p53 promotes revival stem cells in the regenerating intestine after severe radiation injury

Ionizing radiation induces cell death in the gastrointestinal (GI) epithelium by activating p53. However, p53 also prevents animal lethality caused by radiation-induced GI injury. Through single-cell RNA-sequencing of the irradiated mouse intestine, we find that p53 target genes are specifically enriched in stem cells of the regenerating epithelium, including revival stem cells that promote animal survival after GI damage. Accordingly, in mice with p53 deleted specifically in the GI epithelium, ionizing radiation fails to induce revival stem cells. We also use intestinal organoids to show that transient p53 is required for induction of revival stem cells that is controlled by a Mdm2-mediated negative feedback loop. These results suggest that p53 suppresses severe radiation injury by promoting intestinal epithelial cell reprogramming.