Matrix fibroblast function during alveolarization is dependent on GATA6

Alveolarization is dependent on myo-, matrix- and lipo- fibroblast functions by interstitial PDGFRa + fibroblasts. While these fibroblasts are derived from GLI and PDGFRa expressing fibroblasts, the transcriptional control of their functional specification remains unknown. Perinatally, the transcription factor GATA6 is upregulated in PDGFRa + fibroblasts. To study the role of GATA6 during fibroblast differentiation, we generated PDGFRa CreER /GATA6 flx/flx mice and deleted GATA6 in the perinatal period and in adult mice prior to left lobe pneumonectomy. Loss of GATA6 in the PDGFRa + -fibroblasts impaired alveolarization, and extracellular matrix deposition, in association with increased TCF21 expression and lipofibroblast differentiation. Loss of GATA6 in PDGFRa + fibroblasts resulted in loss of alveolar type 1 (AT1) cells and gain of transitional alveolar type 2 (AT2) cells. Loss of GATA6 was associated with reduced WNT signaling. Restoration of WNT signaling in GATA6 deficient alveolar lung organoids restored AT2 and AT1 cell differentiation. GATA6 induces matrix fibroblast functions and represses lipofibroblast functions, serving as key regulator of fibroblast differentiation during alveolarization and regeneration. Present findings link matrix fibroblast functions with the ability of transitional AT2 cells to differentiate into AT1 cells. Graphical abstract Graphical abstract: