{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T06:24:05Z","timestamp":1787725445620,"version":"build-2784847793"},"reference-count":109,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T00:00:00Z","timestamp":1755734400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health","award":["1R01AR074428"],"award-info":[{"award-number":["1R01AR074428"]}]},{"name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health","award":["T32GM100842"],"award-info":[{"award-number":["T32GM100842"]}]},{"name":"National Institute of General Medical Sciences of the National Institutes of Health","award":["1R01AR074428"],"award-info":[{"award-number":["1R01AR074428"]}]},{"name":"National Institute of General Medical Sciences of the National Institutes of Health","award":["T32GM100842"],"award-info":[{"award-number":["T32GM100842"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Monocytes\/macrophages promote the repair of acutely injured muscle while contributing to dystrophic changes in chronically injured muscle in Duchenne muscular dystrophy (DMD) patients and animal models including mdx and mdx5cv mice. To elucidate the molecular mechanisms underlying this functional difference, we compared the transcriptomes of intramuscular monocytes\/macrophages from wild-typed (WT) uninjured muscles, WT acutely injured muscles, and mdx5cv dystrophic muscles, using single cell-based RNA sequencing (scRNA-seq) analysis. Our study identified multiple transcriptomically diverse monocyte\/macrophage subclusters, which appear to be induced by the intramuscular microenvironment. They expressed feature genes differentially involved in muscle inflammation, regeneration, and extracellular matrix (ECM) remodeling, but none of them conform to strict M1 or M2 activation. The Gpnmb+Spp1+ macrophage subcluster, an injury-associated subcluster that features the signature genes of reported scar-associated macrophages (SAMs) involved in ECM remodeling and fibrosis, is present transiently in acutely injured muscle and persistently in chronically injured dystrophic muscle, along with the persistence of monocytes. Our findings suggest that the persistent monocyte\/macrophage infiltration and activation induced by continuous injury may underlie the pathogenic roles of macrophages in mdx5cv muscles. Controlling muscle injury and subsequent macrophage infiltration and activation may be important to the treatment of DMD.<\/jats:p>","DOI":"10.3390\/ijms26168098","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T07:41:45Z","timestamp":1755848505000},"page":"8098","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Heterogeneous Macrophage Activation in Acute Skeletal Muscle Sterile Injury and mdx5cv Model of Muscular Dystrophy"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9097-9627","authenticated-orcid":false,"given":"Xingyu","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Neurology, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7566-2215","authenticated-orcid":false,"given":"Justin K.","family":"Moy","sequence":"additional","affiliation":[{"name":"Graduate Program in Bioinformatics, Boston University, 24 Cummington Mall, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4427-0164","authenticated-orcid":false,"given":"Yinhang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory R.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Neurology, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederique","family":"Ruf-Zamojski","sequence":"additional","affiliation":[{"name":"Department of Neurology, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3360-6936","authenticated-orcid":false,"given":"Pawel F.","family":"Przytycki","sequence":"additional","affiliation":[{"name":"Graduate Program in Bioinformatics, Boston University, 24 Cummington Mall, Boston, MA 02215, USA"},{"name":"Faculty of Computing & Data Sciences, Boston University, 665 Commonwealth Avenue, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart C.","family":"Sealfon","sequence":"additional","affiliation":[{"name":"Department of Neurology, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/s41572-021-00248-3","article-title":"Duchenne muscular dystrophy","volume":"7","author":"Duan","year":"2021","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1152\/physrev.00043.2011","article-title":"Satellite cells and the muscle stem cell niche","volume":"93","author":"Yin","year":"2013","journal-title":"Physiol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1002\/j.2040-4603.2015.tb00646.x","article-title":"Satellite Cells and Skeletal Muscle Regeneration","volume":"5","author":"Dumont","year":"2015","journal-title":"Compr. Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1038\/embor.2013.182","article-title":"Cellular dynamics in the muscle satellite cell niche","volume":"14","author":"Bentzinger","year":"2013","journal-title":"EMBO Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"R1173","DOI":"10.1152\/ajpregu.00735.2009","article-title":"Regulatory interactions between muscle and the immune system during muscle regeneration","volume":"298","author":"Tidball","year":"2010","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2029","DOI":"10.1002\/j.2040-4603.2011.tb00387.x","article-title":"Mechanisms of muscle injury, repair, and regeneration","volume":"1","author":"Tidball","year":"2011","journal-title":"Compr. Physiol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Wang, X., and Zhou, L. (2022). The Many Roles of Macrophages in Skeletal Muscle Injury and Repair. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.952249"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1038\/nature12034","article-title":"Pollard. Macrophages biology in development, homeostasis and disease","volume":"496","author":"Thomas","year":"2013","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.smim.2016.03.017","article-title":"Development and function of tissue resident macrophages in mice","volume":"27","author":"Kierdorf","year":"2015","journal-title":"Semin. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1016\/j.immuni.2013.04.004","article-title":"Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes","volume":"38","author":"Hashimoto","year":"2013","journal-title":"Immunity"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.immuni.2016.02.015","article-title":"Macrophages in Tissue Repair, Regeneration, and Fibrosis","volume":"44","author":"Wynn","year":"2016","journal-title":"Immunity"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1038\/ni.3324","article-title":"New insights into the multidimensional concept of macrophage ontogeny, activation and function","volume":"17","author":"Ginhoux","year":"2016","journal-title":"Nat. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"20729","DOI":"10.1073\/pnas.1915950117","article-title":"Heterogeneous origins and functions of mouse skeletal muscle-resident macrophages","volume":"117","author":"Wang","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1084\/jem.20070075","article-title":"Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis","volume":"204","author":"Arnold","year":"2007","journal-title":"J. Exp. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1096\/fj.10-171579","article-title":"Macrophages recruited via CCR2 produce insulin-like growth factor-1 to repair acute skeletal muscle injury","volume":"25","author":"Lu","year":"2011","journal-title":"FASEB J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3344","DOI":"10.1096\/fj.10-178939","article-title":"Acute skeletal muscle injury: CCL2 expression by both monocytes and injured muscle is required for repair","volume":"25","author":"Lu","year":"2011","journal-title":"FASEB J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"eabg7504","DOI":"10.1126\/scitranslmed.abg7504","article-title":"Metabolic reprogramming of skeletal muscle by resident macrophages points to CSF1R inhibitors as muscular dystrophy therapeutics","volume":"14","author":"Babaeijandaghi","year":"2022","journal-title":"Sci. Transl. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1476","DOI":"10.15252\/emmm.201403967","article-title":"Inflammatory monocytes promote progression of Duchenne muscular dystrophy and can be therapeutically targeted via CCR2","volume":"6","author":"Mojumdar","year":"2014","journal-title":"EMBO Mol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1096\/fj.201600619r","article-title":"CCR2 deficiency does not provide sustained improvement of muscular dystrophy in mdx5cv mice","volume":"31","author":"Zhao","year":"2017","journal-title":"FASEB J."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Emery, A.E.H. (1993). Duchenne Muscular Dystrophy, Oxford University Press.","DOI":"10.1016\/0960-8966(93)90018-F"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.jneuroim.2018.01.004","article-title":"Infiltrating macrophages are broadly activated at the early stage to support acute skeletal muscle injury repair","volume":"317","author":"Wang","year":"2018","journal-title":"J. Neuroimmunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.cmet.2013.06.017","article-title":"AMPKalpha1 regulates macrophage skewing at the time of resolution of inflammation during skeletal muscle regeneration","volume":"18","author":"Mounier","year":"2013","journal-title":"Cell Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1083\/jcb.201104053","article-title":"p38\/MKP-1-regulated AKT coordinates macrophage transitions and resolution of inflammation during tissue repair","volume":"195","author":"Perdiguero","year":"2011","journal-title":"J. Cell Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1016\/j.ajpath.2013.12.020","article-title":"Altered macrophage phenotype transition impairs skeletal muscle regeneration","volume":"184","author":"Wang","year":"2014","journal-title":"Am. J. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"17475","DOI":"10.1073\/pnas.0908641106","article-title":"A CREB-C\/EBPbeta cascade induces M2 macrophage-specific gene expression and promotes muscle injury repair","volume":"106","author":"Ruffell","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1038\/s41590-019-0356-7","article-title":"Dynamic changes to lipid mediators support transitions among macrophage subtypes during muscle regeneration","volume":"20","author":"Giannakis","year":"2019","journal-title":"Nat. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Wang, X., and Zhou, L. (2023). The multifaceted role of macrophages in homeostatic and injured skeletal muscle. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1274816"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2464","DOI":"10.1016\/j.ajpath.2011.07.009","article-title":"mdx((5)cv) mice manifest more severe muscle dysfunction and diaphragm force deficits than do mdx Mice","volume":"179","author":"Beastrom","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1016\/j.cell.2019.05.031","article-title":"Comprehensive Integration of Single-Cell Data","volume":"177","author":"Stuart","year":"2019","journal-title":"Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1038\/s41590-018-0276-y","article-title":"Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage","volume":"20","author":"Aran","year":"2019","journal-title":"Nat. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1038\/ni1008-1091","article-title":"The Immunological Genome Project: Networks of gene expression in immune cells","volume":"9","author":"Heng","year":"2008","journal-title":"Nat. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"eadd8945","DOI":"10.1126\/sciimmunol.add8945","article-title":"Identification of a broadly fibrogenic macrophage subset induced by type 3 inflammation","volume":"8","author":"Fabre","year":"2023","journal-title":"Sci. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1038\/s41586-019-1631-3","article-title":"Resolving the fibrotic niche of human liver cirrhosis at single-cell level","volume":"575","author":"Ramachandran","year":"2019","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1186\/s12967-024-05353-x","article-title":"Macrophage and fibroblast trajectory inference and crosstalk analysis during myocardial infarction using integrated single-cell transcriptomic datasets","volume":"22","author":"Ke","year":"2024","journal-title":"J. Transl. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"eadd9984","DOI":"10.1126\/sciadv.add9984","article-title":"Single-cell and spatial transcriptomics identify a macrophage population associated with skeletal muscle fibrosis","volume":"9","author":"Coulis","year":"2023","journal-title":"Sci. Adv."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e20210420","DOI":"10.1084\/jem.20210420","article-title":"A growth factor-expressing macrophage subpopulation orchestrates regenerative inflammation via GDF-15","volume":"219","author":"Patsalos","year":"2022","journal-title":"J. Exp. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e173858","DOI":"10.1172\/JCI173858","article-title":"Spatiotemporal transcriptomic mapping of regenerative inflammation in skeletal muscle reveals a dynamic multilayered tissue architecture","volume":"134","author":"Patsalos","year":"2024","journal-title":"J. Clin. Investig."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1002\/jcsm.12584","article-title":"Age-related decline of interferon-gamma responses in macrophage impairs satellite cell proliferation and regeneration","volume":"11","author":"Zhang","year":"2020","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1016\/j.immuni.2021.07.007","article-title":"Cross-tissue single-cell landscape of human monocytes and macrophages in health and disease","volume":"54","author":"Mulder","year":"2021","journal-title":"Immunity"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"eabf7777","DOI":"10.1126\/sciimmunol.abf7777","article-title":"Three tissue resident macrophage subsets coexist across organs with conserved origins and life cycles","volume":"7","author":"Dick","year":"2022","journal-title":"Sci. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/S1074-7613(03)00174-2","article-title":"Blood monocytes consist of two principal subsets with distinct migratory properties","volume":"19","author":"Geissmann","year":"2003","journal-title":"Immunity"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"13","DOI":"10.12703\/P6-13","article-title":"The M1 and M2 paradigm of macrophage activation: Time for reassessment","volume":"6","author":"Martinez","year":"2014","journal-title":"F1000prime Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"7303","DOI":"10.4049\/jimmunol.177.10.7303","article-title":"Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: New molecules and patterns of gene expression","volume":"177","author":"Martinez","year":"2006","journal-title":"J. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.immuni.2014.06.008","article-title":"Macrophage activation and polarization: Nomenclature and experimental guidelines","volume":"41","author":"Murray","year":"2014","journal-title":"Immunity"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Yang, Z., and Ming, X.F. (2014). Functions of arginase isoforms in macrophage inflammatory responses: Impact on cardiovascular diseases and metabolic disorders. Front. Immunol., 5.","DOI":"10.3389\/fimmu.2014.00533"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1083\/jcb.9.2.493","article-title":"Satellite cell of skeletal muscle fibers","volume":"9","author":"Mauro","year":"1961","journal-title":"J. Biophys. Biochem. Cytol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3625","DOI":"10.1242\/dev.064162","article-title":"Satellite cells, connective tissue fibroblasts and their interactions are crucial for muscle regeneration","volume":"138","author":"Murphy","year":"2011","journal-title":"Development"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1038\/nrm3265","article-title":"Satellite cells, the engines of muscle repair","volume":"13","author":"Wang","year":"2011","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1242\/dev.114223","article-title":"Intrinsic and extrinsic mechanisms regulating satellite cell function","volume":"142","author":"Dumont","year":"2015","journal-title":"Development"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/s41580-021-00421-2","article-title":"Control of satellite cell function in muscle regeneration and its disruption in ageing","volume":"23","year":"2022","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1074\/jbc.M112.419788","article-title":"Interleukin-6\/signal transducer and activator of transcription 3 (STAT3) pathway is essential for macrophage infiltration and myoblast proliferation during muscle regeneration","volume":"288","author":"Zhang","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"C370","DOI":"10.1152\/ajpcell.00453.2002","article-title":"TNF-\u03b1 is a mitogen in skeletal muscle","volume":"285","author":"Li","year":"2002","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.stem.2012.09.015","article-title":"Fibronectin regulates Wnt7a signaling and satellite cell expansion","volume":"12","author":"Bentzinger","year":"2013","journal-title":"Cell Stem Cell"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2228","DOI":"10.2353\/ajpath.2010.090884","article-title":"Macrophages protect against muscle atrophy and promote muscle recovery in vivo and in vitro: A mechanism partly dependent on the insulin-like growth factor-1 signaling molecule","volume":"176","author":"Dumont","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1038\/mt.2015.66","article-title":"Monocyte\/Macrophage-derived IGF-1 Orchestrates Murine Skeletal Muscle Regeneration and Modulates Autocrine Polarization","volume":"23","author":"Tonkin","year":"2015","journal-title":"Mol. Ther."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1038\/s41586-021-03199-7","article-title":"Macrophages provide a transient muscle stem cell niche via NAMPT secretion","volume":"591","author":"Ratnayake","year":"2021","journal-title":"Nature"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1016\/j.immuni.2016.10.016","article-title":"Macrophage PPARgamma, a Lipid Activated Transcription Factor Controls the Growth Factor GDF3 and Skeletal Muscle Regeneration","volume":"45","author":"Varga","year":"2016","journal-title":"Immunity"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"e12815","DOI":"10.1111\/acel.12815","article-title":"In vivo GDF3 administration abrogates aging related muscle regeneration delay following acute sterile injury","volume":"17","author":"Patsalos","year":"2018","journal-title":"Aging Cell"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1093\/hmg\/ddq523","article-title":"Interleukin-10 reduces the pathology of mdx muscular dystrophy by deactivating M1 macrophages and modulating macrophage phenotype","volume":"20","author":"Villalta","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Huynh, T., Reed, C., Blackwell, Z., Phelps, P., Herrera, L.C.P., Almodovar, J., Zaharoff, D.A., and Wolchok, J. (2023). Local IL-10 delivery modulates the immune response and enhances repair of volumetric muscle loss muscle injury. