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Background Different pools of stem cells assure the intestinal epithelium homeostasis and regeneration. We recently reported that Krt15+ intestinal cells harbor self-renewal, multipotent and regenerative capacities, characteristics consistent with a stem cell population. p53 has been associated with the development of various types of cancer, and recent studies suggested it also regulates adult stem cell behavior in some tissues. However, its role in the maintenance of intestinal stem cells has not been explicitly covered. Therefore, we hypothesize that Trp53 loss specifically in Krt15+ intestinal stem cells will perturb the epithelial homeostasis and differentiation. Aims Identify the role of Trp53 in the regulation of intestinal stem cell and intestinal homeostasis Methods To induce Trp53 loss specifically in Krt15+ cells, we generated Krt15 CrePR1;Trp53fl/fl ( Krt15△Trp53) mice and induced Cre recombination by injecting RU486 (PR agonist). Mice were euthanized after Cre recombination at different time points. Organoid cultures were established from control and experimental mice. Results Two-month post Cre recombination, we observed no major morphological changes in the intestinal epithelium. However, we observed that crypts isolated from Krt15△Trp53 mice died rapidly and had difficulties forming organoids. When hyperactivating the Wnt/beta-catenin pathway through CHIR treatment, we observed that budding capacity was maintained in experimental organoids while control organoids formed mainly cysts as expected. We also observed an increased in Paneth cell-specific genes, suggesting an enrichment in Paneth cells. Interestingly, the expression of EpHB2 receptor and its target genes was decreased in organoids derived from Krt15△Trp53 mice. Ephrin signaling plays a crucial role in intestinal homeostasis by regulating cell position and migration, and previous studies suggest that ephrin receptors are a target of p53. Indeed, twelve-month post Cre recombination, altered architecture of crypt and villi was noted in the small intestinal epithelium of Krt15△Trp53 mice. Differentiation towards secretory cell types, specifically Paneth, goblet, and tuft cells, are significantly increased in Krt15△Trp53 mice. Interestingly, we also observed crypt cells expressing both goblet and Paneth cell markers suggesting dysfunction in the cell fate decision. Finally, decreased Notch pathway activation was also observed supporting that Trp53 loss, specifically in Krt15+ cells, leads to a dysregulation of secretory cell fate. Conclusions Loss of Trp53 specifically in Krt15+ cells affects the small intestinal homeostasis and secretory cell differentiation. Decreased Notch and ephrin signaling support the possible role of Trp53 in cell fate decision and self-renewal. Funding Agencies None

A17 TRP53 REGULATES ESLF-RENEWAL AND CELL DIFFERENTIATION IN KRT15+ INTESTINAL STEM CELLS