The Fibroblast Integrin α11β1 Is Induced in a Mechanosensitive Manner Involving Activin A and Regulates Myofibroblast Differentiation
The Fibroblast Integrin α11β1 Is Induced in a Mechanosensitive Manner Involving Activin A and Regulates Myofibroblast Differentiation
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DOI：
10.1074/jbc.m109.078766
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发表时间：
2010-04-02
影响因子：
4.8
通讯作者：
Gullberg, Donald
中科院分区：
文献类型：
--
作者：
Carracedo, Sergio;Lu, Ning;Gullberg, Donald
纤维化组织的特征在于肌成纤维细胞过多。因此，了解诱导肌成纤维细胞分化的因素对于预防纤维化愈合至关重要。以往的研究表明，来自整合素介导的细胞外基质和细胞骨架之间的相互作用的机械应力促进肌成纤维细胞分化。整合素α 11 β 1是成纤维细胞上的胶原蛋白受体。为了确定α 11 β 1是否可以作为机械传感器来促进肌成纤维细胞表型，利用小鼠胚胎成纤维细胞和人角膜成纤维细胞。我们发现，α 11 mRNA和蛋白质水平上调小鼠胚胎成纤维细胞生长在连接的三维胶原蛋白凝胶和相反下调细胞生长在浮动凝胶。α 11上调可以通过手动分离胶原凝胶或通过细胞松弛素-D处理来防止。此外，SB-431542是一种通过ALK 4、ALK 5和ALK 7进行信号传导的抑制剂，可防止α 11的上调以及在连接条件下伴随的Smad 3磷酸化。在附着的凝胶中，TGF-β 1以其非活性形式分泌，但令人惊讶的是没有进一步活化，因此不影响α 11调节。然而，激活素A的抑制减弱了α 11的上调。为了确定α 11在肌成纤维细胞分化中的作用，用针对α 11的小干扰RNA转染人角膜成纤维细胞，其降低α-平滑肌肌动蛋白表达和肌成纤维细胞分化。我们的数据表明，α 11 β 1是由细胞/基质应力涉及激活素A和Smad 3和α 11 β 1调节肌成纤维细胞分化。
Fibrotic tissue is characterized by an overabundance of myofibroblasts. Thus, understanding the factors that induce myofibroblast differentiation is paramount to preventing fibrotic healing. Previous studies have shown that mechanical stress derived from the integrin-mediated interaction between extracellular matrix and the cytoskeleton promotes myofibroblast differentiation. Integrin alpha 11 beta 1 is a collagen receptor on fibroblasts. To determine whether alpha 11 beta 1 can act as a mechanosensor to promote the myofibroblast phenotype, mouse embryonic fibroblasts and human corneal fibroblasts were utilized. We found that alpha 11 mRNA and protein levels were up-regulated in mouse embryonic fibroblasts grown in attached three-dimensional collagen gels and conversely down-regulated in cells grown in floating gels. alpha 11 up-regulation could be prevented by manually detaching the collagen gels or by cytochalasin-D-treatment. Furthermore, SB-431542, an inhibitor of signaling via ALK4, ALK5, and ALK7, prevented the up-regulation of alpha 11 and the concomitant phosphorylation of Smad3 under attached conditions. In attached gels, TGF-beta 1 was secreted in its inactive form but surprisingly not further activated, thus not influencing alpha 11 regulation. However, inhibition of activin A attenuated the up-regulation of alpha 11. To determine the role of alpha 11 in myofibroblast differentiation, human corneal fibroblasts were transfected with small interfering RNA to alpha 11, which decreased alpha-smooth muscle actin expression and myofibroblast differentiation. Our data suggest that alpha 11 beta 1 is regulated by cell/matrix stress involving activin A and Smad3 and that alpha 11 beta 1 regulates myofibroblast differentiation.