Skeletal Muscle Stem Cells Modulate Niche Function in Duchenne Muscular Dystrophy through YY1-CCL5 Axis

Skeletal Muscle Stem Cells Modulate Niche Function in Duchenne Muscular Dystrophy through YY1-CCL5 Axis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Skeletal Muscle Stem Cells Modulate Niche Function in Duchenne Muscular Dystrophy through YY1-CCL5 Axis Huating Wang, Yang Li, Chuhan Li, Qiang Sun, Fengyuan Chen, Yeelo Cheung, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3919531/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 03 Feb, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract Stem cell activity is known to be tightly regulated by both intrinsic and extrinsic pathways but less is known about whether and how stem cells modulate their niche microenvironment. Adult skeletal muscle stem cells (MuSCs) are indispensable for muscle regeneration and also tightly regulated by macrophages (MPs) and fibro-adipogenic progenitors (FAPs) in the niche. Deregulated MuSC/MP/FAP interactions and the ensuing inflammation and fibrosis are hallmarks of dystrophic muscle. Here in this study we demonstrate that intrinsic deletion of transcription factor YY1 in MuSCs exacerbates dystrophic pathologies by altering the cellular composition and heterogeneity of MPs and FAPs. Further analysis reveals that the YY1 loss induces the expression of immune genes in MuSCs, including Ccl5 . Augmented secretion of CCL5 from MuSCs promotes the recruitment of MPs via CCL5/CCR5 mediated crosstalk, which subsequently hinders the apoptosis and clearance of FAPs through elevated TGFβ1 accumulation. Maraviroc mediated pharmacological blockade of the CCL5/CCR5 axis effectively mitigates muscle dystrophy and improves muscle performance. Lastly, we further demonstrate that YY1 represses Ccl5 transcription in MuSCs by directly binding to its enhancer thus facilitating promoter-enhancer looping. Altogether, our study has demonstrated the previously unappreciated role of MuSCs in actively shaping their niche microenvironment through secreting immunomodulatory cytokines and has also provided novel insight into the therapeutic intervention of muscle dystrophy. Biological sciences/Stem cells/Muscle stem cells Health sciences/Diseases MuSC YY1 DMD niche macrophage fibro-adipogenic progenitor CCL5 Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Full Text Additional Declarations There is NO Competing Interest. Supplementary Tables are not available with this version. Supplementary Files SupplInfo.pdf Supplementary materials Cite Share Download PDF Status: Published Journal Publication published 03 Feb, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3919531","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":270865795,"identity":"9b4e346e-2612-4ff4-b193-8ffdadcdad25","order_by":0,"name":"Huating Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCklEQVRIiWNgGAWjYBACAxCRAON9ALIlgDQQHzDAo4WxAaaFcQbRWmAcZh5itJhLJD9/8HBHLYPB8bOHX9vUHM6TbGA+eJuH4Y4xLi2WM9IMGxLPHGcwOJOXZp1z7HCxNANbsjUPwzMznA67kQDU0naMwexAjplxbsPhxHkMPGbSPAyHbXBrSf8I0XL+jZmxJVgL/zcCWnJAttQwmN3IMX7MCNQym4GHDaQFt8POvCmckdh2gMf+xhszxp5j6Ykzm9mMLecYHMbpfYPj6Rs+/myrk5PszzH+8KPGOnHG8eaHN95UHDZswKUHAg4DY4SBTQLMZgYbhV89ENSB1X4gqG4UjIJRMApGJAAA4NVdSulo65QAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0001-5474-2905","institution":"The Chinese University of Hong Kong","correspondingAuthor":true,"prefix":"","firstName":"Huating","middleName":"","lastName":"Wang","suffix":""},{"id":270865796,"identity":"3ac312ad-fc02-408d-bc4e-8b5a5926902d","order_by":1,"name":"Yang Li","email":"","orcid":"","institution":"Chinese University of Hong Kong","correspondingAuthor":false,"prefix":"","firstName":"Yang","middleName":"","lastName":"Li","suffix":""},{"id":270865797,"identity":"bf303fc7-73ef-4e52-9f5f-4fba4274c201","order_by":2,"name":"Chuhan Li","email":"","orcid":"","institution":"Chinese University of Hong Kong","correspondingAuthor":false,"prefix":"","firstName":"Chuhan","middleName":"","lastName":"Li","suffix":""},{"id":270865798,"identity":"66751188-058f-4366-9c0b-e86ff36bb0db","order_by":3,"name":"Qiang