Diversity Supplement for: Engineered Asymmetric Hydrogel for Muscle Stem Cell Polarity and Fate Specification

项目摘要 纤维成脂前体细胞(FAPs)是一种肌间充质基质细胞，支持肌肉生长 卫星细胞(MUSC)的功能包括激活、增殖和分化。与MuSCs不同，这些细胞 驻留在肌肉间质空间内，因此通过旁分泌因子与MuSCs进行交流。在……里面 正常的肌肉再生，激活的FAP在炎症消退和再生时经历细胞凋亡 收益。然而，在慢性肌肉损伤和疾病中，激活的FAP持续存在，并分化为 肌成纤维细胞或脂肪细胞分别导致纤维化和脂肪渗透。然而，到目前为止，有一个 对FAP如何与其微环境相互作用以调节其激活的了解有限， 扩散和命运决定。在这份多样性补充申请中，我们将确定 FAP通过机械敏感的PIEZO1离子通道对被动和主动机械信号作出反应的作用。 这项研究通过揭示FAP是如何整合的，加强和扩大了母公司R01项目的范围 生物物理信号来自其合成的利基，并提供额外的手段来控制MUSC的极性和 在设计的不对称壁龛中的细胞分裂。为了实现这一目标，目标1将决定PIEZO1如何监管 FAP的激活、增殖和分化。目标2将确定FAP中的PIEZO1如何调节 细胞外基质硬度机械传感。目标3将确定FAP中的PIEZO1如何调节响应性 到拉伸加载和卸载。这项研究的结果将促进对FAP的现有认识 生物学，确定可用来减轻骨骼肌损伤和疾病中的纤维化和脂肪渗透的药物靶点， 以及用于扩展MSC和/或生产FAP的体外FAP制造平台的设计 用于脱细胞治疗的分泌组。

PROJECT ABSTRACT Fibro-adipogenic progenitors (FAPs) are muscle-resident mesenchymal stromal cells that support muscle satellite cell (MuSC) function, including activation, proliferation, and differentiation. Unlike MuSCs, these cells reside within the muscle interstitial space and thus communicate with MuSCs through paracrine factors. In normal muscle regeneration, activated FAPs undergo apoptosis as the inflammation resolves and regeneration proceeds. However, in chronic muscle injuries and diseases, activated FAPs persist and differentiate into either myofibroblasts or adipocytes that drive fibrosis and fatty infiltration, respectively. However, to date, there is a limited understanding of how the FAPs interact with their microenvironment to regulate their activation, proliferation, and fate determination. In this Diversity Supplement application, we will determine the mechanistic role by which FAPs respond to passive and active mechanical signals via mechanosensitive PIEZO1 ion channel. This research strengthens and expands the scope of the parent R01 project by revealing how FAPs integrate biophysical signals derived from their synthetic niche and provide additional means to control MuSC polarity and cell divisions in the engineered asymmetric niche. Towards this goal, Aim 1 will determine how PIEZO1 regulates FAPs activation, proliferation, and differentiation. Aim 2 will determine how PIEZO1 in FAPs regulates extracellular matrix stiffness mechanosensing. Aim 3 will determine how PIEZO1 in FAPs regulates responsivity to tensile loading and unloading. The outcomes of this research will advance the current knowledge of FAPs biology, identify druggable targets to mitigate fibrosis and fatty infiltration in skeletal muscle injuries and diseases, and inform the design of ex vivo FAPs manufacturing platform for expanding MuSCs and/or producing FAPs secretome for acellular therapies.