It takes all kinds: heterogeneity among satellite cells and fibro-adipogenic progenitors during skeletal muscle regeneration

Abstract

Vertebrate skeletal muscle is composed of multinucleate myofibers that are surrounded by muscle connective tissue. Following injury, muscle is able to robustly regenerate because of tissue-resident muscle stem cells, called satellite cells. In addition, efficient and complete regeneration depends on other cells resident in muscle - including fibro-adipogenic progenitors (FAPs). Increasing evidence from single-cell analyses and genetic and transplantation experiments suggests that satellite cells and FAPs are heterogeneous cell populations. Here, we review our current understanding of the heterogeneity of satellite cells, their myogenic derivatives and FAPs in terms of gene expression, anatomical location, age and timing during the regenerative process - each of which have potentially important functional consequences.

Keywords: FAP; Fibro-adipogenic progenitor; Muscle; Regeneration; Satellite cell.

Fig. 1.

Populations of satellite cells, FAPs and myonuclei in uninjured skeletal muscle. Genetic studies support the existence of at least two subpopulations of quiescent satellite cells. Stem quiescent satellite cells have been identified by expression of high levels of Pax7 (Rocheteau et al., 2012) and by absence of expression of Myf5 (Kuang et al., 2007). Stem cells resistant to stress express Pax3 (Der Vartanian et al., 2019; Scaramozza et al., 2019). Myonuclei adjacent to neuromuscular junctions (NMJ) and myotendinous junctions (MTJ) are distinct from myonuclei along the main body of the myofiber (Jacobson et al., 2001; Koch et al., 2004; Petrany et al., 2020). There is currently no consensus on whether there are multiple subpopulations of quiescent FAPs. Muhl et al. (2020) identified FAP subpopulations localized to different muscle regions, including adjacent to the motor neurons. ECM, extracellular matrix.

Fig. 2.

Populations of satellite cells, their myogenic derivatives and FAPs during skeletal muscle regeneration. In response to injury, quiescent satellite cells and FAPs are activated and these activated cells are distinct from their quiescent counterparts (e.g. McKellar et al., 2020 preprint). Activated satellite cells differentiate into myoblasts and then myocytes, which fuse to form regenerated myofibers with characteristic centralized nuclei. Activated FAPs differentiate into fibrogenic or adipogenic FAPs and presumably transition to a quiescent FAP phenotype when regeneration is largely complete at 28 dpi (e.g. McKellar et al., 2020 preprint). ECM, extracellular matrix; MTJ, myotendinous junctions.