Extracellular matrix stiffness dictates Wnt expression through integrin pathway.
Extracellular matrix stiffness dictates Wnt expression through integrin pathway.
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细胞外基质硬度通过整合素途径决定 Wnt 表达
DOI：
10.1038/srep20395
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发表时间：
2016-02-08
影响因子：
4.6
通讯作者：
Yang C
中科院分区：
文献类型：
--
作者：
Du J;Zu Y;Li J;Du S;Xu Y;Zhang L;Jiang L;Wang Z;Chien S;Yang C
细胞外基质（ECM）硬度在调节许多细胞类型的表型和行为中起着重要作用。然而，机械线索和随后的弹性触发通路的感知机制在很大程度上仍然未知。我们观察到坚硬的ECM显著增强了骨髓间充质干细胞和原代软骨细胞中Wnt/β-连环蛋白通路的几个成员的表达水平。刚性ECM对β-catenin的激活不依赖于Wnt信号，而是通过激活整合素/粘着斑激酶（FAK）途径而升高。积累的β-catenin随后结合到wnt 1启动子区域以上调基因转录，从而构成Wnt/β-catenin途径的正反馈。整合素激活的β-catenin/Wnt信号通路通过正反馈放大作用，介导Wnt信号在刚性ECM上的增强，参与骨髓间充质干细胞分化和原代软骨细胞表型维持的调控。目前整合素调控的Wnt 1表达和信号转导有助于理解ECM弹性调节细胞行为的分子机制。
It is well established that extracellular matrix (ECM) stiffness plays a significant role in regulating the phenotypes and behaviors of many cell types. However, the mechanism underlying the sensing of mechanical cues and subsequent elasticity-triggered pathways remains largely unknown. We observed that stiff ECM significantly enhanced the expression level of several members of the Wnt/β-catenin pathway in both bone marrow mesenchymal stem cells and primary chondrocytes. The activation of β-catenin by stiff ECM is not dependent on Wnt signals but is elevated by the activation of integrin/ focal adhesion kinase (FAK) pathway. The accumulated β-catenin then bound to the wnt1 promoter region to up-regulate the gene transcription, thus constituting a positive feedback of the Wnt/β-catenin pathway. With the amplifying effect of positive feedback, this integrin-activated β-catenin/Wnt pathway plays significant roles in mediating the enhancement of Wnt signal on stiff ECM and contributes to the regulation of mesenchymal stem cell differentiation and primary chondrocyte phenotype maintenance. The present integrin-regulated Wnt1 expression and signaling contributes to the understanding of the molecular mechanisms underlying the regulation of cell behaviors by ECM elasticity.