IGF1R controls mechanosignaling in myofibroblasts required for pulmonary alveologenesis
Ventilation throughout life is dependent on the formation of pulmonary alveoli, which create an extensive surface area in which the close apposition of respiratory epithelium and endothelial cells of the pulmonary microvascular enables efficient gas exchange. Morphogenesis of the alveoli initiates a...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2021-03-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.144863 |
| _version_ | 1831584862922866688 |
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| author | Hua He John Snowball Fei Sun Cheng-Lun Na Jeffrey A. Whitsett |
| author_facet | Hua He John Snowball Fei Sun Cheng-Lun Na Jeffrey A. Whitsett |
| author_sort | Hua He |
| collection | DOAJ |
| description | Ventilation throughout life is dependent on the formation of pulmonary alveoli, which create an extensive surface area in which 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 is directed by complex signaling interactions among multiple cell types. Here, we demonstrate that IGF1 receptor gene (Igf1r) expression 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. Moreover, loss of Igf1r impaired contractile properties of lung myofibroblasts and 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. |
| first_indexed | 2024-12-17T21:08:02Z |
| format | Article |
| id | doaj.art-000911eae4024cc79186451846740115 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-12-17T21:08:02Z |
| publishDate | 2021-03-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-000911eae4024cc791864518467401152022-12-21T21:32:32ZengAmerican Society for Clinical investigationJCI Insight2379-37082021-03-0166IGF1R controls mechanosignaling in myofibroblasts required for pulmonary alveologenesisHua HeJohn SnowballFei SunCheng-Lun NaJeffrey A. WhitsettVentilation throughout life is dependent on the formation of pulmonary alveoli, which create an extensive surface area in which 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 is directed by complex signaling interactions among multiple cell types. Here, we demonstrate that IGF1 receptor gene (Igf1r) expression 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. Moreover, loss of Igf1r impaired contractile properties of lung myofibroblasts and 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.https://doi.org/10.1172/jci.insight.144863Pulmonology |
| spellingShingle | Hua He John Snowball Fei Sun Cheng-Lun Na Jeffrey A. Whitsett IGF1R controls mechanosignaling in myofibroblasts required for pulmonary alveologenesis JCI Insight Pulmonology |
| title | IGF1R controls mechanosignaling in myofibroblasts required for pulmonary alveologenesis |
| title_full | IGF1R controls mechanosignaling in myofibroblasts required for pulmonary alveologenesis |
| title_fullStr | IGF1R controls mechanosignaling in myofibroblasts required for pulmonary alveologenesis |
| title_full_unstemmed | IGF1R controls mechanosignaling in myofibroblasts required for pulmonary alveologenesis |
| title_short | IGF1R controls mechanosignaling in myofibroblasts required for pulmonary alveologenesis |
| title_sort | igf1r controls mechanosignaling in myofibroblasts required for pulmonary alveologenesis |
| topic | Pulmonology |
| url | https://doi.org/10.1172/jci.insight.144863 |
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