Yap1-Driven Intestinal Repair Is Controlled by Group 3 Innate Lymphoid Cells

Abstract

Summary: Tissue repair requires temporal control of progenitor cell proliferation and differentiation to replenish damaged cells. In response to acute insult, group 3 innate lymphoid cells (ILC3s) regulate intestinal stem cell maintenance and subsequent tissue repair. ILC3-derived IL-22 is important for stem cell protection, but the mechanisms of ILC3-driven tissue regeneration remain incompletely defined. Here we report that ILC3-driven epithelial proliferation and tissue regeneration are independent of IL-22. In contrast, ILC3s amplify the magnitude of Hippo-Yap1 signaling in intestinal crypt cells, ensuring adequate initiation of tissue repair and preventing excessive pathology. Mechanistically, ILC3-driven tissue repair is Stat3 independent, but it involves activation of Src family kinases. Our findings reveal that ILC3-driven intestinal repair entails distinct transcriptional networks to control stem cell maintenance and epithelial regeneration, which implies that tissue repair and crypt proliferation can be influenced by targeting innate immune cells independent of the well-established effects of IL-22. : Intestinal repair is driven by epithelial stem cells, but how these stem cells are instructed to initiate repair was unknown. Here, Romera-Hernández et al. report that epithelial proliferation after damage is independent of the stem cell-protective signal IL-22 but requires ILC3-dependent amplification of regenerative YAP1 signaling in stem cells. Keywords: innate lymphoid cells, epithelial stem cell, IL-22, YAP1, intestine, tissue damage