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ResearchIn-Press PreviewPulmonology Open Access | 10.1172/jci.insight.144863

IGF1R controls mechanosignaling in myofibroblasts required for pulmonary alveologenesis

Hua He,1 John Snowball,1 Fei Sun,2 Cheng-Lun Na,1 and Jeffrey A. Whitsett3

1Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

2Center for Lung Regenerative Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

3Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

Find articles by He, H. in: JCI | PubMed | Google Scholar

1Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

2Center for Lung Regenerative Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

3Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

Find articles by Snowball, J. in: JCI | PubMed | Google Scholar

1Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

2Center for Lung Regenerative Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

3Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

Find articles by Sun, F. in: JCI | PubMed | Google Scholar

1Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

2Center for Lung Regenerative Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

3Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

Find articles by Na, C. in: JCI | PubMed | Google Scholar |

1Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

2Center for Lung Regenerative Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

3Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

Find articles by Whitsett, J. in: JCI | PubMed | Google Scholar

Published February 16, 2021 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.144863.
Copyright © 2021, He et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 16, 2021 - Version history
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Abstract

Ventilation throughout life is dependent upon the formation of pulmonary alveoli which create an extensive surface area wherein the close apposition of respiratory epithelium and endothelial cells of the pulmonary microvascular enables efficient gas exchange. Morphogenesis of the alveoli initiates at late gestation in humans and the early postnatal period in the mouse. Alveolar septation are directed by complex signaling interactions among multiple cell types. Herein, we demonstrate that the expression of insulin-like growth factor 1 receptor (Igf1r) by a subset of pulmonary fibroblasts is required for normal alveologenesis in mice. Postnatal deletion of Igf1r caused alveolar simplification, disrupting alveolar elastin networks and extracellular matrix without altering myofibroblast differentiation or proliferation. Loss of Igf1r impaired contractile properties of lung myofibroblasts, inhibited myosin light chain (MLC) phosphorylation and mechanotransductive nuclear YAP activity. Activation of p-AKT, p-MLC and nuclear YAP in myofibroblasts was dependent on Igf1r. Pharmacologic activation of AKT enhanced MLC phosphorylation, increased YAP activation and ameliorated alveolar simplification in vivo. IGF1R controls mechanosignaling in myofibroblasts required for lung alveologenesis.

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