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 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.

Automated summary

Ventilation throughout life depends on the formation of pulmonary alveoli, which are initiated in late gestation in humans and early postnatal period in mice. Study shows that the IGF1 receptor gene in a subset of pulmonary fibroblasts is essential for normal alveologenesis in mice, controlling mechanotransduction in myofibroblasts for lung alveologenesis. Loss of IGF1R impairs contractile properties of lung myofibroblasts, inhibiting important signaling pathways for gas exchange.