Enterocyte dedifferentiation drives colonic regeneration following irradiation injury [scRNA-seq]

The intestinal epithelium consistently exposes to various injuries and exhibits remarkable regenerative capacity. Although small intestinal regeneration has been extensively investigated, the mechanisms governing colonic regeneration remain poorly understood. Here, we identify irradiation-induced regenerative cells (IRECs), a previously unrecognized colonic enterocyte population, emerges following irradiation injury. IRECs, marked by the gene YuanShangCao (Ysc), undergo dedifferentiation and transition into a stem-like state, contributing to epithelial regeneration. IREC ablation severely impairs colonic repair. Mechanistically, YSC promotes colonic regeneration by preventing the lysosomal degradation of YAP. Furthermore, we demonstrate a critical role of p53 in colonic regeneration by inducing Ysc expression. Together, our findings define IRECs as an irradiation injury-induced enterocyte population that dedifferentiate into stem cells in colon epithelial repair and establish the p53-YSC-YAP axis plays a key role in this process, deepening the understanding of colonic diseases. Overall design: In this study, leveraging a colon irradiation injury model coupled with single-cell sequencing, we identified a population of irradiation-induced Ysc+ cells. Through RNA velocity analysis and lineage tracing experiments, we demonstrated that these cells are a population of colonic absorptive enterocytes capable of dedifferentiation. They are activated by p53 and play a crucial role in colon regeneration, thereafter we call them irradiation-induced regenerative cells (IRECs). Further, we revealed that as the marker of IRECs, Ysc plays an important role in epithelial injury repair. Organoids deficient of Ysc were found to be more sensitive to irradiation damage, and the colonic injury repair capacity was impaired in mice lacking Ysc. Mechanistically, Ysc can affect lysosome function and activating YAP signaling by inhibiting its lysosomal degradation.