Aged muscle stem cells epigenetically drive the expansion of mesenchymal progenitors [bulk RNA-Seq]
Sarcopenia, the age-related loss of muscle mass and strength, is characterized by impaired muscle repair and increased deposition of fibrotic tissue. Yet, the specific role of individual cell types in the development of fibrosis remains poorly defined. Here, we report that aged muscle stem cells (MuSCs) directly instruct fibro-adipogenic progenitors (FAPs) to proliferate and adopt a fibrogenic phenotype. Polycomb Ezh2-/- or aged mice exhibited regenerative defects, FAP expansion, fibrosis, and elevated levels of MuSC-secreted interleukin 6 (IL-6) and Spp1/Osteopontin.  In aged MuSCs, H3K27me3 erosion at the NF-kB gene correlated with increased expression and enhanced chromatin recruitment at the IL-6 and Spp1 genes, leading to their activation. Blocking IL-6 and Spp1 signaling in co-cultures of aged MuSC and FAPs, or aged mice, reduced FAP proliferation and muscle fibrosis. In summary, our results indicate that aged MuSCs instruct FAPs to proliferate and acquire a fibrogenic phenotype through a mechanism involving epigenetically-mediated derepression of NF-kB and increased activation of IL-6 and Spp1- both of which are potential pharmacological targets. Overall design: To investiate the role of Polycomb Repressive Complex 2 (PRC2) methyltransferase Ezh2 in adult MuSCs, we generated a tamoxifen inducible iEzh2fl/fl mouse model by crossing Pax7 locus (Pax7creER) with mice bearing floxed Ezh2 alleles (Ezh2fl/fl). MuSCs and FAPs from either control or Ezh2-/- mice were FACS-isolated at 3 and 7 days post injury, and RNA was extracted and processed for RNAsequencing.