Stretch Regulates Alveologenesis and Homeostasis Via Mesenchymal G aq/11 -Mediated TGFß2 Activation
Stretch Regulates Alveologenesis and Homeostasis Via Mesenchymal G aq/11 -Mediated TGFß2 Activation
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拉伸通过间充质 G aq/11 介导的 TGFα2 激活调节肺泡生成和体内平衡
DOI：
10.1101/2020.09.06.284778
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Goodwin A
中科院分区：
文献类型：
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作者：
Goodwin A
肺泡的发育和修复需要严格的时空调控的许多信号转导途径的化学和机械刺激的影响。间充质细胞在许多发育过程中发挥关键作用。转化生长因子β（TGFβ）是肺泡形成和肺修复所必需的，G蛋白α亚基Gα q和Gα11（Gαq/11）通过传递机械和化学信号激活上皮细胞中的TGFβ。为了了解间充质Gαq/11在肺发育中的作用，我们产生了组成型（Pdgfrb-Cre+/−;Gnaqfl/fl; Gna 11 −/−）和诱导型（Pdgfrb-Cre/ERT 2 +/−;Gnaqfl/fl; Gna 11 −/−）间充质Gαq/11缺失小鼠。组成性Gαq/11基因缺失的小鼠表现出肺泡发育异常，肌成纤维细胞分化受到抑制，间充质细胞合成功能改变，肺TGFβ2沉积减少，以及肾脏异常。他莫昔芬诱导的成年小鼠间充质Gαq/11基因缺失导致肺气肿，与TGFβ2和弹性蛋白沉积减少相关。周期性机械牵张诱导的TGFβ活化需要Gαq/11信号传导和丝氨酸蛋白酶活性，但不依赖于整合素，表明TGFβ2在该模型中具有亚型特异性作用。这些数据强调了一种以前未描述的间充质细胞中周期性牵张诱导的Gαq/11依赖性TGFβ2信号传导机制，这对于正常肺泡形成和维持肺内稳态至关重要。
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 Gαqand Gα11(Gαq/11) transmit mechanical and chemical signals to activate TGFβ in epithelial cells. To understand the role of mesenchymal Gαq/11in lung development, we generated constitutive (Pdgfrb-Cre+/−;Gnaqfl/fl;Gna11−/−) and inducible (Pdgfrb-Cre/ERT2+/−;Gnaqfl/fl;Gna11−/−) mesenchymal Gαq/11deleted mice. Mice with constitutive Gαq/11gene 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/11gene deletion in adult mice resulted in emphysema associated with reduced TGFβ2 and elastin deposition. Cyclical mechanical stretch-induced TGFβ activation required Gαq/11signalling 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.