Abstract：
Skin is constantly exposed to injuries that are repaired with different outcomes, either regeneration or scarring. Scars result from fibrotic processes modulated by cellular physical forces transmitted by integrins. Fibronectin (FN) is a major component in the provisional matrix assembled to repair skin wounds. FN enables cell adhesion binding of α5β1/αIIbβ3 and αv-class integrins to an RGD-motif. An additional linkage for α5/αIIb is the synergy site located in close proximity to the RGD motif. The mutation to impair the FN synergy region (Fn1syn/syn) demonstrated that its absence permits complete development. However, only with the additional engagement to the FN synergy site do cells efficiently resist physical forces. To test how the synergy site-mediated adhesion affects the course of wound healing fibrosis, we used a mouse model of skin injury and in-vitro migration studies with keratinocytes and fibroblasts on FNsyn. The loss of FN synergy site led to normal re-epithelialization caused by two opposing migratory defects of activated keratinocytes and, in the dermis, induced reduced fibrotic responses, with lower contents of myofibroblasts and FN deposition and diminished TGF-β1-mediated cell signalling. We demonstrate that weakened α5β1-mediated traction forces on FNsyn cause reduced TGF-β1 release from its latent complex.
摘要：
皮肤经常暴露于以不同结果修复的损伤中，再生或疤痕。疤痕是由整合素传递的细胞物理力调节的纤维化过程产生的。纤连蛋白(FN)是组装以修复皮肤创伤的临时基质中的主要组分。FN使α5β1/αIIbβ3和αv类整联蛋白与RGD基序的细胞粘附结合。α5/αIIb的另一个连接是位于RGD基序附近的协同位点。损害FN协同作用区（Fn1syn/syn）的突变表明，其缺失允许完全发育。然而,只有与FN协同位点的额外接合，细胞才能有效抵抗物理力。为了测试协同位点介导的粘附如何影响伤口愈合纤维化的过程，我们使用FNsyn上的角质形成细胞和成纤维细胞的皮肤损伤小鼠模型和体外迁移研究。FN协同作用位点的丧失导致由活化角质形成细胞的两个相反的迁移缺陷引起的正常再上皮化，在真皮中，诱导减少纤维化反应，肌成纤维细胞和FN沉积含量较低，TGF-β1介导的细胞信号传导减弱。我们证明，减弱的α5β1介导的FNsyn牵引力会导致TGF-β1从其潜在复合物中的释放减少。
