Fiore Vincent F, Strane Patrick W, Bryksin Anton V, White Eric S, Hagood James S, Barker Thomas H
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332.
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109.
J Cell Biol. 2015 Oct 12;211(1):173-90. doi: 10.1083/jcb.201505007.
Progressive fibrosis is characterized by excessive deposition of extracellular matrix (ECM), resulting in gross alterations in tissue mechanics. Changes in tissue mechanics can further augment scar deposition through fibroblast mechanotransduction. In idiopathic pulmonary fibrosis, a fatal form of progressive lung fibrosis, previous work has shown that loss of Thy-1 (CD90) expression in fibroblasts correlates with regions of active fibrogenesis, thus representing a pathologically relevant fibroblast subpopulation. We now show that Thy-1 is a regulator of fibroblast rigidity sensing. Thy-1 physically couples to inactive αvβ3 integrins via its RGD-like motif, altering baseline integrin avidity to ECM ligands and also facilitating preadhesion clustering of integrin and membrane rafts via Thy-1's glycophosphatidylinositol tether. Disruption of Thy-1-αvβ3 coupling altered recruitment of Src family kinases to adhesion complexes and impaired mechanosensitive, force-induced Rho signaling, and rigidity sensing. Loss of Thy-1 was sufficient to induce myofibroblast differentiation in soft ECMs and may represent a physiological mechanism important in wound healing and fibrosis.
进行性纤维化的特征是细胞外基质（ECM）过度沉积，导致组织力学发生显著改变。组织力学的变化可通过成纤维细胞的机械转导进一步加剧瘢痕沉积。在特发性肺纤维化（一种进行性肺纤维化的致命形式）中，先前的研究表明，成纤维细胞中Thy-1（CD90）表达的丧失与活跃的纤维化区域相关，因此代表了一种病理相关的成纤维细胞亚群。我们现在表明，Thy-1是成纤维细胞硬度感知的调节因子。Thy-1通过其RGD样基序与无活性的αvβ3整合素物理结合，改变整合素对ECM配体的基线亲和力，并通过Thy-1的糖磷脂酰肌醇连接促进整合素和膜筏的预粘附聚集。Thy-1-αvβ3偶联的破坏改变了Src家族激酶向粘附复合物的募集，并损害了机械敏感的、力诱导的Rho信号传导和硬度感知。Thy-1的缺失足以在柔软的ECM中诱导肌成纤维细胞分化，这可能代表了在伤口愈合和纤维化中起重要作用的一种生理机制。
