YAP/TAZ activity in PDGFRa-expressing alveolar fibroblasts modulates lung fibroblast-epithelial cell crosstalk through Wnt4 [scRNA-seq]

The Hippo signaling pathway, mediated by its transcriptional effectors YAP and TAZ, play vital roles in maintaining lung homeostasis and facilitating injury repair. While the roles of the Hippo pathway in epithelial cells are well-established, its regulatory effects on lung fibroblasts remain less understood. Here, we engineered a novel mouse allele to allow inducible knockdown of YAP and TAZ, and show that fibroblast-specific knockdown enhances the ability of PDGFRa+ alveolar fibroblasts to support organoids derived from alveolar epithelial stem cells in vitro. Single-cell multiomic profiling revealed changes in fibroblast subpopulations, including the emergence of an Mmp9+ cluster containing Wnt4+ cells. Analyses demonstrated shifts in the epigenomic landscape leading to varied enrichment of transcription factor motifs across both fibroblasts and epithelial cells in response to targeted suppression of YAP/TAZ in fibroblasts. Further computational analyses identified an increase in epithelial Wnt signaling which was confirmed by in vivo studies. We found that Wnt4 expression was increased in PDGFRa-lineage+ fibroblasts and enhanced proliferation of SPC+ AT2 cells following fibroblast-specific YAP/TAZ knockdown. These results shed new light on the mechanistic role of YAP/TAZ in PDGFRa+ alveolar fibroblasts in supporting AT2 cell maintenance and proliferation via Wnt4 secretion.