated. Stem cells have the potential to differentiate into various cell types in the body during age. These provide new cells for the body as it grows, and replace specialized cells that are damaged. Since mesenchymal stem cells (MSCs) can be easily harvested from the adipose tissue and can also be cultured and expanded in vitro they have become a good target for tissue regeneration. These cells have been widespread used for cell transplantation in animals and also for clinical trials in humans. The purpose of this review is to provide a summary of our current knowledge regarding the important and types of isolated stem cells from different sources of animal models such as horse, pig, goat, dog, rabbit, cat, rat, mice etc. In this regard, due to the widespread use and lot of attention of MSCs, in this review, we will elaborate on use of MSCs in veterinary medicine as well as in regenerative medicine. Based on the studies in this field, MSCs found wide application in treatment of diseases, such as heart failure, wound healing, tooth regeneration etc.
Keywords: Mesenchymal stem cells (MSCs), animal model, cell-based therapy, regenerative medicine
Stem cells are one of the main cells of the human body that have ability to grow more than 200 types of body cells (1). Stem cells, as non-specialized cells, can be transformed into highly specialized cells in the body (2). In the other words, Stem cells are undifferentiated cells with self-renewal potential, differentiation into several types of cells and excessive proliferation (3). In the past, it was believed that stem cells can only differentiate into mature cells of the same organ. Today, there are many evidences to show that stem cells can differentiate into the other types of cell as well as ectoderm, mesoderm and endoderm. The numbers of stem cells are different in the tissues such as bone marrow, liver, heart, kidney, and etc. (3,4). Over the past 20 years, much attention has been paid to stem cell biology. Therefore, there was a profound increase in the understanding of its characteristics and the therapeutic potential for its application (5). Today, the utilization of these cells in experimental research and cell therapy represents in such disorders including hematological, skin regeneration and heart disease in both human and veterinary medicine (6).The history of stem cells dates back to the 1960s, when Friedenstein and colleagues isolated, cultured and differentiated to osteogenic cell lineage of bone marrow-derived cells from guinea pigs (7). This project created a new perspective on stem cell research. In the following, other researchers discovered that the bone marrow contains fibroblast-like cells with congenic potential in vitro, which were capable of forming colonies (CFU-F) (8). For over 60 years, transplantation of hematopoietic stem cells (HSCs) has been the major curative therapy for several genetic and hematological disorders (9). Almost in 1963, Till and McCulloch described a single progenitor cell type in the bone marrow which expand clonally and give rise to all lineages of hematopoietic cells. This research represented the first characterization of the HSCs (10). Also, the identification of mouse embryonic stem cells (ESCs) in 1981 revolutionized the study of developmental biology, and mice are now used extensively as one of the best option to study stem cell biology in mammals (11). Nevertheless, their application a model, have limitations in the regenerative medicine. But this model, relatively inexpensive and can be easily manipulated genetically (12). Failure to obtain a satisfactory result in the selection of many mouse models, to recapitulate particular human disease phenotypes, has forced researchers to investigate other animal species to be more probably predictive of humans (13). For this purpose, to study the genetic diseases, the pig has been currently determined as one the best option of a large animal model (14).
Stem cells, based on their differentiation ability, are classified into different cell types, including totipotent, pluripotent, multipotent, or unipotent. Also, another classification of these cells are based on the evolutionary stages, including embryonic, fetal, infant or umbilical cord blood and adult stem cells (15). shows an overview of stem cells classifications based on differentiation potency.
An overview of the stem cell classification. Totipotency: after fertilization, embryonic stem cells (ESCs) maintain the ability to form all three germ layers as well as extra-embryonic tissues or placental cells and are termed as totipotent. Pluripotency: these more specialized cells of the blastocyst stage maintain the ability to self-renew and differentiate into the three germ layers and down many lineages but do not form extra-embryonic tissues or placental cells. Multipotency: adult or somatic stem cells are undifferentiated cells found in postnatal tissues. These specialized cells are considered to be multipotent; with very limited ability to self-renew and are committed to lineage species.
Toti-potent cells have the potential for development to any type of cell found in the organism. In the other hand, the capacity of these cells to develop into the three primary germ cell layers of the embryo and into extra-embryonic tissues such as the placenta is remarkable (15).
The pluripotent stem cells are kind of stem cells with the potential for development to approximately all cell types. These cells contain ESCs and cells that are isolated from the mesoderm, endoderm and ectoderm germ layers that are organized in the beginning period of ESC differentiation (15).
