Hic1 Defines Quiescent Mesenchymal Progenitor Subpopulations with Distinct Functions and Fates in Skeletal Muscle Regeneration

Abstract

Highlights d Hic1 marks multiple quiescent mesenchymal progenitor (MP) subsets within skeletal muscle d Conditional deletion of Hic1 leads to MP hyperplasia and an activated MP phenotype d Hic1 + MPs generate transit-amplifying progeny post-injury that support regeneration d Following injury, select Hic1 + progeny persist and regenerate the myotendinous junction

Mesenchymal Stem Cells Adaptively Respond to Environmental Cues Thereby Improving Granulation Tissue Formation and Wound Healing

“…Two very recent studies have identified a subpopulation of perivascular MSCs in the heart and muscle, which are characterized by the expression of PDGFRα, stem cell antigen-1 (Sca-1, Ly6A) and the tumor repressor hypermethylated in cancer 1 (Hic1) (Scott et al, 2019;Soliman et al, 2020). Both studies have shown that Hic1 + MSCs play important roles in the homeostasis and repair of heart and skeletal muscle, differentiate into different cell types including fibroblasts and are kept in a resting state by Hic1 (Kim and Braun, 2020).…”

“…Both studies have shown that Hic1 + MSCs play important roles in the homeostasis and repair of heart and skeletal muscle, differentiate into different cell types including fibroblasts and are kept in a resting state by Hic1 (Kim and Braun, 2020). The transcription repressor Hic1 is required for maintaining quiescence, since deletion of Hic1 leads to activation and expansion of MSCs, and subsequently leads to pathological fibrosis of heart (Soliman et al, 2020) and skeleton muscle (Scott et al, 2019), respectively. The exact molecular targets of Hic1 remain elusive.…”

“…Their relationship to En1 lineage positive fibroblasts or Dlk-1 positive fibroblasts is currently unresolved. Employing single cell sequencing analysis combined with in vivo tracing analysis and genetic deletion of quiescence or other markers have recently allowed to better define the origin and the lineage hierarchy of mesenchymal progenitors and stem cells in tissue and organ regeneration (Scott et al, 2019;Soliman et al, 2020).…”

Human skeletal muscle CD90+fibro-adipogenic progenitors are associated with muscle degeneration in type 2 diabetic patients

“…Interestingly, in the fibrogenic FAPs, we noted a strong enrichment in Periostin (POSTN, Fig S10 F), an extracellular matrix protein acting as a ligand and previously associated with fibrosis and wound healing 48 . More recently, Periostin has been shown to increase in activated FAPs during regeneration in mouse skeletal muscle along with lysyl oxidase enzymes (LOX) 49 . Notably, the lysyl oxidase homolog 4 (LOXL4) was the most differentially expressed gene in our fibrogenic FAPs (Fig S10 F).…”

Direct contribution of skeletal muscle mesenchymal progenitors to bone repair

“…Here, we sought to explore other cell populations within the skeletal muscle interstitium, containing fibro/adipo progenitors (FAP) and mesenchymal progenitors (MP). These cell populations from the skeletal muscle interstitium are known to support skeletal muscle regeneration and become the source of persistent adipose and fibrotic tissue in pathological conditions such as muscular dystrophy [12][13][14][15][16] . We characterized the skeletal muscle mesenchymal progenitors participating in cartilage and bone formation during bone repair and investigated their function in the context of musculoskeletal trauma.…”