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

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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.