Mechanosensing by the α6-integrin confers an invasive fibroblast phenotype and mediates lung fibrosis.
Mechanosensing by the α6-integrin confers an invasive fibroblast phenotype and mediates lung fibrosis.
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DOI：
10.1038/ncomms12564
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发表时间：
2016-08-18
影响因子：
16.6
通讯作者：
Zhou Y
中科院分区：
文献类型：
--
作者：
Chen H;Qu J;Huang X;Kurundkar A;Zhu L;Yang N;Venado A;Ding Q;Liu G;Antony VB;Thannickal VJ;Zhou Y
基质硬化是肺纤维化的一个显著特征。在这项研究中，我们证明基质刚度调节纤维化肺肌成纤维细胞侵袭基底膜（BM）的能力。我们发现α6-整合素是一种机械传感整合素亚基，介导基质刚度调节的肌成纤维细胞侵袭。α6的表达增加，特别是B亚型（α6B），与β1整合素结合介导mmp -2依赖性BM胶原IV的细胞周蛋白水解，导致肌成纤维细胞侵袭。人特发性肺纤维化肺肌成纤维细胞在体外和体内高水平表达α6-整合素。基因消融表达胶原的间充质细胞α6或药物阻断基质刚度调节的α6表达可保护小鼠抗博来霉素损伤诱导的实验性肺纤维化。这些结果表明α6-整合素是一种基质刚度调节的机械敏感分子，赋予侵袭性成纤维细胞表型并介导实验性肺纤维化。针对这种机械传感α6(β1)-整合素提供了一种新的抗肺纤维化策略。基质硬化是肺纤维化的一个特征，在肺肌成纤维细胞中被放大。在这里，作者发现a6整合素在肺肌成纤维细胞中表达上调，以响应基质硬度，并且在实验性疾病模型中，这种整合素是肌成纤维细胞侵袭和纤维化所必需的。
Matrix stiffening is a prominent feature of pulmonary fibrosis. In this study, we demonstrate that matrix stiffness regulates the ability of fibrotic lung myofibroblasts to invade the basement membrane (BM). We identify α6-integrin as a mechanosensing integrin subunit that mediates matrix stiffness-regulated myofibroblast invasion. Increasing α6-expression, specifically the B isoform (α6B), couples β1-integrin to mediate MMP-2-dependent pericellular proteolysis of BM collagen IV, leading to myofibroblast invasion. Human idiopathic pulmonary fibrosis lung myofibroblasts express high levels of α6-integrin in vitro and in vivo. Genetic ablation of α6 in collagen-expressing mesenchymal cells or pharmacological blockade of matrix stiffness-regulated α6-expression protects mice against bleomycin injury-induced experimental lung fibrosis. These findings suggest that α6-integrin is a matrix stiffness-regulated mechanosensitive molecule which confers an invasive fibroblast phenotype and mediates experimental lung fibrosis. Targeting this mechanosensing α6(β1)-integrin offers a novel anti-fibrotic strategy against lung fibrosis. Matrix stiffening is a feature of pulmonary fibrosis, and is amplified by lung myofibroblasts. Here the authors find that a6 integrin expression is upregulated on lung myofibroblasts in response to matrix stiffness, and this integrin is required for myofibroblast invasion, and fibrosis in an experimental disease model.