Stromal Hippo-YAP signaling in stem cell niche controls intestinal homeostasis

Dang K, Singh A, Cotton JL, Tao Z, Liu H, Zhu LJ, Wu X, Mao J.
Preprint from
12 May 2022
Intestinal homeostasis is tightly regulated by the reciprocal interaction between gut epithelium and adjacent mesenchyme. The mammalian Hippo-YAP pathway is intimately associated with intestinal epithelial homeostasis and re-generation; however, its role in postnatal gut mesenchyme remains poorly defined. We find that, although removal of the core Hippo kinases Lats1/2 or activation of YAP in adult intestinal smooth muscle has largely no effect; Hippo-YAP signaling in Gli1/PDGFR-expressing intestinal stromal cells is critical to maintain the stem cell niche. We show that YAP/TAZ activation drives over-proliferation and suppresses smooth muscle actin expression in the niche-forming Gli1 + mesenchymal progenitors. In addition, mesenchymal YAP/TAZ activation disrupts the epithelial-mesenchymal crosstalk by promoting Wnt ligand production, leading to epithelial Wnt pathway activation. Our data also reveal that YAP/TAZ are upregulated in the stroma during DSS-induced injury and stromal YAP activation promotes intestinal epithelial regeneration. Altogether, our data identify an essential requirement for stromal Hippo-YAP signaling in the stem cell niche during intestinal homeostasis.


Lats1/2 control proliferation and differentiation of adult gut mesenchymal progenitors. Mesenchymal YAP/TAZ promotes Wnt ligand production in intestinal stem cell niche. YAP/TAZ is up-regulated in the mesenchyme during intestinal injury. Stromal YAP activation promotes intestinal epithelial regeneration.