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Essential role for autophagy protein ATG7 in the maintenance of intestinal stem cell integrity

Significance Studies on intestinal stem cells (ISC) have increased our understanding of stem cell dynamics, tissue plasticity, and tumor-initiating cells. However, the molecular mechanisms involved in the maintenance and integrity of this stem cell pool remain unclear. Using conditional mice models lacking the autophagy gene Atg7 in intestinal epithelial cells and specifically, in ISC, we show that Atg7 contributes to the unique characteristic of ISC and demonstrate its importance to promote efficient DNA damage repair and survival on homeostasis and following cytotoxic stresses. These findings highlight the translational potential of autophagy activation to induce epithelial regeneration and to protect host toxicity in patients undergoing high doses of chemotherapy or radiotherapy. The intestinal epithelium acts as a barrier between the organism and its microenvironment, including the gut microbiota. It is the most rapidly regenerating tissue in the human body thanks to a pool of intestinal stem cells (ISCs) expressing Lgr5. The intestinal epithelium has to cope with continuous stress linked to its digestive and barrier functions. Epithelial repair is crucial to maintain its integrity, and Lgr5-positive intestinal stem cell (Lgr5+ISC) resilience following cytotoxic stresses is central to this repair stage. We show here that autophagy, a pathway allowing the lysosomal degradation of intracellular components, plays a crucial role in the maintenance and genetic integrity of Lgr5+ISC under physiological and stress conditions. Using conditional mice models lacking the autophagy gene Atg7 specifically in all intestinal epithelial cells or in Lgr5+ISC, we show that loss of Atg7 induces the p53-mediated apoptosis of Lgr5+ISC. Mechanistically, this is due to increasing oxidative stress, alterations to interactions with the microbiota, and defective DNA repair. Following irradiation, we show that Lgr5+ISC repair DNA damage more efficiently than their progenitors and that this protection is Atg7 dependent. Accordingly, we found that the stimulation of autophagy on fasting protects Lgr5+ISC against DNA damage and cell death mediated by oxaliplatin and doxorubicin treatments. Finally, p53 deletion prevents the death of Atg7-deficient Lgr5+ISC but promotes genetic instability and tumor formation. Altogether, our findings provide insights into the mechanisms underlying maintenance and integrity of ISC and highlight the key functions of Atg7 and p53.