The multipotent stem cells have less proliferative potential than the previous two groups and have ability to produce a variety of cells which limited to a germinal layer [such as mesenchymal stem cells (MSCs)] or just a specific cell line (such as HSCs). Adult stem cells are also often in this group. In the word, these cells have the ability to differentiate into a closely related family of cells (15).
Despite the increasing interest in totipotent and pluripotent stem cells, unipotent stem cells have not received the most attention in research. A unipotent stem cell is a cell that can create cells with only one lineage differentiation. Muscle stem cells are one of the example of this type of cell (15). The word uni is derivative from the Latin word unus meaning one. In adult tissues in comparison with other types of stem cells, these cells have the lowest differentiation potential. The unipotent stem cells could create one cell type, in the other word, these cells do not have the self-renewal property. Furthermore, despite their limited differentiation potential, these cells are still candidates for treatment of various diseases (16).
ESCs are self-renewing cells that derived from the inner cell mass of a blastocyst and give rise to all cells during human development. It is mentioned that these cells, including human embryonic cells, could be used as suitable, promising source for cell transplantation and regenerative medicine because of their unique ability to give rise to all somatic cell lineages (17). In the other words, ESCs, pluripotent cells that can differentiate to form the specialized of the various cell types of the body (18). Also, ESCs capture the imagination because they are immortal and have an almost unlimited developmental potential. Due to the ethical limitation on embryo sampling and culture, these cells are used less in research (19).
HSCs are multipotent cells that give rise to blood cells through the process of hematopoiesis (20). These cells reside in the bone marrow and replenish all adult hematopoietic lineages throughout the lifetime of the human and animal (21). Also, these cells can replenish missing or damaged components of the hematopoietic and immunologic system and can withstand freezing for many years (22).The mammalian hematopoietic system containing more than ten different mature cell types that HSCs are one of the most important members of this. The ability to self-renew and multi-potency is another specific feature of these cells (23).
Adult stem cells, as undifferentiated cells, are found in numerous tissues of the body after embryonic development. These cells multiple by cell division to regenerate damaged tissues (24). Recent studies have been shown that adult stem cells may have the ability to differentiate into cell types from various germ layers. For example, bone marrow stem cells which is derived from mesoderm, can differentiate into cell lineage derived mesoderm and endoderm such as into lung, liver, GI tract, skin, etc. (25). Another example of adult stem cells is neural stem cells (NSCs), which is derived from ectoderm and can be differentiate into another lineage such as mesoderm and endoderm (26). Therapeutic potential of adult stem cells in cell therapy and regenerative medicine has been proven (27).
For the first time in the late 1990s, CSCs were identified by John Dick in acute myeloid diseases. CSCs are cancerous cells that found within tumors or hematological cancers. Also, these cells have the characteristics of normal stem cells and can also give rise to all cell types found in a particular cancer sample (28). There is an increasing evidence supporting the CSCs hypothesis. Normal stem cells in an adult living creature are responsible for the repair and regeneration of damaged as well as aged tissues (29). Many investigations have reported that the capability of a tumor to propagate and proliferate relies on a small cellular subpopulation characterized by stem-like properties, named CSCs (30).
Embryonic connective tissue contains so-called mesenchymes, from which with very close interactions of endoderm and ectoderm all other connective and hematopoietic tissues originate, Whereas, MSCs do not differentiate into hematopoietic cell (31). In 1924, Alexander A. Maxi mow used comprehensive histological detection to identify a singular type of precursor cell within mesenchyme that develops into various types of blood cells (32). In general, MSCs are type of cells with potential of multi-lineage differentiation and self-renewal, which exist in many different kinds of tissues and organs such as adipose tissue, bone marrow, skin, peripheral blood, fallopian tube, cord blood, liver and lung et al. (4,5). Today, stem cells are used for different applications. In addition to using these cells in human therapy such as cell transplantation, cell engraftment etc. The use of stem cells in veterinary medicine has also been considered. The purpose of this review is to provide a summary of our current knowledge regarding the important and types of isolated stem cells from different sources of animal models such as horse, pig, goat, dog, rabbit, cat, rat, mice etc. In this regard, due to the widespread use and lot of attention of MSCs, in this review, we will elaborate on use of MSCs in veterinary medicine.
The isolation method, maintenance and culture condition of MSCs differs from the different tissues, these methods as well as characterization of MSCs described as (36). MSCs could be isolated from the various tissues such as adipose tissue, bone marrow, umbilical cord, amniotic fluid etc. (37).
