Tgfb in AT1 cells
Premature birth disrupts normal lung development and places infants at risk for bronchopulmonary dysplasia (BPD), a disease increasing in incidence which disrupts lung health throughout the lifespan. The TGFß superfamily has been implicated in BPD pathogenesis, however, what cell lineage it impacts remains unclear. We show that the primary TGFß receptor, Tgfbr2, is critical for AT1 cell fate maintenance and function. Loss of Tgfbr2 in AT1 cells during late lung development leads to AT1-AT2 cell reprogramming and altered pulmonary architecture, which persists into adulthood. Restriction of fetal lung stretch and associated AT1 cell spreading through a model of oligohydramnios enhances AT1-AT2 reprogramming. Transcriptomic and proteomic analysis reveal that expression of extracellular matrix components by AT1 cells is attenuated with loss of Tgfbr2. Cell spreading assays shows that TGFß signaling regulates integrin transcription to alter AT1 cell morphology, which further impacts ECM expression through changes in mechanotransduction. These data reveal the cell intrinsic necessity of TGFß signaling to maintain AT1 fate and define this cell lineage as a major orchestrator of the alveolar matrisome, which, if altered, may predispose to BPD. Overall design: To determine the role of Tgfbr2 in AT1 cells, we generated HopxCreERT2+/-;Tgfbr2 fl/+; eYFP-/-  and HopxCreERT2+/-;Tgfbr2 fl/fl; eYFP-/- mice, allowing us to inactivate one or two copies of Tgfbr2 in AT1 cells and trace their fate from P0 to P5.