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-β (TGFβ) is essential for alveologenesis and lung repair, and the G protein α subunits Gαq and Gα11 (Gαq/11) transmit mechanical and chemical signals to activate TGFβ in epithelial cells. To understand the role of mesenchymal Gαq/11 in lung development, we generated constitutive (Pdgfrb-Cre+/−;Gnaqfl/fl;Gna11−/−) and inducible (Pdgfrb-Cre/ERT2+/−;Gnaqfl/fl;Gna11−/−) mesenchymal Gαq/11 deleted mice. Mice with constitutive Gαq/11 gene deletion exhibited abnormal alveolar development, with suppressed myofibroblast differentiation, altered mesenchymal cell synthetic function, and reduced lung TGFβ2 deposition, as well as kidney abnormalities. Tamoxifen-induced mesenchymal Gαq/11 gene deletion in adult mice resulted in emphysema associated with reduced TGFβ2 and elastin deposition. Cyclical mechanical stretch-induced TGFβ activation required Gαq/11 signalling and serine protease activity, but was independent of integrins, suggesting an isoform-specific role for TGFβ2. These data highlight a previously undescribed mechanism of cyclical stretch-induced Gαq/11-dependent TGFβ2 signalling in mesenchymal cells, which is imperative for normal alveologenesis and maintenance of lung homeostasis.
Summary statement Mesenchymal cell Gαq/11 signalling regulates myofibroblast function and stretch-mediated TGFβ2 signalling, which are important for alveologenesis and organ homeostasis. These mechanisms are relevant to both developmental and adult lung disease.
Competing Interest Statement
GJ reports grants or contracts from Astra Zeneca, Biogen, Galecto, GlaxoSmithKline, Nordic Biosciences, RedX, Plaint, consulting fees from Bristol Myers Squibb, Chiesi, Daewoong, Veracyre, Resolution Therapeutics and Pliant, honoraria from Boehringer Ingelheim, Chiesi, Roch, PatientMPower, AstraZeneca, advisory roles with Boehringer Ingelheim, Galapagos, and Vicore, non-financial support from NuMedii, and is a Trustee for Action for Pulmonary Fibrosis. ATG, AEJ, CJ, AH, ALT, KS, MP, NCH, SO have no competing interests
Footnotes
An additional mouse model has been performed. This tamoxifen-inducible mesenchymal Gαq/11 deletion model resulted in emphysema in adult mice, suggesting that this pathway is also involved in lung homeostasis.