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Highlights d Cycling Msi1 + ISCs in the intestinal crypt are DNA damage resistant d Msi1 + ISCs enable fast intestinal repair ahead of Lgr5 high CBCs d Paneth cells preferentially arise from Msi1 + ISCs during homeostasis and repair

The Hippo–YAP signaling pathway plays an essential role in epithelial cells during intestinal regeneration and tumorigenesis. However, the molecular mechanism linking stromal signals to YAP‐mediated intestinal regeneration and tumorigenesis is poorly defined. Here, we report a stroma–epithelium ISLR–YAP signaling axis essential for stromal cells to modulate epithelial cell growth during intestinal regeneration and tumorigenesis. Specifically, upon inflammation and in cancer, an oncogenic transcription factor ETS1 in stromal cells induces expression of a secreted protein ISLR that can inhibit Hippo signaling and activate YAP in epithelial cells. Deletion of Islr in stromal cells in mice markedly impaired intestinal regeneration and suppressed tumorigenesis in the colon. Moreover, the expression of stromal cell‐specific ISLR and ETS1 significantly increased in inflamed mucosa of human IBD patients and in human colorectal adenocarcinoma, accounting for the epithelial YAP hyperactivation. Collectively, our findings provide new insights into the signaling crosstalk between stroma and epithelium during tissue regeneration and tumorigenesis.

Hair follicles (HFs) undergo precisely regulated cycles of active regeneration consisting of (anagen), involution (catagen), and relative quiescence (telogen) phases. HF stem cells (HFSCs) play important roles in regenerative cycling. Elucidating mechanisms that governs HFSC behavior can help uncover the underlying principles of hair development, hair growth disorders and skin cancers. RNA-binding proteins of the Musashi (Msi) have been implicated in the biology of different stem cell types, yet they have not been studied in HFSCs. Here we utilized gain- and loss-of-function mouse models to demonstrate that forced MSI2 expression retards anagen entry and consequently, delays hair growth, while loss of Msi2 enhances hair regrowth. Further, our findings show that Msi2 maintains quiescent state of HFSCs in the process of telogen-to-anagen transition. At the molecular level, our unbiased transcriptome profiling shows that Msi2 represses Hh signaling activity and that Shh is its direct target in the HF. Taken together, our findings reveal the importance of Msi2 in suppressing hair regeneration and maintaining HFSC quiescence. Previously unreported Msi2-Shh-Gli1 pathway adds to the growing understanding of the complex network governing cyclic hair growth.