Abstract
Self‐renewal program enables stem cells to be maintained throughout a lifetime, and to retain the capacity to produce the desired functional cells. However, the molecular mechanisms regulating self‐renewal and differentiation remain unclear. We previously reported that Src‐homology 2 domain‐containing phosphatase 2 (Shp2) is essential for stem cell activity; however, its roles in tissue‐specific stem cells remain largely controversial. Here, we aimed to dissect the in vivo role of Shp2 in intestinal stem cells using a genetic approach. Mice with intestinal‐specific Shp2‐deficiency presented growth retardation with dysfunctional lipid absorption and glucose homeostasis, and postnatal lethality at the age of 6–8 weeks. Moreover, an incomplete crypt‐villus axis, with self‐renewal expansion and reduced epithelial differentiation was observed in 4‐week‐old Shp2‐deficient mice. Mechanistically, intestinal epithelium‐specific deletion of Shp2 activated both Notch and JAK/Stat signaling pathways, which fulfill overlapping roles in growth and differentiation regulation by facilitating Hes1/Stat3 complex formation in intestinal epithelia, so contributing to a weakened differentiation capacity in the crypt niche. Furthermore, we found that Shp2 repressed Hes1 and Stat3 interaction, which coordinates cross‐talk between the Notch and JAK/Stat pathways in Lgr5+ cells. Lgr5 expression is enhanced in Shp2‐deficient mice, while the number of BrdU+ cells also increased. Together, these observations provide the first evidence that Shp2 regulates self‐renewal of intestinal stem cells and their functional differentiation.
Published Version
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