Single-cell and spatial transcriptomics identify a macrophage population associated with skeletal muscle fibrosis.
Single-cell and spatial transcriptomics identify a macrophage population associated with skeletal muscle fibrosis.
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DOI：
10.1126/sciadv.add9984
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发表时间：
2023-07-07
期刊：
影响因子：
13.6
通讯作者：
中科院分区：
文献类型：
--
作者：
巨噬细胞对于骨骼肌稳态至关重要，但巨噬细胞的失调如何导致肌肉疾病纤维化的发展仍不清楚。在这里，我们使用单细胞转录组学来确定营养不良和健康肌肉巨噬细胞的分子属性。我们确定了 6 个簇，并意外地发现没有一个簇符合 M1 或 M2 巨噬细胞的传统定义。相反，营养不良性肌肉中主要的巨噬细胞特征是纤维化因子、半乳糖凝集素 3 (gal-3) 和骨桥蛋白 (Spp1) 的高表达。空间转录组学、细胞间通讯的计算推断和体外测定表明，巨噬细胞衍生的 Spp1 调节基质祖细胞分化。 Gal-3+巨噬细胞在营养不良的肌肉中被长期激活，过继转移试验表明gal-3+表型是营养不良环境中诱导的主要分子程序。 Gal-3+巨噬细胞在多种人类肌病中也升高。这些研究通过定义巨噬细胞的转录程序加深了我们对肌营养不良症中巨噬细胞的理解，并揭示了 Spp1 作为巨噬细胞和基质祖细胞相互作用的主要调节因子。转录组学鉴定了与肌肉纤维化相关的 Spp1 介导的肌肉巨噬细胞和基质祖细胞相互作用。
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. Transcriptomics identifies a Spp1-mediated muscle macrophage and stromal progenitor interaction associated with muscle fibrosis.
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影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
14.9
作者：
Frankish A;Diekhans M;Ferreira AM;Johnson R;Jungreis I;Loveland J;Mudge JM;Sisu C;Wright J;Armstrong J;Barnes I;Berry A;Bignell A;Carbonell Sala S;Chrast J;Cunningham F;Di Domenico T;Donaldson S;Fiddes IT;García Girón C;Gonzalez JM;Grego T;Hardy M;Hourlier T;Hunt T;Izuogu OG;Lagarde J;Martin FJ;Martínez L;Mohanan S;Muir P;Navarro FCP;Parker A;Pei B;Pozo F;Ruffier M;Schmitt BM;Stapleton E;Suner MM;Sycheva I;Uszczynska-Ratajczak B;Xu J;Yates A;Zerbino D;Zhang Y;Aken B;Choudhary JS;Gerstein M;Guigó R;Hubbard TJP;Kellis M;Paten B;Reymond A;Tress ML;Flicek P
通讯作者：
Flicek P
影响因子：
5.4
作者：
Gordon, Siamon;Hamann, Joerg;Stacey, Martin
通讯作者：
Stacey, Martin
影响因子：
30.5
作者：
Dick, Sarah A.;Macklin, Jillian A.;Epelman, Slava
通讯作者：
Epelman, Slava