Sun","email":"","orcid":"","institution":"Chinese University of Hong Kong","correspondingAuthor":false,"prefix":"","firstName":"Qiang","middleName":"","lastName":"Sun","suffix":""},{"id":270865799,"identity":"d46a4c5f-dcd6-4780-aafd-744477e21ab1","order_by":4,"name":"Fengyuan Chen","email":"","orcid":"","institution":"Chinese University of Hong Kong","correspondingAuthor":false,"prefix":"","firstName":"Fengyuan","middleName":"","lastName":"Chen","suffix":""},{"id":270865800,"identity":"f6dd8b6d-8205-4faa-b8ef-a5c7ac0b1998","order_by":5,"name":"Yeelo Cheung","email":"","orcid":"","institution":"Chinese University of Hong Kong","correspondingAuthor":false,"prefix":"","firstName":"Yeelo","middleName":"","lastName":"Cheung","suffix":""},{"id":270865801,"identity":"1100dcbc-3dc7-41c5-a663-430f9d9458fd","order_by":6,"name":"Yu Zhao","email":"","orcid":"","institution":"Chinese University of Hong Kong","correspondingAuthor":false,"prefix":"","firstName":"Yu","middleName":"","lastName":"Zhao","suffix":""},{"id":270865802,"identity":"ef1b2b2e-f1fe-4cf7-bdff-0ca0d9d6c73b","order_by":7,"name":"Ting Xie","email":"","orcid":"","institution":"Hong Kong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Ting","middleName":"","lastName":"Xie","suffix":""},{"id":270865803,"identity":"5b8b107f-2b83-4f4d-bba0-a7d465869a27","order_by":8,"name":"Bénédicte Chazaud","email":"","orcid":"","institution":"Université Claude Bernard Lyon 1","correspondingAuthor":false,"prefix":"","firstName":"Bénédicte","middleName":"","lastName":"Chazaud","suffix":""},{"id":270865804,"identity":"6bc85151-5b6f-4424-9b1a-7885a7922d4e","order_by":9,"name":"Hao Sun","email":"","orcid":"https://orcid.org/0000-0002-5547-9501","institution":"The Chinese University of Hong Kong","correspondingAuthor":false,"prefix":"","firstName":"Hao","middleName":"","lastName":"Sun","suffix":""}],"badges":[],"createdAt":"2024-02-02 04:20:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3919531/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3919531/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41467-025-56474-w","type":"published","date":"2025-02-03T05:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":53270605,"identity":"7590d88a-b287-41a7-a261-fa115ad10f8e","added_by":"auto","created_at":"2024-03-22 16:30:38","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":3149146,"visible":true,"origin":"","legend":"\u003cp\u003eInducible deletion of YY1 in MuSCs aggravates muscle dystrophy in mdx mouse. A Schematic of the experimental design for analyzing dystrophic phenotypes in Ctrl and dKO mice. B-D Validation of YY1 ablation in dKO MuSCs by RT–qPCR, Western blot and IF staining, n=3. E Left panel: H\u0026amp;E staining of TA and DP muscles collected from the Ctrl and dKO mice at the age of 2.5M. Scale bar: 50 μm. Right panel: quantification of cross-sectional areas (CSAs) of the stained fibers, n≥3. F Left panel: Masson’s Trichrome staining of TA and DP muscles collected from the Ctrl and dKO mice at the age of 2.5M. Scale bar: 50 μm. Right panel: quantification of the stained fibrotic areas, n=3. G-H IF staining of Collagen1a1 (COL1a1, red) and PDGFRα (green) was performed on the above TA and DP muscles from the Ctrl and dKO mice. Mean fluorescence intensity (MFI) of the stained sections was quantified, correlation of COL1a1 and PDGFRα MFI was calculated. Scale bar: 50 μm, n=4. I-J Left: IF staining of DAPI (blue), Laminin (green) and CD68 (red) on the above TA and DP muscles. Right: quantification of the number of CD68+ cells per area. Scale bar: 50 μm, n=3. K-L Left: IF staining of DAPI (blue) and CD206 (green) on the above TA and DP muscles. Right: quantification of the number of CD206+ cells per area. Scale bar: 50 μm, n=3. M Representative images of Ctrl and dKO mice at the age of 8.5M. N-P Body weight, TA muscle weight and DP muscle thickness were measured in the aforementioned mice, n≥3. Q 2.5M Ctrl and dKO mice were subject to treadmill exercise and the running distance until exhaustion is shown, n=5. R The above mice were subject to voluntary wheel-running exercise and the weekly running distance is shown, n=4. S Survival rate of Ctrl and dKO mice at 6 months), n=10. All the bar graphs are presented as mean ± SD, Student’s t test (two-tailed unpaired) was used to calculate the statistical significance (B, E–L, N-Q): *p \u0026lt; 0.05, **p \u0026lt; 0.01, ***p \u0026lt; 0.001, n.s. = no significance.