YAP/TAZ activity in PDGFRα-expressing alveolar fibroblasts modulates AT2 proliferation through Wnt4.

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.