YAP/TAZ activity in PDGFRα-expressing alveolar fibroblasts modulates AT2 proliferation through Wnt4
Jane Y. Song, Fabien Wehbe, Aaron K. Wong, Ben M. Hall, Jason A. Vander Heiden, Hans D. Brightbill, Joseph R. Arron, David Garfield, Anwesha Dey, Jason R. Rock
Abstract
The Hippo pathway, mediated by its transcriptional effectors Yes-associated protein 1 (YAP) and WW-domain-containing transcription regulator 1 (TAZ), is crucial in maintaining lung homeostasis and facilitating injury repair. While its roles in epithelial cells are well established, its regulatory effects on lung fibroblasts remain less understood. We engineered a mouse model for the inducible knockdown of YAP/TAZ and showed that fibroblast-specific knockdown enhances PDGFRα+ alveolar fibroblasts' support for alveolar-epithelial-stem-cell-derived organoids in vitro. Single-cell profiling revealed changes in fibroblast subpopulations, including the emergence of a Wnt4+ enriched subpopulation. Epigenomic analyses revealed shifts in transcription factor motif enrichment in both fibroblasts and epithelial cells due to fibroblast YAP/TAZ suppression. Further computational and in vivo analyses confirmed increased Wnt signaling and Wnt4 expression in PDGFRα-lineage+ fibroblasts, which enhanced SPC+ alveolar type 2 (AT2) cell proliferation. These findings highlight a mechanistic role of YAP/TAZ in PDGFRα+ alveolar fibroblasts in supporting AT2 cell maintenance and proliferation via Wnt4 secretion.