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

Autor: Coulis G; Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA.; Institute for Immunology, University of California Irvine, Irvine, CA, USA., Jaime D; Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA.; Institute for Immunology, University of California Irvine, Irvine, CA, USA., Guerrero-Juarez C; Carle Illinois College of Medicine, University of Illinois at Urbana-Champaign, Champaign, IL, USA., Kastenschmidt JM; Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA.; Institute for Immunology, University of California Irvine, Irvine, CA, USA., Farahat PK; Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA.; Institute for Immunology, University of California Irvine, Irvine, CA, USA., Nguyen Q; Department of Biological Chemistry, University of California Irvine, Irvine, CA USA., Pervolarakis N; Department of Biological Chemistry, University of California Irvine, Irvine, CA USA., McLinden K; Department of Molecular Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA., Thurlow L; Department of Molecular Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA., Movahedi S; Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA., Hughes BS; Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA., Duarte J; Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA., Sorn A; Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA., Montoya E; Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA., Mozaffar I; Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA., Dragan M; Department of Biological Chemistry, University of California Irvine, Irvine, CA USA., Othy S; Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA.; Institute for Immunology, University of California Irvine, Irvine, CA, USA., Joshi T; Department of Health Management and Informatics, University of Missouri, Columbia, MO, USA., Hans CP; Department of Cardiovascular Medicine, University of Missouri, Columbia, MO USA., Kimonis V; Department of Pediatrics, University of California Irvine, Irvine, CA, USA., MacLean AL; Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA., Nie Q; Department of Mathematics, Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA, USA., Wallace LM; Center for Gene Therapy, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA., Harper SQ; Center for Gene Therapy, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.; Department of Pediatrics, The Ohio State University, Columbus, OH, USA., Mozaffar T; Department of Neurology, University of California Irvine, Irvine, CA, USA.; Department of Pathology and Laboratory Medicine, University of California Irvine, Irvine, CA, USA., Hogarth MW; Children's National Hospital, Research Center for Genetic Medicine, Washington, DC, USA., Bhattacharya S; Children's National Hospital, Research Center for Genetic Medicine, Washington, DC, USA., Jaiswal JK; Children's National Hospital, Research Center for Genetic Medicine, Washington, DC, USA., Golann DR; Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA., Su Q; Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA., Kessenbrock K; Department of Biological Chemistry, University of California Irvine, Irvine, CA USA., Stec M; Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA., Spencer MJ; Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA., Zamudio JR; Department of Molecular Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA., Villalta SA; Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA.; Institute for Immunology, University of California Irvine, Irvine, CA, USA.; Department of Neurology, University of California Irvine, Irvine, CA, USA.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2023 Jul 07; Vol. 9 (27), pp. eadd9984. Date of Electronic Publication: 2023 Jul 07.
DOI: 10.1126/sciadv.add9984
Abstrakt: 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.
Databáze: MEDLINE