Dynamics of cellular states of fibro-adipogenic progenitors during myogenesis and muscular dystrophy

Abstract

Fibro-adipogenic progenitors (FAPs) are currently defined by their anatomical position, expression of non-specific membrane-associated proteins, and ability to adopt multiple lineages in vitro. Gene expression analysis at single-cell level reveals that FAPs undergo dynamic transitions through a spectrum of cell states that can be identified by differential expression levels of Tie2 and Vcam1. Different patterns of Vcam1-negative Tie2high or Tie2low and Tie2low/Vcam1-expressing FAPs are detected during neonatal myogenesis, response to acute injury and Duchenne Muscular Dystrophy (DMD). RNA sequencing analysis identified cell state-specific transcriptional profiles that predict functional interactions with satellite and inflammatory cells. In particular, Vcam1-expressing FAPs, which exhibit a pro-fibrotic expression profile, are transiently activated by acute injury in concomitance with the inflammatory response. Aberrant persistence of Vcam1-expressing FAPs is detected in DMD muscles or upon macrophage depletion, and is associated with muscle fibrosis, thereby revealing how disruption of inflammation-regulated FAPs dynamics leads to a pathogenic outcome.

The regenerating skeletal muscle niche guides muscle stem cell self-renewal

“…Genes expressed in FAPs including CD34, Ly6a (Sca1), and PDGFra do not segregate with a specific cell subpopulation but instead appear dispersed within the entire fibroblast cohort in either uninjured or injured TA muscle ( Fig 2I-2K). Tek and Vcam, whose proteins identify FAP subsets (Malecova et al, 2018), are expressed predominately in uninjured TA muscle fibroblasts or both the uninjured and injured fibroblasts, respectively but do not segregate to a subpopulation (Supplemental Information Fig S2). Cells that express twist2 or Pw1/Peg appear in the general fibroblast population in uninjured and injured muscle tissue (Supplemental Information Fig S2).…”

Advancements in magnetic resonance imaging‐based biomarkers for muscular dystrophy

“…In the muscular dystrophies and late‐stage myopathies, contractile skeletal muscle is gradually replaced. Although much of the muscle volume is replaced by adipose tissue (making it convenient to describe dystrophic muscle degeneration in terms of fat infiltration), the dystrophic muscle also stimulates the growth of fibroblasts that produce scar tissue intermixed with the fatty infiltrates . There has been growing interest in imaging fibrosis in dystrophic muscle tissue and, specifically, in distinguishing fibrotic tissue from adipose tissue.…”

TGF-β-driven downregulation of the Wnt/β-Catenin transcription factor TCF7L2/TCF4 in PDGFRα+ fibroblasts

“…(2018), and contrary to what we found for TGF-β-mediated myofibroblast differentiation where Tcf7l2 gene expression was repressed, we did not find Tcf7l2 gene expression changes after adipogenic differentiation but increased Tcf7l2 mRNA levels after osteogenic differentiation. The results presented above suggest that different MSC sub-populations (expressing different levels of TCF7L2) participate in the regenerative process after damage (Malecova et al, 2018). However, the precise role of TCF7L2 in fibroblast fate and decisions still needs to be addressed.…”

“…The study of the heterogeneity of tissue-resident mesenchymal stromal populations emerges as an attractive field to underpin regeneration versus degenerative fibrosis (Mahmoudi et al, 2019; Lemos and Duffield, 2018; Lynch and Watt, 2018). Central to this idea is that different MSC populations and their lineage may have intrinsic properties that favor either permanent scar formation or regeneration via scar regression (Driskell et al, 2013; Malecova et al, 2018; Plikus et al, 2017; Rinkevich et al, 2015; Rognoni et al, 2018; Soliman et al, 2019 preprint; Furtado et al, 2016). Thus, investigating different sub-populations of fibroblasts, with particular niches and genetic programs, is important to understand how these cells and their progeny influence wound healing and tissue repair.…”

“…Even though TCF7L2 was initially described as a marker for CT fibroblasts (Kardon et al, 2003; Mathew et al, 2011; Merrell et al, 2015), increasing evidence suggests that CT fibroblasts shared many cell properties with FAPs (Contreras et al, 2019b; Malecova et al, 2018; Wosczyna and Rando, 2018). A recent report demonstrates that TCF7L2 protein but not mRNA levels are increased during adipocyte differentiation, thereby TCF7L2 plays a regulatory role in fibroblast-adipocyte fate decisions in vitro and in vivo (Chen et al, 2018).…”