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

Abstract

SummaryAccumulation 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 (PDGFRa) as the origin of adipocytes in skeletal muscle. However, the origin of muscle fibrosis remains largely unknown. In this study, clonal analyses show that PDGFRa + cells also differentiate into collagen type-I-producing cells. In fact, PDGFRa + 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 PDGFRa + cell fraction in the mdx diaphragm. Importantly, TGF-b isoforms, known as potent profibrotic cytokines, induced expression of markers of fibrosis in PDGFRa + cells but not in myogenic cells. Transplantation studies revealed that fibrogenic PDGFRa + cells mainly derived from pre-existing PDGFRa + cells and that the contribution of PDGFRa 2 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.

Uncoupling protein 1 expression in adipocytes derived from skeletal muscle fibro/adipogenic progenitors is under genetic and hormonal control

“…Analysing both polyclonal and monoclonal cell cultures, we could not identify any MP subpopulation with adipogenic potential. Our results further support previous work showing that MPs are committed to the myogenic fate30, 31, 49, 51 and that FAPs are the adipocyte precursor population residing in murine30, 31, 32, 52 and human24, 51, 53, 54 adult skeletal muscle. Although we cannot reject the hypothesis that a small subpopulation of satellite cells could form brown adipocytes—as shown by Yin et al 27.…”

Fatty acid‐binding protein 4 regulates fatty infiltration after rotator cuff tear by hypoxia‐inducible factor 1 in mice

“…Uezumi et al reported that PDGFRα‐positive mesenchymal progenitors are the major contributor to ectopic fat cell formation in skeletal muscle 21. Moreover, they suggested that mesenchymal progenitors are the main origin of not only fat accumulation but also fibrosis in skeletal muscle 22. Adipogenic transcription factors have been considered key regulators for fatty degeneration of muscle after RCT.…”

“…Although the factors leading to fat accumulation in the muscle are not yet fully defined, it has been reported that aging, muscle injury, mechanical unloading, and hormonal imbalance are main causes of ectopic fat formation 1, 2, 18, 19, 20. With respect to the molecular mechanism underlying muscle fat accumulation, it has been reported that pluripotent stem cells or progenitor cells residing in the muscle differentiate into adipocytes by the action of adipogenic transcription factors such as CCAAT/enhancer binding protein alpha (C/EBPα) and peroxisome proliferator activated receptor gamma (PPARγ) 8, 21, 22. Previous studies have suggested that rotator cuff fatty infiltration is also mediated by these adipogenic transcription factors 8, 23, 24, 25.…”

Identifying the Cellular Mechanisms Leading to Heterotopic Ossification

“…One study that isolated rat serum following severe burns (40% total surface area) and applied it to satellite cell cultures found enhanced cell proliferation, migration and osteogenic differentiation [61]. However, more recent studies suggest that the image of a satellite cell as a multipotent cell type capable of contributing to osteochondrogenic differentiation may be untrue, with some authors claiming that any non-myogenic differentiation observed in these cultures potentially results from contamination with other stem/progenitor cells obtained during myofibre isolation [62,63]. In fact, a number of studies can be found that claim satellite cells are committed to the myogenic lineage, and as such are crucial for muscle regeneration following injury but unlikely to contribute to the formation of ectopic bone seen in HO [64,65].…”