Diagram for adipose tissue-derived mesenchymal stem cell isolation (3).
Diagram for bone marrow-derived MSCs isolation (33). MSC, mesenchymal stem cell.
Diagram for umbilical cord-derived MSCs isolation (34). MSC, mesenchymal stem cell.
Diagram for isolation of amniotic fluid stem cells (AFSCs) (35).
Diagram for MSCs characterization (35). MSC, mesenchymal stem cell.
The diversity of stem cell or MSCs sources and a wide aspect of potential applications of these cells cause to challenge for selecting an appropriate cell type for cell therapy (38). Various diseases in animals have been treated by cell-based therapy. However, there are immunity concerns regarding cell therapy using stem cells. Improving animal models and selecting suitable methods for engraftment and transplantation could help address these subjects, facilitating eventual use of stem cells in the clinic. Therefore, for this purpose, in this section of this review, we provide an overview of the current as well as previous studies for future development of animal models to facilitate the utilization of stem cells in regenerative medicine (14). Significant progress has been made in stem cells-based regenerative medicine, which enables researchers to treat those diseases which cannot be cured by conventional medicines. The unlimited self-renewal and multi-lineage differentiation potential to other types of cells causes stem cells to be frontier in regenerative medicine (24). More researches in regenerative medicine have been focused on human cells including embryonic as well as adult stem cells or maybe somatic cells. Today there are versions of embryo-derived stem cells that have been reprogrammed from adult cells under the title of pluripotent cells (39). Stem cell therapy has been developed in the last decade. Nevertheless, obstacles including unwanted side effects due to the migration of transplanted cells as well as poor cell survival have remained unresolved. In order to overcome these problems, cell therapy has been introduced using biocompatible and biodegradable biomaterials to reduce cell loss and long-term in vitro retention of stem cells.
Currently in clinical trials, these biomaterials are widely used in drug and cell-delivery systems, regenerative medicine and tissue engineering in which to prevent the long-term survival of foreign substances in the body the release of cells are controlled (40).
Today, the incidence and prevalence of heart failure in human societies is a major and increasing problem that unfortunately has a poor prognosis. For decades, MSCs have been used for cardiovascular regenerative therapy as one of the potential therapeutic agents (41). Dhein et al. [2006] found that autologous bone marrow-derived mesenchymal stem cells (BMSCs) transplantation improves cardiac function in non-ischemic cardiomyopathy in a rabbit model. In one study, Davies et al. [2010] reported that transplantation of cord blood stem cells in ovine model of heart failure, enhanced the function of heart through improvement of right ventricular mass, both systolic and diastolic right heart function (42). In another study, Nagaya et al. [2005] found that MSCs dilated cardiomyopathy (DCM), possibly by inducing angiogenesis and preventing cardial fibrosis. MSCs have a tremendous beneficial effect in cell transplantation including in differentiating cardiomyocytes, vascular endothelial cells, and providing anti-apoptotic as well angiogenic mediators (43). Roura et al. [2015] shown that umbilical cord blood mesenchymal stem cells (UCBMSCs) are envisioned as attractive therapeutic candidates against human disorders progressing with vascular deficit (44). Ammar et al., [2015] compared BMSCs with adipose tissue-derived MSCs (ADSCs). It was demonstrated that both BMSCs and ADSCs were equally effective in mitigating doxorubicin-induced cardiac dysfunction through decreasing collagen deposition and promoting angiogenesis (45).
There are many advantages of small animal models usage in cardiovascular research compared with large animal models. Small model of animals has a short life span, which allow the researchers to follow the natural history of the disease at an accelerated pace. Some advantages and disadvantages are listed in (46).
Despite of the small animal model, large animal models are suitable models for studies of human diseases. Some advantages and disadvantages of using large animal models in a study protocol planning was elaborated in (47).
Chronic wound is one of the most common problem and causes significant distress to patients (48). Among the types of tissues that stem cells derived it, dental tissuederived MSCs provide good sources of cytokines and growth factors that promote wound healing. The results of previous studies showed that stem cells derived deciduous teeth of the horse might be a novel approach for wound care and might be applied in clinical treatment of non-healing wounds (49). However, the treatment with stem cells derived deciduous teeth needs more research to understand the underlying mechanisms of effective growth factors which contribute to the wound healing processes (50). This preliminary investigation suggests that deciduous teeth-derived stem cells have the potential to promote wound healing in rabbit excisional wound models (49). In the another study, Lin et al. [2013] worked on the mouse animal model and showed that ADSCs present a potentially viable matrix for full-thickness defect wound healing (51).