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3919531/v1/0ac001fad94d66928c44719b.jpg"},{"id":53270606,"identity":"95a4b794-0c35-417a-817b-29b987134dec","added_by":"auto","created_at":"2024-03-22 16:30:38","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1553212,"visible":true,"origin":"","legend":"\u003cp\u003eIntrinsic YY1 deletion in MuSCs alters cellular microenvironment in dystrophic muscle A Schematic of the experimental design for analyzing MuSC, FAP and MP populations in Ctrl and dKO mice. B-D The percentages of isolated MuSCs, FAPs and MPs from Ctrl and dKO mice at 5, 21 and 60 days after TMX administration, n=3. E Schematic of scRNA-seq experimental design, mononuclear cells from three pairs of Ctrl and dKO mice were combined for FACS sorting and living cell selection. A total of 4435 and 3329 living cells from Ctrl and dKO mice were identified respectively. F scRNA-seq was performed in the whole muscle from three pairs of Ctrl and dKO mice. Data are shown as a uniform manifold approximation and projection (UMAP) to visualize variation in single-cell transcriptomes. Unsupervised clustering resolved at least 14 cell types (colour coded). G Dot plot showing the expression signatures of representative marker genes for each cell type. H Top: Sankey plots showing the distribution of Ctrl and dKO cells across different cell types. Bottom: pie plots showing the relative cell proportion between Ctrl and dKO groups across different cell types. I-J Left: pseudotime trajectory inference of the identified FAP subpopulations in Ctrl and dKO. Right: pie charts showing the relative cell proportion of each subtype. K Ridge map showing the global distribution density of anti-apoptotic of Ctrl and dKO FAPs. The corresponding dashed line represents the peak position of each group. L-M Left: pseudotime trajectory inference of the identified MO/MP subpopulations in Ctrl and dKO. Right: pie charts showing the relative cell proportion of each subtype. N Ridge map showing the global distribution density of inflammatory score of Ctrl and dKO MO/MP. The corresponding dashed line represents the peak position of each group. All the bar graphs are presented as mean ± SD, Student’s t test (two-tailed unpaired) was used to calculate the statistical significance (B-D, K, N): *p \u0026lt; 0.05, **p \u0026lt; 0.01, ***p \u0026lt; 0.001, n.s. = no significance.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3919531/v1/8d302c36f2ee3f309b715d4d.jpg"},{"id":53270608,"identity":"907f3624-f9ef-4ea5-a1ba-04b99dc42374","added_by":"auto","created_at":"2024-03-22 16:30:39","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1576239,"visible":true,"origin":"","legend":"\u003cp\u003eIntrinsic deletion of YY1 in MuSC induces enhanced crosstalk between MuSC and MP via CCL5/CCR5 axis. A Schematic of the experimental design for testing MuSC/MP interaction in Ctrl and dKO mice. B Differentiability expressed genes (DEGs) were identified from the RNA-seq profiling in Ctrl vs dKO MuSCs using Log2FC \u0026gt;0.5 as a cut-off. C-D GO analysis of the above identified 1090 up and 1527 down-regulated DEGs. E RT-qPCR detection of Ccl5 mRNA in freshly isolated MuSCs form Ctrl and dKO. F IF staining of CCL5 protein in freshly isolated MuSCs from Ctrl and dKO. Scale bar: 25 μm, n=5. G ELISA detection of secreted CCL5 protein from Ctrl and dKO MuSCs, n=3. H Western blot detection of CCL5 protein in TA muscles of Ctrl and dKO at the designated times after TMX administration, n=3. I RT-qPCR