Atoh1+ secretory progenitors possess renewal capacity independent of Lgr5+ cells during colonic regeneration

During homeostasis, the colonic epithelium is replenished every 3–5 days by rapidly cycling Lgr5 + stem cells. However, various insults can lead to depletion of Lgr5 + stem cells, and colonic epithelium can be regenerated from Lgr5‐ negative cells. While studies in the small intestine have addressed the lineage identity of the Lgr5‐ negative regenerative cell population, in the colon this question has remained unanswered. Here, we set out to identify which cell(s) contribute to colonic regeneration by performing genetic fate‐mapping studies of progenitor populations in mice. First, using keratin ‐19 ( Krt19 ) to mark a heterogeneous population of cells, we found that Lgr5‐ negative cells can regenerate colonic crypts and give rise to Lgr5 + stem cells. Notch1 + absorptive progenitor cells did not contribute to epithelial repair after injury, whereas Atoh1 + secretory progenitors did contribute to this process. Additionally, while colonic Atoh1 + cells contributed minimally to other lineages during homeostasis, they displayed plasticity and contributed to epithelial repair during injury, independent of Lgr5 + cells. Our findings suggest that promotion of secretory progenitor plasticity could enable gut healing in colitis. Synopsis Lgr5 + stem cells function as the source of regeneration in the small intestine, but the cell types contributing to colonic tissue repair have remained controversial. Here, using genetic fate‐mapping and tracing studies in the mouse, Atoh1 + secretory progenitors are shown to revert to Lgr5 ‐expressing stem cells and renew intestinal epithelium during homeostasis and upon injury. Atoh1 + secretory progenitors display cell plasticity under homeostasis in colon and small intestine. Atoh1 + cell plasticity and multipotency are enhanced during colonic regeneration post‐colitis even in the absence of Lgr5 + stem cells. Atoh1 + secretory cell ablation impairs epithelial regeneration in colitis. Notch1 + absorptive progenitors lack regenerative capacity in the setting of colonic injury. Graphical Abstract Lgr5‐negative secretory cells in the large intestine are plastic and contribute to tissue expansion and repair after injury.