Abstract
Striated muscle is a highly plastic and regenerative organ that regulates body movement, temperature, and metabolism—all the functions needed for an individual’s health and well-being. The muscle connective tissue’s main components are the extracellular matrix and its resident stromal cells, which continuously reshape it in embryonic development, homeostasis, and regeneration. Fibro-adipogenic progenitors are enigmatic and transformative muscle-resident interstitial cells with mesenchymal stem/stromal cell properties. They act as cellular sentinels and physiological hubs for adult muscle homeostasis and regeneration by shaping the microenvironment by secreting a complex cocktail of extracellular matrix components, diffusible cytokines, ligands, and immune-modulatory factors. Fibro-adipogenic progenitors are the lineage precursors of specialized cells, including activated fibroblasts, adipocytes, and osteogenic cells after injury. Here, we discuss current research gaps, potential druggable developments, and outstanding questions about fibro-adipogenic progenitor origins, potency, and heterogeneity. Finally, we took advantage of recent advances in single-cell technologies combined with lineage tracing to unify the diversity of stromal fibro-adipogenic progenitors. Thus, this compelling review provides new cellular and molecular insights in comprehending the origins, definitions, markers, fate, and plasticity of murine and human fibro-adipogenic progenitors in muscle development, homeostasis, regeneration, and repair.
Highlights
In mammals, skeletal muscle represents ~ 30–40% of the total body mass, regulating body temperature, metabolism, and physical activity
Vallecillo-García and colleagues showed that the source of developmental extracellular matrix (ECM) in limb muscles is a heterogeneous population of Platelet-derived growth factor receptor alpha (PDGFRα)-expressing progenitors called embryonic Fibro-adipogenic progenitors (FAPs), closely resembling the population of adult stromal cells we have described, along with other groups [1, 2, 6, 23, 24, 26]
Using similar lineage tracing strategies we have demonstrated that cardiac PDGFRα+ FAPs can cause fibrofatty infiltration within the myocardium in an arrhythmogenic cardiomyopathy mouse model driven by the conditional deletion of the quiescence-associated factor Hypermethylated in Cancer 1 (Hic1) in heart FAPs [73]
Summary
Skeletal muscle represents ~ 30–40% of the total body mass, regulating body temperature, metabolism, and physical activity. Skeletal muscles are recognized as highly plastic tissue, illustrated by atrophic or hypertrophic changes when disused or trained. Mammalian adult skeletal muscle has extraordinary regeneration capabilities upon injury, making the organ a perfect model to study regeneration and repair, and investigate the contribution of adult stem and interstitial cells in settings of acute or chronic injury. The muscle connective tissue (MCT) components are the extracellular matrix (ECM) and its stromal cells, which actively produce, maintain, and remodel this dynamic scaffold during development, homeostasis, and after trauma. Among the several cell types that participate in muscle regeneration, tissue-resident mesenchymal progenitors play a crucial role by providing signaling cues that modulate other muscle-resident cells’ function, and actively remodel the ECM during this process.
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