PDGF-A signaling is required for secondary alveolar septation and controls epithelial proliferation in the developing lung

Abstract

Platelet-derived growth factor A (PDGF-A) signaling through PDGF receptor α is essential for alveogenesis. Previous studies have shown that Pdgfa^-/- mouse lungs have enlarged alveolar airspace with absence of secondary septation, both distinctive features of bronchopulmonary dysplasia. To study how PDGF-A signaling is involved in alveogenesis, we generated lung-specific Pdgfa knockout mice (Pdgfa^fl/-; Spc-cre) and characterized their phenotype postnatally. Histological differences between mutant mice and littermate controls were visible after the onset of alveogenesis and maintained until adulthood. Additionally, we generated Pdgfa^fl/-; Spc-cre; Pdgfra^GFP/+ mice in which Pdgfra⁺ cells exhibit nuclear GFP expression. In the absence of PDGF-A, the number of Pdgfra^GFP+ cells was significantly decreased. In addition, proliferation of Pdgfra^GFP+ cells was reduced. During alveogenesis, Pdgfra^GFP+ myofibroblasts failed to form the α-smooth muscle actin rings necessary for alveolar secondary septation. These results indicate that PDGF-A signaling is involved in myofibroblast proliferation and migration. In addition, we show an increase in both the number and proliferation of alveolar type II cells in Pdgfa^fl/-; Spc-cre lungs, suggesting that the increased alveolar airspace is not caused solely by deficient myofibroblast function.

Keywords: Alveogenesis; Lung development; PDGF-A; PDGFRα.