StemCell Therapy

After passing through thestomach, the next stage of the digestive system occurs in the small intestine,where nutrients and minerals are absorbed. With a host of digestive enzymes, inaddition to a diverse microbiome present, the lining of the small intestine isexposed to quite the chemical soup that causes the cells much wear and tear. Betweenthe villi of the small intestine, that increase the surface area available toabsorb nutrients, are crypts, at the bottom of which reside stem cells. Thesestem cells are the source for new cells to replace the ones lost at the epitheliallining maintaining the balance of life and death. However, not all the stemcells stay as stem cells. This is important to prevent overgrowth of theintestine which could lead to cancer. The exact molecular mechanisms thatunderpin this critical balance between stem cell life and death is stillincomplete. However, a new paper published in Nature 1 by Koren et al. provides new light on the role of ARTS inthis process.

Making the intestine pretty

Goblet cells may not soundvery pretty, but they make up one of the six different differentiated celltypes in the intestine epithelium. Along with enterocytes covered inmicrovilli, the goblet cells make up the villus lining. At the other end, atthe bottom of the crypt, are the Paneth cells, the crypt-base columnar cells(CBCs) and the +4 cells, so named for their position from the base of the crypt(Figure 1).

Figure 1 cells in the smallintestine crypt

Of these cells, the CBCs arethought to be the true stem cells of the small intestine, replicating toproduce more stem cells or cells that will later differentiate to become theother cell types. Since some stem cells will divide to produce more stem cellswhilst others divide and differentiate, over time the small intestine crypt becomesdominated by cells originating from one stem cell clone it becomes monoclonal.A previous study beautifully illustrated this phenomenon using differentcoloured fluorescent markers as can be seen in Figure 2.

Figure 2 taken from ref(2),the crypt shows that differentiated cells originate from stem cells at thebottom of the crypt

These results clearly showed howthe regeneration of the small intestine occurs through a conveyor beltmechanism 2 . It also confirmed known ideas that the stemcells resided near the bottom of crypts. But how are the stem cells eliminated?

Apoptosis a type of celldeath

There are many ways thatcells can die they can get damaged and release all of their contents, cellscan get infected by bacteria or viruses, or cells can trigger their own death.The last case is best known as apoptosis. There are proteins in a cell that promote apoptosis. So, to prevent cells from killing themselves all the time, there are also proteins that prevent cell death. The proteins are referred to as pro-apoptotic or anti-apoptotic respectively. One family of the anti-apoptotic proteins are literally called IAP, for inhibitor of apoptosis. However, these inhibitors can also get inhibited. For example, one IAP, xIAP, can be inhibited by ARTS. ARTS is therefore a pro-apoptotic protein. Its like how the enemy of an enemy is your friend xIAP is an enemy of ARTS and apoptosis is an enemy of IAP so ARTS and apoptosis are friends Well, I reckon that would be an interesting friendship, but by antagonising xIAP, the inhibitor of apoptosis can no longer inhibit apoptosis.

Where ARTS thou?

By using a tagged antibodythat specifically recognises ARTS, the authors were able to stain and locateARTS within the crypt of the small intestine. ARTS was mainly found both in thestem cells and the neighbouring Paneth cells. When they deleted the ARTS genefrom the cells they saw that the crypt increased in size and cell number. Thisis somewhat expected given ARTS role as a pro-cell-death factor and thephenotype was reversed when xIAP was also genetically removed. By using astem-cell specific reporter, it became clear that part of this increased cellsnumber was due to an increase in stem cell number. Paneth cells also increasedin number.

But is this cell expansiondue to less death or more proliferation?

To determine this, the teamtreated the crypt cells with staurosporine, a chemical that induces apoptosis.Compared to a wild type control, the crypts lacking ARTS showed less expressionof a pro-apoptotic protein, cleaved-caspase 3.

But could proliferation alsobe increased?

The Paneth cells, neighbouringthe stem cells, promote stem cell proliferation by providing growth factors. Themain growth pathway activated in the stem cells is the Wnt/-catenin. When cells lacked ARTS, the authors saw not onlyincreased levels of a proliferation marker but also increased -catenin levels in the nucleus a good indication that the growthpathway has been activated. However, preventing Wnt signalling does not preventthe apoptosis resistance seen without ARTS.

The function of ARTS in theintestine

Korens teams work is one ofthe first to examine the death of stem cells, an important mechanism as leftunregulated could result in uncontrollable tissue growth. Since uncontrollablegrowth is one of the hallmarks of cancer, including colorectal cancer, and thatloss of ARTS promotes crypt cell growth, this work provides new theory forrational drug development.

Further reading

1. Koren, E. et al. ARTSmediates apoptosis and regeneration of the intestinal stem cell niche. Nat.Commun. 117 doi:10.1038/s41467-018-06941-4

2. Snippert, H. J. et al.Intestinal crypt homeostasis results from neutral competition betweensymmetrically dividing Lgr5 stem cells. Cell 143, 134144 (2010).

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The ARTS of life and death in the intestinal stem cells

This entry was posted on November 21, 2018 at 6:41 pm and is filed under Death by Stem Cells. You can follow any responses to this entry through the RSS 2.0 feed. Both comments and pings are currently closed. |