Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle

Accumulation of adipocytes and collagen type-I-producing cells (fibrosis) is observed in muscular dystrophies. The origin of these cells had been largely unknown, but recently we identified mesenchymal progenitors positive for platelet-derived growth factor receptor alpha (PDGFR alpha) as the origin of adipocytes in skeletal muscle. However, the origin of muscle fibrosis remains largely unknown. In this study, clonal analyses show that PDGFR alpha(+) cells also differentiate into collagen type-I-producing cells. In fact, PDGFR alpha(+) cells accumulated in fibrotic areas of the diaphragm in the mdx mouse, a model of Duchenne muscular dystrophy. Furthermore, mRNA of fibrosis markers was expressed exclusively in the PDGFR alpha(+) cell fraction in the mdx diaphragm. Importantly, TGF-beta isoforms, known as potent profibrotic cytokines, induced expression of markers of fibrosis in PDGFR alpha(+) cells but not in myogenic cells. Transplantation studies revealed that fibrogenic PDGFR alpha(+) cells mainly derived from pre-existing PDGFR alpha(+) cells and that the contribution of PDGFR alpha(-) cells and circulating cells was limited. These results indicate that mesenchymal progenitors are the main origin of not only fat accumulation but also fibrosis in skeletal muscle.