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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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