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

Authors :
Coulis G
Jaime D
Guerrero-Juarez C
Kastenschmidt JM
Farahat PK
Nguyen Q
Pervolarakis N
McLinden K
Thurlow L
Movahedi S
Duarte J
Sorn A
Montoya E
Mozaffar I
Dragan M
Othy S
Joshi T
Hans CP
Kimonis V
MacLean AL
Nie Q
Wallace LM
Harper SQ
Mozaffar T
Hogarth MW
Bhattacharya S
Jaiswal JK
Golann DR
Su Q
Kessenbrock K
Stec M
Spencer MJ
Zamudio JR
Villalta SA
Source :
BioRxiv : the preprint server for biology [bioRxiv] 2023 Apr 18. Date of Electronic Publication: 2023 Apr 18.
Publication Year :
2023

Abstract

The monocytic/macrophage system is essential for skeletal muscle homeostasis, but its dysregulation contributes to the pathogenesis of muscle degenerative disorders. Despite our increasing knowledge of the role of macrophages in degenerative disease, it still remains unclear how macrophages contribute to muscle fibrosis. Here, we used single-cell transcriptomics to determine the molecular attributes of dystrophic and healthy muscle macrophages. We identified six novel clusters. Unexpectedly, none corresponded to traditional definitions of M1 or M2 macrophage activation. Rather, the predominant macrophage signature in dystrophic muscle was characterized by high expression of fibrotic factors, galectin-3 and spp1. Spatial transcriptomics and computational inferences of intercellular communication indicated that spp1 regulates stromal progenitor and macrophage interactions during muscular dystrophy. Galectin-3 <superscript>+</superscript> macrophages were chronically activated in dystrophic muscle and adoptive transfer assays showed that the galectin-3 <superscript>+</superscript> phenotype was the dominant molecular program induced within the dystrophic milieu. Histological examination of human muscle biopsies revealed that galectin-3 <superscript>+</superscript> macrophages were also elevated in multiple myopathies. These studies advance our understanding of macrophages in muscular dystrophy by defining the transcriptional programs induced in muscle macrophages, and reveal spp1 as a major regulator of macrophage and stromal progenitor interactions.

Details

Language :
English
ISSN :
2692-8205
Database :
MEDLINE
Journal :
BioRxiv : the preprint server for biology
Publication Type :
Academic Journal
Accession number :
37131694
Full Text :
https://doi.org/10.1101/2023.04.18.537253