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Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle
Abstract
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 (PDGFRα) as the origin of adipocytes in skeletal muscle. However, the origin of muscle fibrosis remains largely unknown. In this study, clonal analyses show that PDGFRα+ cells also differentiate into collagen type-I-producing cells. In fact, PDGFRα+ 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 PDGFRα+ cell fraction in the mdx diaphragm. Importantly, TGF-β isoforms, known as potent profibrotic cytokines, induced expression of markers of fibrosis in PDGFRα+ cells but not in myogenic cells. Transplantation studies revealed that fibrogenic PDGFRα+ cells mainly derived from pre-existing PDGFRα+ cells and that the contribution of PDGFRα− 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.
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“In muscle disuse or pathological conditions, such as Duchenne muscular dystrophy, FAPs proliferate and differentiate into adipose and fibrous tissue.[ 41 ]”
From Pathogenesis of sarcopenia and the relationship with fat mass: descriptive review (2022) · cites this paper as [41]
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“In addition, Joe and colleagues have reported that CD31(2) CD45(2) Inga7(2) Sca-1 cells (identical to PDGFRa mesenchymal progenitors) promote normal skeletal muscle regeneration (Joe et al., 2010; Rodeheffer, 2010).”
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Metadata
- Authors
- Uezumi, A., Ito, T., Morikawa, D., Shimizu, N., Yoneda, T., Segawa, M., Yamaguchi, M., Ogawa, R., Matev, M. M., Miyagoe-Suzuki, Y., Takeda, S., Tsujikawa, K., Tsuchida, K., Yamamoto, H., & Fukada, S.-I.
- Affiliations
- Fujita Health University (JP)
- The University of Osaka (JP)
- Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo 187-8502, Japan
- National Center of Neurology and Psychiatry (JP)
- Corresponding author
- Fukada, So-ichiro
- ORCID
- Venue
- Journal of Cell Science
- Publisher
- The Company of Biologists
- Published
- 2011-11-01
- Volume
- 124
- Issue
- 21
- Pages
- 3654-3664
- ISSN
- 0021-9533 (ISSN-L)
- 1477-9137
- OpenAlex
- W1964124818
- Cited by
- 680
- References
- 38
- Citations by year
- 2026: 47 · 2025: 54 · 2024: 57 · 2023: 52 · 2022: 58 · 2021: 61 · 2020: 69 · 2019: 55 · 2018: 46 · 2017: 36 · 2016: 42 · 2015: 34 · 2014: 28 · 2013: 28 · 2012: 13
- FWCI
- 8.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Cell Science (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Japan Society for the Promotion of Science (21590320, 21300149, 21790884)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Genetics (clinical) › Neurogenetic and Muscular Disorders Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Keywords
- muscle fibrosis, adipogenesis, mesenchymal progenitor cells, PDGFRA, Duchenne muscular dystrophy, mdx mice, diaphragm, TGF-beta, type I collagen, fat deposition, cell of origin, clonal analysis, transplantation
- MeSH terms
- Animals, Cell Differentiation, Disease Models, Animal, Fibrosis, Humans, Mice, Inbred C57BL, Muscular Dystrophies, Adipocytes, Mice, Inbred mdx, Muscle, Skeletal, Receptor, Platelet-Derived Growth Factor alpha, Adipogenesis, Mice, Mesenchymal Stem Cells
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