detection of Ccl5 and Ccr5 mRNAs in freshly isolated MPs from Ctrl and dKO, n=4. J RT-qPCR detection of Ccl5 and Ccr5 mRNAs in Ctrl and dKO TA muscles. K IF staining of CCL5 and CCR5 proteins on TA muscles sections of Ctrl and dKO. Co-localization of CCL5 and CCR5 is shown in the red frame. Scale bar: 50 μm, n=5. L BMDMs were isolated from mdx mice and co-cultured with MuSCs from Ctrl and dKO in transwell. Quantification of migrated BMDMs is shown, n=3. M-N CCL5 or CCR5 antibody was added to the above transwell. Quantification of migrated BMDM is shown, n=3. All the bar graphs are presented as mean ± SD, Student’s t test (two-tailed unpaired) was used to calculate the statistical significance (E, G, I, J, L-N): *p \u0026lt; 0.05, **p \u0026lt; 0.01, ***p \u0026lt; 0.001, n.s. = no significance.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3919531/v1/aeaeb64f4c5a91fe1e4f0baa.jpg"},{"id":53270609,"identity":"790c1db3-80e5-4599-99cf-1338e1462603","added_by":"auto","created_at":"2024-03-22 16:30:39","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":2572894,"visible":true,"origin":"","legend":"\u003cp\u003eTGFβ1 enriched niche inhibits FAP apoptosis and causes FAP accumulation in dKO muscle. A Schematic of the experimental design for testing FAP/MuSC interaction in Ctrl and dKO mice. B TUNEL staining of FAPs isolated from Ctrl and dKO muscles. The percentage of TUNEL+ cells is shown. Scale bar: 50 μm, n=3. C-D TUNEL and PDGFRα staining of TA or DP muscles from Ctrl and dKO mice. The percentage of TUNEL+ PDGFRα+ cells is shown. Scale bar: 50 μm, n=5. E EdU staining of in vitro cultured (6 hr) FAPs from Ctrl and dKO. The percentage of EdU+ cells is shown. Scale bar: 50 μm, n=3. F EdU and PDGFRα staining of freshly isolated FAPs from EdU injected Ctrl and dKO mice (Fig. 1A). The percentage of EdU+ PDGFRα+ cells is shown. Scale bar: 100 μm, n=3. G Schematic of the MuSC and FAP co-culture experiment. H TUNEL staining of the above co-cultured FAPs. The percentage of TUNEL+ cells is shown Scale bar: 100 μm, n=4. I Ki67 staining of the above co-cultured FAPs. The percentage of Ki67+ cells is shown Scale bar: 100 μm, n=4. J Schematic of MP and FAP interaction. K RT-qPCR detection of TGFβ1 mRNA in TA muscles form Ctrl and dKO mice, n=5. L Western blot detection of TGFβ1 protein in TA muscles from Ctrl and dKO mice, n=2. M-N IF staining of TGFβ1 in TA muscles 2 months or 7 days after TMX administration. Scale bar: 50 μm, n=3. O-P RT-qPCR detection of TGFβ1 mRNA in inflammatory and restorative MPs macrophages isolated from Ctrl and dKO muscles, n=2. All the bar graphs are presented as mean ± SD, Student’s t test (two-tailed unpaired) was used to calculate the statistical significance (B-F, H-K, K): *p \u0026lt; 0.05, **p \u0026lt; 0.01, ***p \u0026lt; 0.001, n.s. = no significance.\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3919531/v1/fd451dda093142b5712bd402.jpg"},{"id":53270607,"identity":"72aeb0e4-b35a-457a-8020-9fe4e954c44f","added_by":"auto","created_at":"2024-03-22 16:30:39","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":2699245,"visible":true,"origin":"","legend":"\u003cp\u003eTargeting CCL5/CCR5 axis with MVC alleviates muscle dystrophy. A Schematic of the DMSO or MVC treatment and assessment in Ctrl and dKO mice. B Left: H\u0026amp;E staining of the TA and DP muscles collected after the treatment of Ctrl and dKO mice. Scale bar: 50 μm. Right: quantification of cross-sectional areas (CSAs) of fibers is shown, n≥3. C Left: Masson’s Trichrome staining of the above collected TA and DP muscles. Scale bar: 50 μm. Right: quantification of fibrotic areas is shown, n=3. D IF staining of DAPI (blue), PDGFRα (green) and Laminin (red) was performed on TA muscles of Ctrl and dKO mice after the treatment. The quantification of relative MFI of PDGFRα is shown. Scale bar: 50 μm, n=3. E IF staining of DAPI (blue), F4/80 (red) and Laminin (green) was performed on TA muscles of Ctrl and dKO mice after the treatment. The quantification of F4/80+ cell number per area is shown. Scale bar: 50 μm, n=3. F-H Flow cytometry detection of MP, FAP and MuSC population in Ctrl and dKO mice after the treatment, n=5. I Schematic of the muscle performance assessment by treadmill or voluntary wheel-running exercise. J The treated Ctrl and dKO mice were subjected to treadmill exercise and the running distance until exhaustion is shown, n=3. K The treated Ctrl and dKO mice were subjected to voluntary wheel-running exercise and the weekly running distance is shown, n=3. L Body weight of Ctrl and dKO mice after the treatment, n=5. All the bar graphs are presented as mean ± SD, Student’s t test (two-tailed unpaired) was used to calculate the statistical significance (C-I, K, M): *p \u0026lt; 0.05, **p \u0026lt; 0.01, ***p \u0026lt; 0.001, n.s. = no significance.\u003c/p\u003e","description":"","filename":"5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3919531/v1/4ed81cd66a230b170798c37b.jpg"},{"id":53270602,"identity":"8a95190e-61f8-4604-b262-c6bd55e303aa","added_by":"auto","created_at":"2024-03-22 16:30:38","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":1791361,"visible":true,"origin":"","legend":"\u003cp\u003eYY1 controls Ccl5 expression in MuSC via regulating 3D looping interaction. A Schematic of the experimental design for dissecting YY1 regulation of Ccl5 expression. B Enrichment of YY1 motif in the identified YY1 ChIP-seq binding regions. C Genomic distribution of the identified 4681 YY1 binding peaks. D GO analysis of the identified YY1 ChIP-seq targets. E Venn diagram showing the overlapping between the above identified YY1 ChIP-Seq targets and the down- or up-regulated genes. F Genomic snapshots on Ccl5 locus showing co-binding of H3K27ac and YY1. G Pie chart showing HiC identified A/B compartment switch between Ctrl and dKO. H Venn diagram showing the changed TAD boundaries between Ctrl and dKO. I- J Comparison of TAD number and size between Ctrl and dKO. K-L Comparison of loop size and number comparison between Ctrl and dKO. M Heatmap showing the Hi-C interactions encompassing Ccl5 locus (yellow box indicates TAD). Enhanced E-P interaction (grey curve) is shown in dKO vs Ctrl. N Schematic of 3C-qPCR experiment design. O 3C-qPCR detection of Ccl5 enhancer proximal region on chromatin 11 showing decreased E-P interaction in dKO vs. Ctrl MuSC. P Schematic of YY1 tethering experiment design in C2C12 cells. Q ChIP-qPCR detection of YY1 enrichment on the tethered site in dCas9-YY1 vs. dCas9 cells, primers 1-5 were designed to target the proximal region of the tethered site, n=3. R 3C-qPCR detection of E-P interaction on Ccl5 locus in dCas9-YY1 vs. dCas9 cells. S RT-qPCR detection of Ccl5 expression in dCas9-YY1 vs. dCas9 cells, n=3. T Left: Luciferase reporter (L) with promoter (P) and enhancer (E) sequences was transfected into MuSCs from Ctrl and dKO. Right: Relative fluorescence unit (RFU) of reporter activity is shown, n=3. U Left: Luciferase reporters with Ccl5 P or P+E sequences were transfected into Ctrl MuSC. Right: RFU of reporter activity is shown, n=3. All the bar graphs are presented as mean ± SD, Student’s t test (two-tailed unpaired) was used to calculate the statistical significance (I, K, Q, S-U): *p \u0026lt; 0.05, **p \u0026lt; 0.01, ***p \u0026lt; 0.001, n.s. = no significance.\u003c/p\u003e","description":"","filename":"6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3919531/v1/76f2c3cea4f9d4f3e62fc9b9.jpg"},{"id":53270603,"identity":"dcee1f6e-1daa-4bd8-ad97-cf3e29be8172","added_by":"auto","created_at":"2024-03-22 16:30:38","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":1228317,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version.