Division of Pulmonary Biology and.
Center for Lung Regenerative Medicine, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
JCI Insight. 2021 Mar 22;6(6):144863. doi: 10.1172/jci.insight.144863.
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.
一生中的通气依赖于肺腺泡的形成，肺腺泡形成广泛的表面积，使呼吸上皮细胞和肺微血管内皮细胞紧密相邻，从而实现有效的气体交换。肺泡的形态发生始于人类晚期妊娠和小鼠出生后的早期。肺泡分隔由多种细胞类型之间复杂的信号相互作用指导。在这里，我们证明了 IGF1 受体基因（Igf1r）在一小部分肺成纤维细胞中的表达是小鼠正常肺泡发生所必需的。出生后 Igf1r 的缺失导致肺泡简化，破坏了肺泡弹力蛋白网络和细胞外基质，而不改变肌成纤维细胞的分化或增殖。此外，Igf1r 的缺失损害了肺肌成纤维细胞的收缩特性，并抑制了肌球蛋白轻链（MLC）磷酸化和机械转导核 YAP 活性。肌成纤维细胞中 p-AKT、p-MLC 和核 YAP 的激活依赖于 Igf1r。AKT 的药理学激活增强了 MLC 磷酸化，增加了 YAP 的激活，并改善了体内的肺泡简化。IGF1R 控制着肌成纤维细胞中的机械信号转导，这是肺肺泡发生所必需的。
