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Skeletal muscle stem cells modulate niche function in Duchenne muscular dystrophy mouse through YY1-CCL5 axis

Author

Listed:
  • Yang Li

    (Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong
    Hong Kong Science Park)

  • Chuhan Li

    (Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong)

  • Qiang Sun

    (Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong
    Hong Kong Science Park)

  • Xingyuan Liu

    (Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong)

  • Fengyuan Chen

    (Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong)

  • Yeelo Cheung

    (Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong)

  • Yu Zhao

    (Sun Yat-sen University)

  • Ting Xie

    (Hong Kong University of Science and Technology)

  • Bénédicte Chazaud

    (UMR CNRS 5261, Inserm U1315, Université Claude Bernard Lyon 1)

  • Hao Sun

    (Chinese University of Hong Kong (Shenzhen))

  • Huating Wang

    (Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong
    Hong Kong Science Park)

Abstract

Adult skeletal muscle stem cells (MuSCs) are indispensable for muscle regeneration and tightly regulated by macrophages (MPs) and fibro-adipogenic progenitors (FAPs) in their niche. Deregulated MuSC/MP/FAP interactions and the ensuing inflammation and fibrosis are hallmarks of dystrophic muscle. Here we demonstrate intrinsic deletion of transcription factor Yin Yang 1 (YY1) in MuSCs exacerbates dystrophic pathologies by altering composition and heterogeneity of MPs and FAPs. Further analysis reveals YY1 loss induces expression of immune genes in MuSCs, including C-C motif chemokine ligand 5 (Ccl5). Augmented CCL5 secretion promotes MP recruitment via CCL5/C-C chemokine receptor 5 (CCR5) crosstalk, which subsequently hinders FAP clearance through elevated Transforming growth factor-β1 (TGFβ1). Maraviroc-mediated pharmacological blockade of the CCL5/CCR5 axis effectively mitigates muscle dystrophy and improves muscle performance. Lastly, we demonstrate YY1 represses Ccl5 transcription by binding to its enhancer thus facilitating promoter-enhancer looping. Altogether, our study demonstrates the critical role of MuSCs in actively shaping their niche and provides novel insight into the therapeutic intervention of muscle dystrophy.

Suggested Citation

  • Yang Li & Chuhan Li & Qiang Sun & Xingyuan Liu & Fengyuan Chen & Yeelo Cheung & Yu Zhao & Ting Xie & Bénédicte Chazaud & Hao Sun & Huating Wang, 2025. "Skeletal muscle stem cells modulate niche function in Duchenne muscular dystrophy mouse through YY1-CCL5 axis," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56474-w
    DOI: 10.1038/s41467-025-56474-w
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    References listed on IDEAS

    as
    1. Yuying Li & Jie Yuan & Fengyuan Chen & Suyang Zhang & Yu Zhao & Xiaona Chen & Leina Lu & Liang Zhou & Ching Yan Chu & Hao Sun & Huating Wang, 2020. "Long noncoding RNA SAM promotes myoblast proliferation through stabilizing Sugt1 and facilitating kinetochore assembly," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    2. Suyang Zhang & Feng Yang & Yile Huang & Liangqiang He & Yuying Li & Yi Ching Esther Wan & Yingzhe Ding & Kui Ming Chan & Ting Xie & Hao Sun & Huating Wang, 2023. "ATF3 induction prevents precocious activation of skeletal muscle stem cell by regulating H2B expression," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    3. Suyang Zhang & Feng Yang & Yile Huang & Liangqiang He & Yuying Li & Yi Ching Esther Wan & Yingzhe Ding & Kui Ming Chan & Ting Xie & Hao Sun & Huating Wang, 2023. "Author Correction: ATF3 induction prevents precocious activation of skeletal muscle stem cell by regulating H2B expression," Nature Communications, Nature, vol. 14(1), pages 1-1, December.
    4. Yu Zhao & Jiajian Zhou & Liangqiang He & Yuying Li & Jie Yuan & Kun Sun & Xiaona Chen & Xichen Bao & Miguel A. Esteban & Hao Sun & Huating Wang, 2019. "MyoD induced enhancer RNA interacts with hnRNPL to activate target gene transcription during myogenic differentiation," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
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