Origins, potency, and heterogeneity of skeletal muscle fibro-adipogenic progenitors—time for new definitions

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.

Facioscapulohumeral dystrophy transcriptome signatures correlate with different stages of disease and are marked by different MRI biomarkers

“…This may be a reflection of the complex tissue changes that occur during disease progression as the earliest RNA microarray studies in FSHD already identified a transcriptional dysregulation of vascular smooth muscle or endothelial cell genes 46 , 47 . Finally, we observed an increase of both defined fibro-adipogenic progenitor cell types (FAPs), which corresponds with the role for FAPs in response to muscle inflammation, regeneration and repair 48 . Of note, FAPs have been described to be increased after DUX4 expression in an inducible DUX4 mouse model, and FAPs may play a role in muscle fibrosis and fat replacement in FSHD 49 .…”

A guide to examining intramuscular fat formation and its cellular origin in skeletal muscle

“…The infiltration of healthy muscle tissue with fatty fibrosis is a prominent feature of Duchenne Muscular Dystrophy (DMD) and other neuromuscular diseases, as well as sarcopenia, obesity, and diabetes 1,2 . Although increased fat infiltration in these conditions is strongly associated with decreased muscle function, our knowledge of why and how intramuscular fat forms is still limited.…”

Fibro-adipogenic progenitors in skeletal muscle homeostasis, regeneration and diseases

“…The developmental origin of FAPs has been comprehensively reviewed recently [ 21 , 22 ]. The seminal work of Kardon and colleagues in the early 2000s identified a population of TCF7L2/TCF4+ (transcription factor 4; also known as transcription factor 7 like 2; TCF7L2) cells arising from the mesoderm lateral plate in the chick and mouse [ 23 ].…”

“…FAPs are located in the interstitial space of resting [ 21 ] or regenerating skeletal muscle ( figure 2 ). They were initially described for their bi-potent ability to differentiate into fibrogenic or adipogenic cells, but not myogenic cells [ 15 , 17 ].…”