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-27981-x"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/ncb2015","article-title":"Muscle injury activates resident fibro\/adipogenic progenitors that facilitate myogenesis","volume":"12","author":"Joe","year":"2010","journal-title":"Nat. Cell Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/ncb2014","article-title":"Mesenchymal progenitors distinct from satellite cells contribute to ectopic fat cell formation in skeletal muscle","volume":"12","author":"Uezumi","year":"2010","journal-title":"Nat. Cell Biol."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Uezumi, A., Ikemoto-Uezumi, M., and Tsuchida, K. (2014). Roles of nonmyogenic mesenchymal progenitors in pathogenesis and regeneration of skeletal muscle. Front. Physiol., 5.","DOI":"10.3389\/fphys.2014.00068"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"105775","DOI":"10.1016\/j.isci.2022.105775","article-title":"Diverse effector and regulatory functions of fibro\/adipogenic progenitors during skeletal muscle fibrosis in muscular dystrophy","volume":"26","author":"Wang","year":"2023","journal-title":"Iscience"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1038\/nm.3869","article-title":"Nilotinib reduces muscle fibrosis in chronic muscle injury by promoting TNF-mediated apoptosis of fibro\/adipogenic progenitors","volume":"21","author":"Lemos","year":"2015","journal-title":"Nat. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3654","DOI":"10.1242\/jcs.086629","article-title":"Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle","volume":"124","author":"Uezumi","year":"2011","journal-title":"J. Cell Sci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1161\/CIRCRESAHA.107.160408","article-title":"Osteopontin expression is required for myofibroblast differentiation","volume":"102","author":"Lenga","year":"2008","journal-title":"Circ. Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1161\/CIRCRESAHA.109.209189","article-title":"TIMP2 deficiency accelerates adverse post-myocardial infarction remodeling because of enhanced MT1-MMP activity despite lack of MMP2 activation","volume":"106","author":"Kandalam","year":"2010","journal-title":"Circ. Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2501","DOI":"10.1016\/j.yexcr.2008.05.018","article-title":"MT1-MMP releases latent TGF-beta1 from endothelial cell extracellular matrix via proteolytic processing of LTBP-1","volume":"314","author":"Tatti","year":"2008","journal-title":"Exp. Cell Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"26411","DOI":"10.1074\/jbc.M001270200","article-title":"TIMP-2 is required for efficient activation of proMMP-2 in vivo","volume":"275","author":"Wang","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1186\/s41232-023-00308-z","article-title":"Extracellular matrix: The critical contributor to skeletal muscle regeneration-a comprehensive review","volume":"43","author":"Ahmad","year":"2023","journal-title":"Inflamm. Regen."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1007\/s00441-018-2955-2","article-title":"Skeletal muscle fibrosis: An overview","volume":"375","author":"Mahdy","year":"2019","journal-title":"Cell Tissue Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"5363","DOI":"10.1096\/fj.201901719RR","article-title":"IPF pathogenesis is dependent upon TGFbeta induction of IGF-1","volume":"34","author":"Hernandez","year":"2020","journal-title":"FASEB J."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1186\/1465-9921-14-102","article-title":"Role of IGF-1 pathway in lung fibroblast activation","volume":"14","author":"Hung","year":"2013","journal-title":"Respir. Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"112131","DOI":"10.1016\/j.celrep.2023.112131","article-title":"Platelet-instructed SPP1(+) macrophages drive myofibroblast activation in fibrosis in a CXCL4-dependent manner","volume":"42","author":"Hoeft","year":"2023","journal-title":"Cell Rep."