[HTML][HTML] Mechanosensing by the α6-integrin confers an invasive fibroblast phenotype and mediates lung fibrosis

H Chen, J Qu, X Huang, A Kurundkar, L Zhu… - Nature …, 2016 - nature.com
H Chen, J Qu, X Huang, A Kurundkar, L Zhu, N Yang, A Venado, Q Ding, G Liu, VB Antony…
Nature communications, 2016nature.com
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 …
Abstract
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 α61)-integrin offers a novel anti-fibrotic strategy against lung fibrosis.
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