P53 terminates the regenerative state after colitis-associated injury

Cell clones that lack P53 signaling occur frequently in ulcerative colitis (UC) and are considered drivers in UC-associated colorectal cancer. Trp53 mutant cells often display decreased P53 signaling and have previously been shown to outcompete wild type (WT) cells in a mouse model of colitis (DSS colitis), but not in healthy mice. However, the mechanism responsible for the observed context-dependent effects of P53 are not understood. Therefore, we aimed to explore this by studying the behavior of Trp53-deficient cells specifically in injured mucosa. We have developed murine and organoid-based models to study the context dependent role of Trp53 knock-out (KO). We use inducible KO systems in mouse models of DSS colitis to study the loss of Trp53 in the injury and regenerative state. Colon organoids are employed to recapitulate the in vivo findings in order to elucidate the pathways involved. Tissue of P53 KO mice were compared to mice with P53 WT in two independent biological replicates. In both arms, mice were treated for 5-7 days with DSS and sacrificed at 2 months after DSS. Organoids from with P53 KO, P53 WT and P53 KO organoids grown in Wnt-deficient medium were compared to each other in two independent biological replicates.