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1016\/j.jhep.2022.06.004","article-title":"Soluble TREM2 levels reflect the recruitment and expansion of TREM2(+) macrophages that localize to fibrotic areas and limit NASH","volume":"77","author":"Hendrikx","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"e85530","DOI":"10.7554\/eLife.85530","article-title":"Systems level identification of a matrisome-associated macrophage polarisation state in multi-organ fibrosis","volume":"12","author":"Ouyang","year":"2023","journal-title":"eLife"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1802441","DOI":"10.1183\/13993003.02441-2018","article-title":"Proliferating SPP1\/MERTK-expressing macrophages in idiopathic pulmonary fibrosis","volume":"54","author":"Morse","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Palma, A. (2025). The Landscape of SPP1(+) Macrophages Across Tissues and Diseases: A Comprehensive Review. Immunology.","DOI":"10.1111\/imm.13952"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"100993","DOI":"10.1016\/j.isci.2020.100993","article-title":"Temporal Dynamics and Heterogeneity of Cell Populations during Skeletal Muscle Regeneration","volume":"23","author":"Oprescu","year":"2020","journal-title":"Iscience"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Nirgude, S., and Choudhary, B. (2021). Insights into the role of GPX3, a highly efficient plasma antioxidant, in cancer. Biochem. Pharmacol., 184.","DOI":"10.1016\/j.bcp.2020.114365"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"111878","DOI":"10.1016\/j.isci.2025.111878","article-title":"RGS2 is an innate immune checkpoint for suppressing G\u03b1q-mediated IFN\u03b3 generation and lung injury","volume":"28","author":"Joshi","year":"2025","journal-title":"Iscience"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"5858","DOI":"10.1172\/JCI130996","article-title":"Inhibition of mitophagy drives macrophage activation and antibacterial defense during sepsis","volume":"130","author":"Patoli","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.1016\/j.immuni.2023.06.017","article-title":"Hypoxic niches attract and sequester tumor-associated macrophages and cytotoxic T cells and reprogram them for immunosuppression","volume":"56","author":"Sattiraju","year":"2023","journal-title":"Immunity"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"e12055","DOI":"10.1002\/ccs3.12055","article-title":"Cytokine expression and cytokine-mediated cell-cell communication during skeletal muscle regeneration revealed by integrative analysis of single-cell RNA sequencing data","volume":"18","author":"Barai","year":"2024","journal-title":"J. Cell Commun. Signal."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1038\/s12276-025-01467-4","article-title":"Temporal single-cell sequencing analysis reveals that GPNMB-expressing macrophages potentiate muscle regeneration","volume":"57","author":"Chen","year":"2025","journal-title":"Exp. Mol. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"114975","DOI":"10.1016\/j.celrep.2024.114975","article-title":"The immune landscape of murine skeletal muscle regeneration and aging","volume":"43","author":"Sousa","year":"2024","journal-title":"Cell Rep."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"114197","DOI":"10.1016\/j.yexcr.2024.114197","article-title":"Integration of single-cell datasets depicts profiles of macrophages and fibro\/adipogenic progenitors in dystrophic muscle","volume":"442","author":"Vitaliti","year":"2024","journal-title":"Exp. Cell Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"6669","DOI":"10.1016\/j.cell.2024.08.041","article-title":"Profound cellular defects attribute to muscular pathogenesis in the rhesus monkey model of Duchenne muscular dystrophy","volume":"187","author":"Ren","year":"2024","journal-title":"Cell"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"105415","DOI":"10.1016\/j.isci.2022.105415","article-title":"Single cell sequencing maps skeletal muscle cellular diversity as disease severity increases in dystrophic mouse models","volume":"25","author":"Saleh","year":"2022","journal-title":"Iscience"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"e2410095122","DOI":"10.1073\/pnas.2410095122","article-title":"Expansion and pathogenic activation of skeletal muscle-resident macrophages in mdx(5cv)\/Ccr2(-\/-) mice","volume":"122","author":"Wang","year":"2025","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.cytogfr.2023.08.007","article-title":"The critical role of osteopontin (OPN) in fibrotic diseases","volume":"74","author":"Tang","year":"2023","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1172\/JCI37662","article-title":"Osteopontin promotes fibrosis in dystrophic mouse muscle by modulating immune cell subsets and intramuscular