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bioRxiv · 10.1101/2022.05.12.491640

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

Mao, J.·Dang, K.·Singh, A.·Jennifer, C. L.·Tao, Z.·Liu, H.·Zhu, L.·Wu, X.
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Abstract

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. HIGHTLIGHTSO_LILats1/2 control proliferation and differentiation of adult gut mesenchymal progenitors. C_LIO_LIMesenchymal YAP/TAZ promotes Wnt ligand production in intestinal stem cell niche. C_LIO_LIYAP/TAZ is up-regulated in the mesenchyme during intestinal injury. C_LIO_LIStromal YAP activation promotes intestinal epithelial regeneration. C_LI

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Mao, J., Dang, K., Singh, A., Jennifer, C. L., Tao, Z., Liu, H., Zhu, L., Wu, X.. 2022-05-12. Stromal Hippo-YAP signaling in stem cell niche controls intestinal homeostasis. https://doi.org/10.1101/2022.05.12.491640

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