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Cited by 150Muscle Physiology and DisordersCardiac Fibrosis and RemodelingInflammatory Myopathies and Dermatomyositis

Single-cell and spatial transcriptomics identify a macrophage population associated with skeletal muscle fibrosis

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Coulis, Gerald, Jaime, Diego, Guerrero-Juarez, Christian, Kastenschmidt, Jenna M., Farahat, Philip K., Nguyen, Quy, Pervolarakis, Nicholas, McLinden, Katherine +27 more·2023·Science Advances
DOI 10.1126/sciadv.add9984PMC PMC10328414

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Abstract

Macrophages are essential for skeletal muscle homeostasis, but how their dysregulation contributes to the development of fibrosis in muscle disease remains unclear. Here, we used single-cell transcriptomics to determine the molecular attributes of dystrophic and healthy muscle macrophages. We identified six clusters and unexpectedly found that none corresponded to traditional definitions of M1 or M2 macrophages. Rather, the predominant macrophage signature in dystrophic muscle was characterized by high expression of fibrotic factors, galectin-3 (gal-3) and osteopontin ( Spp1 ). Spatial transcriptomics, computational inferences of intercellular communication, and in vitro assays indicated that macrophage-derived Spp1 regulates stromal progenitor differentiation. Gal-3 + macrophages were chronically activated in dystrophic muscle, and adoptive transfer assays showed that the gal-3 + phenotype was the dominant molecular program induced within the dystrophic milieu. Gal-3 + macrophages were also elevated in multiple human myopathies. These studies advance our understanding of macrophages in muscular dystrophy by defining their transcriptional programs and reveal Spp1 as a major regulator of macrophage and stromal progenitor interactions.

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  • The LAM phenotype is not unique to the fibrotic liver, also being identified in other tissues in the context of sterile injury as well as in macrophages surrounding the bile duct in the healthy liver.

    “Interestingly, this phenotype is not unique to the fibrotic liver, also being identified in other tissues in the context of sterile injury (32, 33, 38, 110–121) as well as in macrophages surrounding the bile duct in the healthy liver (62).”

    From Targeting macrophages in liver fibrosis (2026) · cites this paper as [112]

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Cited by

Sorted by citations

Authors
Coulis, G., Jaime, D., Guerrero-Juarez, C., Kastenschmidt, J. M., Farahat, P. K., Nguyen, Q., Pervolarakis, N., McLinden, K., Thurlow, L., Movahedi, S., Hughes, B. S., Duarte, J., Sorn, A., Montoya, E., Mozaffar, I., Dragan, M., Othy, S., Joshi, T., Hans, C. P., Kimonis, V., MacLean, A. L., Nie, Q., Wallace, L. M., Harper, S. Q., Mozaffar, T., Hogarth, M. W., Bhattacharya, S., Jaiswal, J. K., Golann, D. R., Su, Q., Kessenbrock, K., Stec, M., Spencer, M. J., Zamudio, J. R., & Villalta, S. A.
Affiliations
  • Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA.
  • University of California, Irvine (US)
  • Carle Illinois College of Medicine, University of Illinois at Urbana-Champaign, Champaign, IL, USA.
  • University of California, Los Angeles (US)
  • University of Missouri (US)
  • University of Southern California (US)
  • Nationwide Children's Hospital (US)
  • Children's National (US)
  • Regeneron (United States) (US)
Corresponding author
Villalta, S. Armando
ORCID
Venue
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Published
2023-07-07
Volume
9
Issue
27
Pages
eadd9984-eadd9984
ISSN
2375-2548 (ISSN-L)
DOI
10.1126/sciadv.add9984
PMC
PMC10328414
OpenAlex
W4383499814
Cited by
150
References
15
Citations by year
2026: 48 · 2025: 64 · 2024: 29 · 2023: 9
FWCI
13.81
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Science Advances (publishedVersion, cc-by-nc)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
  • National Science Foundation (GM007185, DMS11763272, 1650604)
  • U.S. Department of Defense (MD190060)
  • California Institute for Regenerative Medicine (DISC2-08824, DISC0-13765)
  • Muscular Dystrophy Association (R01NS120060, U54 AR052646, MDA635862, W81XWH1910012)
  • National Institutes of Health (594598, DGE-1650604, UL1TR001414, KL2TR001416, AR052646, U54-AR052646)
  • National Cancer Institute (P30CA062203)
  • National Institute of General Medical Sciences (GM 007185, R01GM143536, T32GM007185, R35GM143019)
  • National Institute of Allergy and Infectious Diseases (T32AI060573, GM007185, R01AI168063)
  • National Institute of Neurological Disorders and Stroke (U24NS107210, R21NS114918, R01NS117912, R01NS120060)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (U54AR052646, AR052646, R01AR055686, P50AR052646, T32AR065972, P30AR075047, R01AR078340)
  • National Center for Advancing Translational Sciences
  • Congressionally Directed Medical Research Programs
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
  • Health Sciences › Medicine › Epidemiology › Inflammatory Myopathies and Dermatomyositis
Keywords
skeletal muscle fibrosis, muscular dystrophy, galectin-3, osteopontin, macrophage polarization, M1/M2 macrophages, intercellular communication, myopathy

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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