三维细胞力学微环境对肌管形成及成熟化的作用机制研究

Injury of skeletal muscle can significantly affect human health and even induce disability and death. The emergence of engineered tissue constructs holds a potential for skeletal muscle repair and regeneration, which has an important academic value and clinical significance. The formation and maturation of myotube with polarity and multi-nucleus structures are key factors in skeletal muscle repair and regeneration. Recently, the effects of mechanical microenvironment on myotube formation and maturation have attracted lots of attention. However, the effects and mechanisms of mechanical microenvironment on such behaviors in three dimensions (3D) still remain unclear. Based on the previous research experience on construction of cell mechanical microenvironment in vitro, I propose to study the effect of mechanical microenvironment on myoblast behaviors in 3D. Firstly, the effects of tensile stress on myotube formation and maturation will be studied. Secondly, the key mechanotransduction pathways of myotube formation and maturation in 3D will be investigated. Finally, a mechanical model will be established to understand the effect of tensile stress on myotube formation and maturation at the molecular level. The results would provide new insight into skeletal muscle regeneration and related mechanobiology studies.

骨骼肌损伤会严重影响人类健康，重者可导致残疾或死亡。工程化组织的体外构建为骨骼肌的修复和再生提供了可能，具有重要的学术价值和临床意义。极性多核肌管的形成和成熟化是骨骼肌修复和再生的关键环节。近年来，力学微环境在肌管形成及成熟化中的作用受到了越来越多的关注。但是，目前三维微环境下应力刺激对肌管的形成及成熟化的作用及机制仍不清楚。本项目拟结合申请人前期在三维细胞力学微环境构建方面的研究基础，研究三维微环境中应力刺激对肌管形成及成熟化的影响规律；采用分子生物学实验方法，揭示应力刺激对肌管形成及成熟化的关键信号通路；借鉴统计力学、连续介质力学和分子模拟等方法，建立描述应力刺激对肌管形成及成熟化的力学模型，刻画力学-生物学信号综合调控网络，揭示应力刺激过程中可能的分子机制。研究结果将为功能性骨骼肌再生及相关力学生物学研究提供新的思路和方法。

骨骼肌修复和再生对治疗骨骼肌损伤具有重要的临床意义。极性多核肌管的形成和成熟化是骨骼肌修复和再生的关键环节。近年来，三维细胞模型越来越多的应用于功能性肌组织的体外构建。然而，微环境中力学刺激如何影响肌管的形成及成熟化仍不明晰。针对这一关键问题，本项目拟以实验和理论建模为研究手段，系统研究三维微环境中应力刺激对肌管形成及成熟化的作用机制。首先，基于前期建立的平台方法，构建应变可控的三维成肌细胞力学微环境，揭示拉伸应力刺激对肌管形成及成熟化的影响规律；并通过研究力学刺激，三维基质结构，细胞形态的相互关系，揭示力学调控肌管形成的作用机制。最后，通过构建大鼠废用型肌萎缩疾病模型，采用可注射性磁性水凝胶，系统研究了在体力学刺激对废用型肌萎缩的治疗效果，并开发了相关可穿戴设备，为力学生物学成果的临床转换提供可能。

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