PT  - JOURNAL ARTICLE
AU  - Amanda T Goodwin
AU  - Alison E John
AU  - Chitra Joseph
AU  - Anthony Habgood
AU  - Amanda L Tatler
AU  - Stefan Offermanns
AU  - Neil C Henderson
AU  - Gisli Jenkins
TI  - Stretch Regulates Alveologenesis Via Mesenchymal G<sub>αq/11</sub>-Mediated TGFβ2 Activation
AID  - 10.1101/2020.09.06.284778
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.09.06.284778
4099  - http://biorxiv.org/content/early/2020/09/07/2020.09.06.284778.short
4100  - http://biorxiv.org/content/early/2020/09/07/2020.09.06.284778.full
AB  - Alveolar development requires tight spatiotemporal regulation of numerous signalling pathways that are influenced by chemical and mechanical stimuli. Pericytes, perivascular mesenchymal cells, are key lung progenitor cells that are important for many developmental processes. Transforming growth factor-β (TGFβ) is essential for alveologenesis, and the G protein α subunits Gαq and Gα11 (Gαq/11) can transmit mechanical and chemical signals to activate TGFβ in epithelial cells. To understand the role of mesenchymal Gαq/11 in lung TGFβ signalling and lung development, we generated a mesenchymal Gαq/Gα11 knockout mouse (Pdgfrb-Cre+/−;Gnaqfl/fl;Gna11−/−). Pdgfrb-Cre+/−;Gnaqfl/fl;Gna11−/− mice exhibited abnormal alveolar development, with evidence of suppressed pericyte to myofibroblast differentiation and reduced lung TGFβ2 deposition. Cyclical mechanical stretch-induced TGFβ activation required Gαq/11 signalling and serine protease activity, but was independent of integrins, suggesting a 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.Competing Interest StatementGJ reports grants from Astra Zeneca, grants from Biogen, personal fees from Boehringer Ingelheim, personal fees from Daewoong, personal fees from Galapagos, grants from Galecto, grants from GlaxoSmithKline, personal fees from Heptares, non-financial support from NuMedii, grants and personal fees from Pliant, personal fees from Promedior, non-financial support from Redx, personal fees from Roche, Trustee for Action for Pulmonary Fibrosis.