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

Akiyoshi Uezumi, Takahito Ito, Daisuke Morikawa, Natsuko Shimizu, Tomohiro Yoneda, Masashi Segawa, Masahiko Yamaguchi, Ryo Ogawa, Miroslav M. Matev, Yuko Miyagoe-Suzuki, Shin'ichi Takeda, Kazutake Tsujikawa, Kunihiro Tsuchida, Hiroshi Yamamoto, So Ichiro Fukada

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)3654-3664
Number of pages11
JournalJournal of Cell Science
Volume124
Issue number21
DOIs
Publication statusPublished - 01-11-2011

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Adipogenesis
Platelet-Derived Growth Factor alpha Receptor
Skeletal Muscle
Fibrosis
Collagen Type I
Diaphragm
Adipocytes
Inbred mdx Mouse
Duchenne Muscular Dystrophy
Muscular Dystrophies
Protein Isoforms
Transplantation

All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

Uezumi, A., Ito, T., Morikawa, D., Shimizu, N., Yoneda, T., Segawa, M., ... Fukada, S. I. (2011). Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle. Journal of Cell Science, 124(21), 3654-3664. https://doi.org/10.1242/jcs.086629
Uezumi, Akiyoshi ; Ito, Takahito ; Morikawa, Daisuke ; Shimizu, Natsuko ; Yoneda, Tomohiro ; Segawa, Masashi ; Yamaguchi, Masahiko ; Ogawa, Ryo ; Matev, Miroslav M. ; Miyagoe-Suzuki, Yuko ; Takeda, Shin'ichi ; Tsujikawa, Kazutake ; Tsuchida, Kunihiro ; Yamamoto, Hiroshi ; Fukada, So Ichiro. / Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle. In: Journal of Cell Science. 2011 ; Vol. 124, No. 21. pp. 3654-3664.
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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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Uezumi, A, Ito, T, Morikawa, D, Shimizu, N, Yoneda, T, Segawa, M, Yamaguchi, M, Ogawa, R, Matev, MM, Miyagoe-Suzuki, Y, Takeda, S, Tsujikawa, K, Tsuchida, K, Yamamoto, H & Fukada, SI 2011, 'Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle', Journal of Cell Science, vol. 124, no. 21, pp. 3654-3664. https://doi.org/10.1242/jcs.086629

Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle. / Uezumi, Akiyoshi; Ito, Takahito; Morikawa, Daisuke; Shimizu, Natsuko; Yoneda, Tomohiro; Segawa, Masashi; Yamaguchi, Masahiko; Ogawa, Ryo; Matev, Miroslav M.; Miyagoe-Suzuki, Yuko; Takeda, Shin'ichi; Tsujikawa, Kazutake; Tsuchida, Kunihiro; Yamamoto, Hiroshi; Fukada, So Ichiro.

In: Journal of Cell Science, Vol. 124, No. 21, 01.11.2011, p. 3654-3664.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle

AU - Uezumi, Akiyoshi

AU - Ito, Takahito

AU - Morikawa, Daisuke

AU - Shimizu, Natsuko

AU - Yoneda, Tomohiro

AU - Segawa, Masashi

AU - Yamaguchi, Masahiko

AU - Ogawa, Ryo

AU - Matev, Miroslav M.

AU - Miyagoe-Suzuki, Yuko

AU - Takeda, Shin'ichi

AU - Tsujikawa, Kazutake

AU - Tsuchida, Kunihiro

AU - Yamamoto, Hiroshi

AU - Fukada, So Ichiro

PY - 2011/11/1

Y1 - 2011/11/1

N2 - 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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Uezumi A, Ito T, Morikawa D, Shimizu N, Yoneda T, Segawa M et al. Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle. Journal of Cell Science. 2011 Nov 1;124(21):3654-3664. https://doi.org/10.1242/jcs.086629