中文摘要：

细胞外基质弹性对细胞的迁移、周期、增殖、分化等功能均具有重要影响,尤其是对干细胞的分化命运具有重要调控作用.迄今为止,人们对这一现象背后的机理还远未认识清楚.整合素（integrin）作为细胞黏附分子,被认为是位于多种力学信号转导通路起点的力学传感器.本实验室在之前的工作中观察到细胞外基质弹性显著改变了β1 integrin的活化状态、亚细胞定位等.然而,细胞外基质弹性对β1 integrin活化水平的调节机制还不清楚.本文利用特异性识别β1 integrin活性构象的单克隆抗体观察到：a.与硬基底相比,较软的细胞外基质能够诱导骨髓间充质干细胞中活化的β1 integrin水平升高;b.较硬的细胞外基质能明显上调FAK-Raf-MEK-ERK通路的活性;c.抑制FAK-Raf信号通路能挽救较硬细胞外基质上较低的β1integrin活化水平.这些结果提示,较硬的细胞外基质可能通过激活FAK-Raf信号通路负反馈调控integrin的活性.综上所述,本文发现了一种细胞外基质弹性对integrin活化水平及其下游信号的调控方式,为理解细胞对基质弹性的感知机理提供了一个新的线索.

英文摘要：

ECM stiffness has profound effects on cell migration, cell cycle, proliferation, differentiation,especially stem cell fate dictation. The underlying mechanism has not been elucidated so far. As a cell-adhesive protein, integrin is known as a mechanosensor positioned at the beginning of mechanotransduction. Our previous work demonstrates that ECM stiffness regulates the activity level and subcellular distribution of β1 integrin.However, the mechanism of β1 integrin activity regulation by ECM stiffness is still unclear. In the present paper,by using a monoclonal antibody specifically recognizing the active conformation of β1 integrin, we observed that soft ECM significantly enhanced the level of active β1 integrin in comparison of stiff ECM. Meanwhile, the activity of FAK-Raf-MEK-ERK was markedly promoted by stiff ECM. The inhibition of FAK-Raf pathway rescued the low activity level of β1 integrin on stiff ECM, indicating that stiff ECM may inhibits β1 integrin activity by FAK-Raf pathway in a negative feedback manner. In summary, we found a mechanism of the regulation of β1 integrin activity and downstream signal by ECM stiffness and provide a cue for understanding the mechanosensing of ECM stiffness by cells.