\u003c/p\u003e","description":"","filename":"7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3919531/v1/399789f07acd6b4a255f6adb.jpg"},{"id":75402778,"identity":"ad74b758-7b41-413f-aa7f-c27ea7ae8356","added_by":"auto","created_at":"2025-02-04 08:09:16","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":15229052,"visible":true,"origin":"","legend":"","description":"","filename":"Manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3919531/v1_covered_706153e2-aad5-4da7-b8e9-d4c9a6b32774.pdf"},{"id":53270604,"identity":"4c9defa4-fff4-4c9d-a277-3cc4389c558d","added_by":"auto","created_at":"2024-03-22 16:30:38","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":1315539,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary materials\u003c/p\u003e","description":"","filename":"SupplInfo.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3919531/v1/9ec5e2a9ef4a0417bf2e623b.pdf"}],"financialInterests":"\u003cp\u003eThere is \u003cstrong\u003eNO\u003c/strong\u003e Competing Interest.\u003c/p\u003e\n\u003cp\u003eSupplementary Tables are not available with this version.\u003c/p\u003e","formattedTitle":"Skeletal Muscle Stem Cells Modulate Niche Function in Duchenne Muscular Dystrophy through YY1-CCL5 Axis","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"MuSC, YY1, DMD, niche, macrophage, fibro-adipogenic progenitor, CCL5","lastPublishedDoi":"10.21203/rs.3.rs-3919531/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3919531/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eStem cell activity is known to be tightly regulated by both intrinsic and extrinsic pathways but less is known about whether and how stem cells modulate their niche microenvironment. Adult skeletal muscle stem cells (MuSCs) are indispensable for muscle regeneration and also tightly regulated by macrophages (MPs) and fibro-adipogenic progenitors (FAPs) in the niche. Deregulated MuSC/MP/FAP interactions and the ensuing inflammation and fibrosis are hallmarks of dystrophic muscle. Here in this study we demonstrate that intrinsic deletion of transcription factor YY1 in MuSCs exacerbates dystrophic pathologies by altering the cellular composition and heterogeneity of MPs and FAPs. Further analysis reveals that the YY1 loss induces the expression of immune genes in MuSCs, including \u003cem\u003eCcl5\u003c/em\u003e. Augmented secretion of CCL5 from MuSCs promotes the recruitment of MPs via CCL5/CCR5 mediated crosstalk, which subsequently hinders the apoptosis and clearance of FAPs through elevated TGFβ1 accumulation. Maraviroc mediated pharmacological blockade of the CCL5/CCR5 axis effectively mitigates muscle dystrophy and improves muscle performance. Lastly, we further demonstrate that YY1 represses \u003cem\u003eCcl5 \u003c/em\u003etranscription in MuSCs by directly binding to its enhancer thus facilitating promoter-enhancer looping. Altogether, our study has demonstrated the previously unappreciated role of MuSCs in actively shaping their niche microenvironment through secreting immunomodulatory cytokines and has also provided novel insight into the therapeutic intervention of muscle dystrophy.\u003c/p\u003e","manuscriptTitle":"Skeletal Muscle Stem Cells Modulate Niche Function in Duchenne Muscular Dystrophy through YY1-CCL5 Axis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-22 16:30:32","doi":"10.21203/rs.3.rs-3919531/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"72878834-4eac-46d0-9958-8d7877d46799","owner":[],"postedDate":"March 22nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":28552413,"name":"Biological sciences/Stem cells/Muscle stem cells"},{"id":28552414,"name":"Health sciences/Diseases"}],"tags":[],"updatedAt":"2025-02-04T08:08:56+00:00","versionOfRecord":{"articleIdentity":"rs-3919531","link":"https://doi.org/10.1038/s41467-025-56474-w","journal":{"identity":"nature-communications","isVorOnly":false,"title":"Nature Communications"},"publishedOn":"2025-02-03 05:00:00","publishedOnDateReadable":"February 3rd, 2025"},"versionCreatedAt":"2024-03-22 16:30:32","video":"","vorDoi":"10.1038/s41467-025-56474-w","vorDoiUrl":"https://doi.org/10.1038/s41467-025-56474-w","workflowStages":[]},"version":"v1","identity":"rs-3919531","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3919531","identity":"rs-3919531","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}