Stretch Regulates Alveologenesis Via Mesenchymal Gαq/11-Mediated TGFβ2 Activation

Abstract

Alveolar development and repair require tight spatiotemporal regulation of numerous signalling pathways that are influenced by chemical and mechanical stimuli. Mesenchymal cells play key roles in numerous developmental processes. Transforming growth factor-{beta} (TGF{beta}) is essential for alveologenesis and lung repair, and the G protein subunits Gq and G11 (Gq/11) transmit mechanical and chemical signals to activate TGF{beta} in epithelial cells. To understand the role of mesenchymal Gq/11 in lung development, we generated constitutive (Pdgfrb-Cre+/-;Gnaqfl/fl;Gna11-/-) and inducible (Pdgfrb-Cre/ERT2+/-;Gnaqfl/fl;Gna11-/-) mesenchymal Gq/11 deleted mice. Mice with constitutive Gq/11 gene deletion exhibited abnormal alveolar development, with suppressed myofibroblast differentiation, altered mesenchymal cell synthetic function, and reduced lung TGF{beta}2 deposition, as well as kidney abnormalities. Tamoxifen-induced mesenchymal Gq/11 gene deletion in adult mice resulted in emphysema associated with reduced TGF{beta}2 and elastin deposition. Cyclical mechanical stretch-induced TGF{beta} activation required Gq/11 signalling and serine protease activity, but was independent of integrins, suggesting an isoform-specific role for TGF{beta}2. These data highlight a previously undescribed mechanism of cyclical stretch-induced Gq/11-dependent TGF{beta}2 signalling in mesenchymal cells, which is imperative for normal alveologenesis and maintenance of lung homeostasis. Summary statementMesenchymal cell Gq/11 signalling regulates myofibroblast function and stretch-mediated TGF{beta}2 signalling, which are important for alveologenesis and organ homeostasis. These mechanisms are relevant to both developmental and adult lung disease.