Skeletal muscle stem cells modulate niche function in Duchenne muscular dystrophy mouse through YY1-CCL5 axis
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 mu...
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56474-w |
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| author | Yang Li Chuhan Li Qiang Sun Xingyuan Liu Fengyuan Chen Yeelo Cheung Yu Zhao Ting Xie Bénédicte Chazaud Hao Sun Huating Wang |
| author_facet | Yang Li Chuhan Li Qiang Sun Xingyuan Liu Fengyuan Chen Yeelo Cheung Yu Zhao Ting Xie Bénédicte Chazaud Hao Sun Huating Wang |
| author_sort | Yang Li |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-d6e4122a29e04b9bb7998db3263e3415 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-d6e4122a29e04b9bb7998db3263e34152025-02-09T12:45:59ZengNature PortfolioNature Communications2041-17232025-02-0116111910.1038/s41467-025-56474-wSkeletal muscle stem cells modulate niche function in Duchenne muscular dystrophy mouse through YY1-CCL5 axisYang Li0Chuhan Li1Qiang Sun2Xingyuan Liu3Fengyuan Chen4Yeelo Cheung5Yu Zhao6Ting Xie7Bénédicte Chazaud8Hao Sun9Huating Wang10Department of Orthopaedics and Traumatology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong KongDepartment of Orthopaedics and Traumatology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong KongDepartment of Orthopaedics and Traumatology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong KongDepartment of Chemical Pathology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong KongDepartment of Chemical Pathology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong KongDepartment of Orthopaedics and Traumatology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong KongMolecular Cancer Research Center, School of Medicine, Shenzhen Campus of Sun Yat-sen University, Sun Yat-sen UniversityCenter for Tissue Regeneration and Engineering, Division of Life Science, Hong Kong University of Science and TechnologyUnité Physiopathologie et Génétique du Neurone et du Muscle, UMR CNRS 5261, Inserm U1315, Université Claude Bernard Lyon 1Warshel Institute for Computational Biology, Faculty of Medicine, Chinese University of Hong Kong (Shenzhen)Department of Orthopaedics and Traumatology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong KongAbstract 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.https://doi.org/10.1038/s41467-025-56474-w |
| spellingShingle | Yang Li Chuhan Li Qiang Sun Xingyuan Liu Fengyuan Chen Yeelo Cheung Yu Zhao Ting Xie Bénédicte Chazaud Hao Sun Huating Wang Skeletal muscle stem cells modulate niche function in Duchenne muscular dystrophy mouse through YY1-CCL5 axis Nature Communications |
| title | Skeletal muscle stem cells modulate niche function in Duchenne muscular dystrophy mouse through YY1-CCL5 axis |
| title_full | Skeletal muscle stem cells modulate niche function in Duchenne muscular dystrophy mouse through YY1-CCL5 axis |
| title_fullStr | Skeletal muscle stem cells modulate niche function in Duchenne muscular dystrophy mouse through YY1-CCL5 axis |
| title_full_unstemmed | Skeletal muscle stem cells modulate niche function in Duchenne muscular dystrophy mouse through YY1-CCL5 axis |
| title_short | Skeletal muscle stem cells modulate niche function in Duchenne muscular dystrophy mouse through YY1-CCL5 axis |
| title_sort | skeletal muscle stem cells modulate niche function in duchenne muscular dystrophy mouse through yy1 ccl5 axis |
| url | https://doi.org/10.1038/s41467-025-56474-w |
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