YAP/TAZ信号及核纤层蛋白在内源性应力微环境诱导干细胞成骨分化中的作用研究

项目名称： YAP/TAZ信号及核纤层蛋白在内源性应力微环境诱导干细胞成骨分化中的作用研究

项目编号： No.31470904

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 赵志河

作者单位： 四川大学

项目金额： 88万元

中文摘要： 促进干细胞定向分化并维持其表型稳定是再生医学研究的热点。课题组前期也发现外源性应力可促进MSCs成骨分化，但难以维持其体内表型稳定。内源性应力对MSCs定向分化的调控是近年来的新发现,且被证实对分化表型的维持较稳定，但其机制尚不清楚。Nature和Science分别在2012年和2013年报道了细胞骨架、YAP/TAZ信号以及核纤层蛋白Lamin A在不同组织硬度介导的力学信号转导中的重要作用。以此为依据，课题组建立了MSCs成骨分化的硬度-微环境应力刺激模型，发现Lamin蛋白与YAP/TAZ信号在内源性力学信号转导过程中存在偶联反馈效应。本项目拟在此基础上深入研究该偶联效应调控MSCs成骨分化的机制，阐明力学转导的细胞骨架与细胞核骨架调控机制，并将其应用于骨质疏松动物骨缺损模型，拓展该机制在病理性骨折修复及其它医学领域中的应用。

中文关键词： YAP/TAZ信号；核纤层蛋白；力学信号转导；骨组织工程；间充质干细胞

英文摘要： The leading eadge of tissue engineering is to learn how to regulate the differentiation of stem cells toward specific lineages and maintain their phenotypes. We have devoted to investigate the mechanotransduction mechanism during the osteogenic differentiation of MSCs (mesenchymal stem cells), and found that extrinsic force can induce osteogenic differentiation of MSCs in vitro; however, it failed to keep the osteogenic phenotypes stable in vivo. Recently, intrinsic force was found to regulate stem cell fate, and evidenced the effect of such intrinsic force in maintaining cell phenotypes. In 2012 and 2013, Nature and Science reported that YAP/TAZ/cytoskeleton signaling and nuclear lamin A played significant roles in tissue stiffness induced mechanotransduction. Moreover, Science reorted that lamin A scales with tissue stiffness and determine the intrinsic mechanotransduction pathways. Based on these previous studies in extrinsic mechanotransduction pathway, this project has established models of stiffness-mechanical induced osteogenic differentiation and found the coupling effect of lamins and YAP/TAZ in intrinsic mechanotransduction. This project will study the mechanism of such effect induced osteogenic differentiation of MSCs and elucidate the mechanisms of cytoskeleton and nucleoskeleton in mechanotransduction. This study will apply such mechanism in bone defect animal models, and will promote the application of biomechanics to bone tissue engineering and other medical areas.

英文关键词： YAP/TAZ signaling;lamin;mechanotransduction;bone tissue engineering;mesenchymal stem cells