Mechanobiology of tendon development, growth, and maturation

项目总结 在受伤的情况下，由于愈合不良和无法再生天然结构，肌腱功能受到影响。 有一个尚未满足的临床需求，有效的生物疗法，以改善肌腱愈合。然而，这是 受限于我们对基本肌腱生物学的不完全了解。尤其是对肌腱细胞命运的调控， 对于发育过程中的生长和成熟仍然知之甚少。 肌腱发育的一个关键调节因素是肌肉力量。在发育过程中，肌肉力量是 是肌腱形成和生长所必需的。然而，肌腱细胞翻译的机制 生物反应的机械线索(机械转导途径)，以及机械力是如何 调控发育的特定方面(细胞增殖、基质形成和功能成熟)不是 明白了。为了解决这一知识鸿沟，我们建立了一个3D工程肌腱平台来建模肌腱 发育过程中的机械生物学，因为在体内肌肉力量在发育过程中不易测量或控制 发育阶段。我们现在建议应用这个工程化肌腱平台来定义 细胞和基质对肌腱生长的要求及检测两条主要的力学转导途径 (YAP/TAZ、MRTF/SRF)。我们的中心前提是肌肉介导的肌腱在体内生长和成熟 体外和体内发育由YAP/TAZ和MRTF/SRF机械转导介导。我们进一步 提出这些途径调控肌腱发育的不同方面和不同阶段。

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.