Stretch regulates alveologenesis and homeostasis via mesenchymal Gαq/11-mediated TGFβ2 activation

Goodwin, Amanda T.; John, Alison E.; Joseph, Chitra; Habgood, Anthony; Tatler, Amanda L.; Susztak, Katalin; Palmer, Matthew; Offermanns, Stefan; Henderson, Neil C.; Jenkins, R. Gisli

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 in this model. 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.

• Journal Article Type: Article
• Acceptance Date: Apr 5, 2023
• Online Publication Date: Apr 27, 2023
• Publication Date: May 1, 2023
• Deposit Date: May 6, 2023
• Publicly Available Date: May 11, 2023
• Journal: Development
• Print ISSN: 0950-1991
• Electronic ISSN: 1477-9129
• Publisher: The Company of Biologists
• Peer Reviewed: Peer Reviewed
• Volume: 150
• Issue: 9
• DOI: https://doi.org/10.1242/dev.201046
• Keywords: Alveologenesis, TGFβ, Gαq/11, GPCR, Lung development, Cyclical mechanical stretch
• Public URL: https://nottingham-repository.worktribe.com/output/20008340
• Publisher URL: https://journals.biologists.com/dev/article/doi/10.1242/dev.201046/307341/Stretch-regulates-alveologenesis-and-homeostasis
• Additional Information: © 2023. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed