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

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.

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。

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。课题组前期建立了 MSCs 成骨分化的硬度-微环境应力刺激模型，发现 Lamins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。本项目拟明确Lamin A在响应并传导力学刺激中的核心地位及作用，探索力学刺激跨细胞核膜转导的机制及通路，为微环境应力调控干细胞分化提供靶标；明确BAPN在机体内骨缺损中干细胞成骨分化的调控作用，为治疗性干预骨组织改建提供新的思路。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。