Mesenchymal Hippo signaling regulates intestinal homeostasis in adult mice.

Intestinal homeostasis is tightly regulated by the reciprocal interaction between the gut epithelium and adjacent mesenchyme. The Hippo pathway is intimately associated with intestinal epithelial homeostasis and regeneration; however, its role in postnatal gut mesenchyme remains poorly defined. Here, we find that removal of the core Hippo kinases Lats1/2 or activation of YAP in adult intestinal smooth muscle layers has largely no effect; however, Hippo-YAP signaling in the niche-forming Gli1+ mesenchymal cells plays intrinsic roles in regulating intestinal homeostasis. We find that Lats1/2 deletion drives robust mesenchymal over-proliferation, and YAP activation in Gli1+ pericryptal cells disrupts the intestinal epithelial-mesenchymal crosstalk via promoting Wnt ligand production. We show that YAP is upregulated in the stroma during dextran sodium sulfate (DSS)-induced injury, and mesenchymal YAP activation facilitates intestinal epithelial regeneration. Altogether, our data suggest an important role for mesenchymal Hippo-YAP signaling in the stem cell niche during intestinal homeostasis and pathogenesis.