Many studies have been done on dental reconstruction with MSCs. In one study, Khorsand et al. [2013] reported that dental pulp-derived stem cells (DPSCs) could promote periodontal regeneration in canine model. Also, it was shown that canine DPSCs were successfully isolated and had the rapid proliferation and multi-lineage differentiation capacity (52). Other application of dental-derived stem cells is shown in .
Diagram for application of dental stem cell in dentistry/regenerative medicine (53).
As noted above, stem cells have different therapeutic applications and self-renewal capability. These cells can also differentiate into the different cell types. There is now a great hope that stem cells can be used to treat diseases such as Alzheimer, Parkinson and other serious diseases. In stem cell-based therapy, ESCs are essentially targeted to differentiate into functional neural cells. Today, a specific category of stem cells called induced pluripotent stem (iPS) cells are being used and tested to generate functional dopamine neurons for treating Parkinson's disease of a rat animal model. In addition, NSC as well as MSCs are being used in neurodegenerative disorder therapies for Alzheimers disease, Parkinsons disease, and stroke (54). Previous studies have shown that BMSCs could reduce brain amyloid deposition and accelerate the activation of microglia in an acutely induced Alzheimers disease in mouse animal model. Lee et al. [2009] reported that BMSCs can increase the number of activated microglia, which effective therapeutic vehicle to reduce A deposits in AD patients (55). In confirmation of previous study, Liu et al. [2015] showed that transplantation of BMSCs in brain of mouse model of Alzheimers disease cause to decrease in amyloid beta deposition, increase in brain-derived neurotrophic factor (BDNF) levels and improvements in social recognition (56). In addition of BMSCs, NSCs have been proposed as tools for treating neurodegeneration disease because of their capability to create an appropriate cell types which transplanted. kerud et al. [2001] demonstrated that NSCs efficiently express high level of glial cell line-derived neurotrophic factor (GDNF) in vivo, suggesting a use of these cells in the treatment of neurodegenerative disorders, including Parkinsons disease (57). In the following, Venkataramana et al. [2010] transplanted BMSCs into the sub lateral ventricular zones of seven Parkinsons disease patients and reported encouraging results (58).
The human body is fortified with specialized cells named MSCs, which has the ability to self-renew and differentiate into various cell types including, adipocyte, osteocyte, chondrocyte, neurons etc. In addition to mentioned properties, these cells can be easily isolated, safely transplanted to injured sites and have the immune regulatory properties. Numerous in vitro and in vivo studies in animal models have successfully demonstrated the potential of MSCs for various diseases; however, the clinical outcomes are not very encouraging. Based on the studies in the field of stem cells, MSCs find wide application in treatment of diseases, such as heart failure, wound healing, tooth regeneration and etc. In addition, these cells are particularly important in the treatment of the sub-branch neurodegenerative diseases like Alzheimer and Parkinson.
The authors wish to thank staff of the Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Funding: The project described was supported by Grant Number IR.TBZMED.REC.1396.1218 from the Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Conflicts of Interest: The authors have no conflicts of interest to declare.
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Regenerative medicine therapy, including cell therapy, gene therapy, and therapeutic tissue engineering, provides unprecedented potential to treat, modify, reverse, or cure previously intractable diseases, such as cancer and organ failures. This class of therapy has completely changed the paradigm and the trajectory for medical treatment. Broad clinical translation and patient access requires advances in manufacturing technologies and measurements to ensure the safety, quality, and consistency of the therapy and to reduce the cost.
NIST is committed to solving the measurement challenges of this fast-moving sector of the bioeconomy by providing underpinning measurement infrastructure and platform technologies, as well as standards to promote manufacturing innovation, improve supply chain resilience, and support characterization and testing to facilitate regulatory approval.
The NIST Regenerative Medicine program is working closely with the U.S. Food and Drug Administration'sCenter for Biologics Evaluation and Research(FDA/CBER) and the Standards Coordinating Body (SCB) as well as the broader industry to develop global manufacturing and measurement standards underpinned by a robust measurement infrastructure needed to advance product development and translation as directed by Sec. 3036 of the 21st Century Cures Act.
The NIST laboratory programs support this growing industry as well as the broader industry ecosystem by:
NIST has developed a suite of standards and tools for characterizing biological systems and components using advanced measurement science strategies that enable the generation of high-quality data. Some recent examples of NISTs work include:
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Regenerative medicine | NIST