Researchers from the Technion Faculty of Biology have identified the protein responsible for critical processes in intestinal diseases. They also found that the deletion of a protein called ARTS protects the stem cells that are essential for intestinal function. The findings are expected to pave the way for new treatments of intestinal diseases and reduce the side effects of anti-cancer treatments.

Published in the journal Nature Communications, the research was led by Associate Prof. Yaron Fuchs and doctoral student Elle Koren from the Laboratory of Stem Cell Biology and Regenerative Medicine and the Lorry Lokey Interdisciplinary Center for Life Sciences and Engineering.

The intestinal lining is a tissue that regenerates very quickly, more so than any other tissue in the human body. It plays a critical role in the digestion and absorption of food and its effectiveness is related to its unique structure. The small intestine increases its area with small finger-shaped projections called villi, which are comprised of epithelial cells. The stem cells of the small intestine are present in intestinal invaginations, known as Crypts of Lieberkühn, which are the folds between the protrusions at the base of the intestine. The cells divide steadily, differentiate and form different epithelial cells along the villi.

Stem cells are responsible for the regeneration of various tissues such as skin, bowel and blood vessels. To date, much research has been done on stem cell regeneration and differentiation, but the mechanisms responsible for their suicide (apoptosis) has hardly been studied. The reason for this is that for many years stem cells were considered “immortal” cells that live until the end of the life of the organism.

The present study deals with stem cell suicide, and the dramatic effect of this process on tissue regeneration and recovery processes in the intestines. Prof. Fuchs and Koren assumed that due to the long life span of the stem cells in the intestine, they may accumulate mutations and cause various diseases such as cancer. Therefore, although they are more resistant than “normal” cells, they should be subject to a control mechanism that eliminates them in a controlled manner should mutations develop in them.

The study found that stem cells in the intestine are indeed subject to such a process of programmed death. The researchers found that a critical protein for this process is ARTS, which is expressed in mouse and human intestinal crypts. The research team discovered that deletion of the gene responsible for encoding this protein leads to a dramatic increase in the number of stem cells in the intestine and the size of the niche containing them.

In order to confirm their results, the researchers isolated stem cells from the mice and succeeded in creating a “mini-gut in a plate” — a mini laboratory organ (organoid) that ideally mimics the intestine in the whole animal and can also be implanted into the animal as an organ that functions as a normal intestine. Here, the researchers found that the deletion of ARTS caused a significant increase in organoid size, the number of stem cells and often displayed pre-cancerous morphology. The reason for this is that the stem cells that were supposed to commit suicide did not undergo this process.

The stem cell population in the intestine tends to get severely damaged when a person receives cancer treatment. This is one of the reasons for the formation of side effects such as fatigue, nausea, vomiting and diarrhea. The researchers found that in the absence of the ARTS protein, these treatments did almost no damage to the intestinal stem cells. Moreover, they found that in ARTS-free mice, intestinal diseases such as colitis do not manifest with severe symptoms as seen in ordinary patients.

The researchers believe that this study will pave the way for new treatments of intestinal disease and even prevention, as well as reduce the side effects of anti-cancer treatments. This can be achieved by the development of specific drugs that will inhibit ARTS in a focused manner.

Assistant Professor Yaron Fuchs is head of the Laboratory of Stem Cell Biology and Regenerative Medicine in the Department of Biology, and a faculty member of both the Lorry Lokey Interdisciplinary Center for Life Sciences and Engineering and the Technion Integrated Cancer Center. The laboratory team focuses on isolated new populations of stem cells, studying the mechanism of suicide of these special cells and promoting new techniques for regenerative medicine and treatment of cancer.

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