Mechanobiology of tendon development, growth, and maturation

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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.