Mechanobiology of tendon development, growth, and maturation

项目摘要 损伤后，由于愈合不良和无法再生天然结构，肌腱功能受损。 对于改善肌腱愈合的有效生物疗法存在未满足的临床需求。但这是 受限于我们对基本肌腱生物学的不完全理解。特别是，肌腱细胞命运的调节， 生长和发育过程中的成熟仍然知之甚少。 肌腱发育的一个关键调节器是肌肉力量。在发育过程中，肌肉力量 肌腱形成和生长所必需的。然而，肌腱细胞翻译的机制 机械信号转化为生物反应（机械传导途径），以及机械力如何 调节发育的特定方面（细胞增殖、基质加工和功能成熟）， 明白为了解决这一知识缺口，我们建立了一个3D工程肌腱平台来建模肌腱 由于肌肉力量在发育过程中不容易在体内测量或控制， 发育阶段我们现在建议应用这种工程化肌腱平台来定义以下方面的贡献： 细胞和基质对肌腱生长的影响，并测试两种主要的机械传导途径的要求 (YAP/TAZ，MRTF/SRF）。我们的中心前提是，肌肉介导的肌腱生长和成熟过程中， 体外和体内发育由雅普/TAZ和MRTF/SRF机械转导介导。我们进一步 提出这些途径调节肌腱发育的不同方面和阶段。

PROJECT SUMMARY With injury, tendon function is compromised due to poor healing and failure to regenerate native structure. There is an unmet clinical need for effective biologic therapies that improve tendon healing. However, this is limited by our incomplete understanding of basic tendon biology. In particular, the regulation of tendon cell fate, growth, and maturation during development remains poorly understood. One critical regulator of tendon development is muscle forces. During development, muscle forces are required for tendon patterning and growth. However, the mechanisms by which tendon cells translate mechanical cues into biological responses (mechanotransduction pathways), and how mechanical forces regulate specific aspects of development (cell proliferation, matrix elaboration, and functional maturation) is not understood. To address this knowledge gap, we established a 3D engineered tendon platform to model tendon mechanobiology during development, since muscle forces are not easily measured or controlled in vivo during developmental stages. We now propose to apply this engineered tendon platform to define the contributions of cells and matrix to tendon growth and test the requirement of two major mechanotransduction pathways (YAP/TAZ, MRTF/SRF). Our central premise is that muscle-mediated tendon growth and maturation during in vitro and in vivo development is mediated by YAP/TAZ and MRTF/SRF mechanotransduction. We further propose these pathways regulate distinct aspects and stages of tendon development.