The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-beta1.
The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-beta1.
复制标题
纤连蛋白结构域ED-A通过转化生长因子-Beta1，对于肌纤维细胞表型诱导至关重要。
DOI：
10.1083/jcb.142.3.873
复制
发表时间：
1998-08-10
影响因子：
7.8
通讯作者：
Gabbiani, G
中科院分区：
文献类型：
--
作者：
Serini, G;Bochaton-Piallat, M L;Ropraz, P;Geinoz, A;Borsi, L;Zardi, L;Gabbiani, G
转化生长因子-β1（TGFβ1）是肌成纤维细胞分化的主要促进剂，可诱导α-平滑肌（sn）肌动蛋白，调节粘附受体的表达，并增强细胞外基质（ECM）分子的合成，包括ED-A纤连蛋白（FN），一种在伤口愈合和纤维化变化期间重新表达的同种型。我们在此报道，在体内肉芽组织演变过程中和体外TGFβ1刺激后，成纤维细胞的ED-A FN沉积先于α-SM肌动蛋白表达。此外，不同成纤维细胞群体中α-SM actin和ED-A FN的体外表达之间存在相关性。将成纤维细胞接种在ED-A FN上本身并不引起α-SM肌动蛋白表达;然而，将成纤维细胞与抗ED-A单克隆抗体IST-9孵育可特异性阻断TGFβ1触发的α-SM肌动蛋白和I型胶原蛋白的增强，但不能阻断纤溶酶原激活物抑制剂-1 mRNA的增强。有趣的是，相同的抑制作用是由可溶性重组结构域ED-A，但这些抑制剂都不改变FN矩阵组装。我们的研究结果表明，含有ED-A的聚合FN是TGFβ1诱导成肌纤维细胞表型所必需的，并确定了一种迄今为止未知的基于ECM衍生的允许性外部信号传导的、在细胞因子本身控制下的、由姜黄素决定的基因刺激机制。
Transforming growth factor-β1 (TGFβ1), a major promoter of myofibroblast differentiation, induces α-smooth muscle (sn) actin, modulates the expression of adhesive receptors, and enhances the synthesis of extracellular matrix (ECM) molecules including ED-A fibronectin (FN), an isoform de novo expressed during wound healing and fibrotic changes. We report here that ED-A FN deposition precedes α-SM actin expression by fibroblasts during granulation tissue evolution in vivo and after TGFβ1 stimulation in vitro. Moreover, there is a correlation between in vitro expression of α-SM actin and ED-A FN in different fibroblastic populations. Seeding fibroblasts on ED-A FN does not elicit per se α-SM actin expression; however, incubation of fibroblasts with the anti-ED-A monoclonal antibody IST-9 specifically blocks the TGFβ1-triggered enhancement of α-SM actin and collagen type I, but not that of plasminogen activator inhibitor-1 mRNA. Interestingly, the same inhibiting action is exerted by the soluble recombinant domain ED-A, but neither of these inhibitory agents alter FN matrix assembly. Our findings indicate that ED-A–containing polymerized FN is necessary for the induction of the myofibroblastic phenotype by TGFβ1 and identify a hitherto unknown mechanism of cytokine-determined gene stimulation based on the generation of an ECM-derived permissive outside in signaling, under the control of the cytokine itself.