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 p57^Kip2 (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.

成体干细胞不断对局部变化做出反应，以确保组织稳态。在胃的主体中，主细胞产生消化酶；然而，在受伤后，它们会快速增殖以促进组织再生。在这里，我们确定 p57 ^Kip2 (p57) 是小鼠主细胞储备干细胞状态的分子开关。在稳态过程中，p57 在主细胞中持续表达，但在损伤后迅速减少，随后出现强劲增殖。单细胞 RNA 测序和 dox 诱导的谱系追踪均证实了主细胞谱系内 p57 的连续丢失和增殖的激活。在语料库类器官中，p57 过度表达诱导长期储备干细胞状态，伴随着生态位要求的改变和成熟的主细胞/分泌表型。p57在体内组成型表达后，主细胞表现出受损的损伤反应。因此，p57 是一个在体内平衡中强制主细胞储备干细胞状态的看门人。