TGF-beta","volume":"119","author":"Vetrone","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"e181946","DOI":"10.1172\/jci.insight.181946","article-title":"Macrophage-derived Spp1 promotes intramuscular fat in dystrophic muscle","volume":"10","author":"Farahat","year":"2025","journal-title":"JCI Insight"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1038\/s41467-025-57024-0","article-title":"TREM2 promotes lung fibrosis via controlling alveolar macrophage survival and pro-fibrotic activity","volume":"16","author":"Cui","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1038\/s41418-023-01252-8","article-title":"TREM2 macrophage promotes cardiac repair in myocardial infarction by reprogramming metabolism via SLC25A53","volume":"31","author":"Gong","year":"2024","journal-title":"Cell Death Differ."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Scripture-Adams, D.D., Chesmore, K.N., Barthelemy, F., Wang, R.T., Nieves-Rodriguez, S., Wang, D.W., Mokhonova, E.I., Douine, E.D., Wan, J., and Little, I. (2022). Single nuclei transcriptomics of muscle reveals intra-muscular cell dynamics linked to dystrophin loss and rescue. Commun. Biol., 5.","DOI":"10.1038\/s42003-022-03938-0"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1038\/nri2873","article-title":"Sterile inflammation: Sensing and reacting to damage","volume":"10","author":"Chen","year":"2010","journal-title":"Nat. Rev. Immunol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1016\/j.immuni.2024.03.002","article-title":"DAMPs and DAMP-sensing receptors in inflammation and diseases","volume":"57","author":"Ma","year":"2024","journal-title":"Immunity"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1146\/annurev-pathmechdis-051222-015009","article-title":"Neutrophils in Physiology and Pathology","volume":"19","author":"Vicanolo","year":"2024","journal-title":"Annu. Rev. Pathol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/s41587-023-01767-y","article-title":"Dictionary learning for integrative, multimodal and scalable single-cell analysis","volume":"42","author":"Hao","year":"2024","journal-title":"Nat Biotechnol"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1126\/science.aad0501","article-title":"Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq","volume":"352","author":"Tirosh","year":"2016","journal-title":"Science"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"709","DOI":"10.12688\/f1000research.24956.2","article-title":"gprofiler2\u2014An R package for gene list functional enrichment analysis and namespace conversion toolset g:Profiler","volume":"9","author":"Kolberg","year":"2020","journal-title":"F1000Res"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"5701","DOI":"10.1093\/bioinformatics\/btaa1009","article-title":"glmGamPoi: Fitting Gamma-Poisson generalized linear models on single cell count data","volume":"36","author":"Huber","year":"2021","journal-title":"Bioinformatics"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1038\/s41592-019-0619-0","article-title":"Fast, sensitive and accurate integration of single-cell data with Harmony","volume":"16","author":"Korsunsky","year":"2019","journal-title":"Nat. Methods"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/nbt.2859","article-title":"The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells","volume":"32","author":"Trapnell","year":"2014","journal-title":"Nat. Biotechnol."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Street, K., Risso, D., Fletcher, R.B., Das, D., Ngai, J., Yosef, N., Purdom, E., and Dudoit, S. (2018). Slingshot: Cell lineage and pseudotime inference for single-cell transcriptomics. BMC Genom., 19.","DOI":"10.1186\/s12864-018-4772-0"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"W130","DOI":"10.1093\/nar\/gkx356","article-title":"WebGestalt 2017: A more comprehensive, powerful, flexible and interactive gene set enrichment analysis toolkit","volume":"45","author":"Wang","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"iyad031","DOI":"10.1093\/genetics\/iyad031","article-title":"The Gene Ontology knowledgebase in 2023","volume":"224","author":"Aleksander","year":"2023","journal-title":"Genetics"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/16\/8098\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:33:03Z","timestamp":1760034783000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/16\/8098"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,21]]},"references-count":109,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["ijms26168098"],"URL":"https:\/\/doi.org\/10.3390\/ijms26168098","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,21]]}}}