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What happens when tissues appear to lose their stem cells

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Charité researchers discover mechanism for the regeneration of the intestine after stem cell loss

Wenn der Körper nach einer Schädigung des Darms das Notfallprogramm aktiviert, übernehmen gesunde Zellen der Darmwandoberfläche (rot) die Funktion von tiefer liegenden Stammzellen (grün). Einige Zellen leuchten deshalb zweifarbig auf. Foto: Harnack/Charité
When the intestine has been damaged, the body activates its contingency plan: healthy cells in the surface layer of the intestinal wall (red) take on the function of stem cells, which reside in deeper tissue layers (green) – this explains why some cells appear as dual-color structures. Photo: Harnack/Charité

Stem cells are responsible for the regeneration of the intestinal wall. But what happens when the stem cells responsible for regeneration are damaged by an infection? Researchers from Charité – Universitätsmedizin Berlin and the Max Planck Institute for Infection Biology set out to address this question. They were able to identify the precise mechanism involved in restoring the body’s ability to regenerate the intestinal wall. This knowledge may be able to help researchers develop new treatment options for patients with intestinal disorders. Results from this study have been published in the journal Nature Communications*.

Our gut represents an interface between the body’s own tissues and its environment. As such, it is exposed to a myriad of factors. Many of these are beneficial to our health or even essential for our survival. Others, however, such as pathogens and toxic food components, can damage the lining of our intestinal walls, causing injury and inflammation. Faced with this situation, the body can activate its ‘tissue regeneration program’, which prompts stem cells residing in the base of invaginations of the intestinal wall (crypts) to proliferate. Newly formed ‘daughter cells’ then move to replace damaged cells within the tissue’s surface layer, thereby restoring the tissue's normal barrier function. However, some foreign materials do not merely attack cells within the surface layer of the intestinal wall, they will also destroy stem cells deep within the intestinal crypts. Using an animal model, a team of researchers led by Dr. Michael Sigal of Charité’s Medical Department, Division of Hepatology and Gastroenterology (Campus Charité Mitte and Campus Virchow-Klinikum), has been exploring how the intestinal wall can recover from such damage and restore its normal barrier function.

“We were able to show that muscle cells located directly below the damaged cell layer play a crucial role in this regard,” explains Dr. Sigal. The researchers proved that, as soon as the stem cells stop functioning, these muscle cells release the protein R-spondin 3. This signaling molecule prompts some of the remaining healthy cells to take on the function of stem cells. They start to produce daughter cells, which then restore damaged tissue sections. Experiments which involved ‘knocking out’ the gene responsible for the release of R-spondin 3 showed that this mechanism of regeneration is essential to survival after severe intestinal injury.

Explaining the study’s findings, Dr. Sigal, who is the Leader of an Emmy Noether Independent Junior Research Group and a BIH Charité Clinician Scientist, says: “Our study also shows that the body has a contingency plan for when the gut's normal tissue regeneration program is impaired.” He adds: “When the body is unable to implement this contingency plan, however, a severe gut infection may prove fatal. Here, our observations show parallels to what we see in patients with inflammatory bowel disorder: many of these patients will recover quickly, others will develop a chronic form of the disease or develop severe complications.” The researchers hope to use their new insights into the body's capacity for regeneration to develop new treatment options for both acute and chronic inflammatory bowel disorders. “By finding ways to activate the gut's regenerative capacity, we may one day be able to positively influence the course of intestinal disorders,” says Dr. Sigal.

*Harnack C et al., R-spondin 3 promotes stem cell recovery and epithelial regeneration in the colon. Nat Commun. 2019 Sep 25;10(1):4368. doi: 10.1038/s41467-019-12349-5


Original article

Press release ‘Searching for dangerous gut bacteria’ (22.08.2019)


Dr. Michael Sigal
Medical Department, Division of Hepatology and Gastroenterology
Campus Charité Mitte and Campus Virchow-Klinikum
Charité – Universitätsmedizin Berlin
t: +49 30 450 514 102

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