p57Kip2 imposes the reserve stem cell state of gastric chief cells

Adult stem cells constantly react to local changes to ensure tissue homeostasis. In the main body of the stomach, chief cells produce digestive enzymes; however, upon injury, they undergo rapid proliferation for prompt tissue regeneration. Here, we identified p57Kip2 (p57) as a molecular switch for the reserve stem cell state of chief cells in mice. During homeostasis, p57 is constantly expressed in chief cells but rapidly diminishes after injury, followed by robust proliferation. Both single-cell RNA sequencing and dox-induced lineage tracing confirmed the sequential loss of p57 and activation of proliferation within the chief cell lineage. In corpus organoids, p57 overexpression induced a long-term reserve stem cell state, accompanied by altered niche requirements and a mature chief cell/secretory phenotype. Following the constitutive expression of p57 in vivo, chief cells showed an impaired injury response. Thus, p57 is a gatekeeper that imposes the reserve stem cell state of chief cells in homeostasis. [Display omitted] •Gastric chief cells undergo rapid transcriptional changes during injury repair•p57+ chief cells rapidly switch to distinct injury-responsive chief cells upon injury•p57 induces RSC-like state in gastric corpus organoids•p57 expression inhibits the induction of injury-responsive chief cells in vivo The teams of Kim, Koo, and Choi show that p57 acts as a molecular switch governing the injury response of gastric chief cells. Upon injury, chief cells lose p57 expression for rapid proliferation and tissue regeneration. The p57 expression imposes the reserve stem cell state of chief cells in homeostasis.