Macrophages in the infarcted heart acquire a fibrogenic phenotype, expressing matricellular proteins, but do not undergo fibroblast conversion

IF 4.9 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Journal of molecular and cellular cardiology Pub Date : 2024-11-01 DOI:10.1016/j.yjmcc.2024.07.010
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Abstract

Although some studies have suggested that macrophages may secrete structural collagens, and convert to fibroblast-like cells, macrophage to fibroblast transdifferentiation in infarcted and remodeling hearts remains controversial. Our study uses linage tracing approaches and single cell transcriptomics to examine whether macrophages undergo fibroblast conversion, and to characterize the extracellular matrix expression profile of myeloid cells in myocardial infarction. To examine whether infarct macrophages undergo fibroblast conversion, we identified macrophage-derived progeny using the inducible CX3CR1CreER mice crossed with the PDGFRαEGFP reporter line for reliable fibroblast identification. The abundant fibroblasts that infiltrated the infarcted myocardium after 7 and 28 days of coronary occlusion were not derived from CX3CR1+ macrophages. Infarct macrophages retained myeloid cell characteristics and did not undergo conversion to myofibroblasts, endothelial or vascular mural cells. Single cell RNA-seq of CSF1R+ myeloid cells harvested from control and infarcted hearts showed no significant expression of fibroblast identity genes by myeloid cell clusters. Moreover, infarct macrophages did not express significant levels of genes encoding structural collagens. However, infarct macrophage and monocyte clusters were the predominant source of the fibrogenic growth factors Tgfb1 and Pdgfb, and of the matricellular proteins Spp1/Osteopontin, Thbs1/Thrombospondin-1, Emilin2, and Fn1/fibronectin, while expressing significant amounts of several other matrix genes, including Vcan/versican, Ecm1 and Sparc. ScRNA-seq data suggested similar patterns of matrix gene expression in human myocardial infarction. In conclusion, infarct macrophages do not undergo fibroblast or myofibroblast conversion and do not exhibit upregulation of structural collagens but may contribute to fibrotic remodeling by producing several fibrogenic matricellular proteins.
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梗塞心脏中的巨噬细胞获得纤维表型,表达母细胞蛋白,但不会发生成纤维细胞转化。
尽管一些研究表明巨噬细胞可分泌结构性胶原并转化为成纤维细胞样细胞,但在梗死和重塑心脏中巨噬细胞向成纤维细胞的转分化仍存在争议。我们的研究采用血系追踪方法和单细胞转录组学研究巨噬细胞是否发生成纤维细胞转化,并描述心肌梗死中髓系细胞细胞外基质的表达谱。为了研究梗死巨噬细胞是否会发生成纤维细胞转化,我们使用诱导型 CX3CR1CreER 小鼠与 PDGFRαEGFP 报告基因杂交,对巨噬细胞衍生的后代进行了可靠的成纤维细胞鉴定。冠状动脉闭塞 7 天和 28 天后浸润梗死心肌的大量成纤维细胞并非来自 CX3CR1+ 巨噬细胞。梗死的巨噬细胞保留了髓样细胞的特征,没有转化为肌成纤维细胞、内皮细胞或血管壁细胞。从对照组和梗死心脏中提取的CSF1R+髓系细胞的单细胞RNA-seq显示,髓系细胞集群没有明显的成纤维细胞特征基因表达。此外,梗死巨噬细胞也没有表达大量编码结构胶原的基因。然而,梗死巨噬细胞和单核细胞集群是纤维生长因子Tgfb1和Pdgfb以及基质蛋白Spp1/Osteopontin、Thbs1/Thrombospondin-1、Emilin2和Fn1/纤连蛋白的主要来源,同时表达大量其他几个基质基因,包括Vcan/versican、Ecm1和Sparc。ScRNA-seq数据表明,人类心肌梗死中基质基因的表达模式与此类似。总之,梗死巨噬细胞不会发生成纤维细胞或成肌纤维细胞的转化,也不会表现出结构胶原的上调,但可能会通过产生几种纤维母细胞蛋白来促进纤维化重塑。
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来源期刊
CiteScore
10.70
自引率
0.00%
发文量
171
审稿时长
42 days
期刊介绍: The Journal of Molecular and Cellular Cardiology publishes work advancing knowledge of the mechanisms responsible for both normal and diseased cardiovascular function. To this end papers are published in all relevant areas. These include (but are not limited to): structural biology; genetics; proteomics; morphology; stem cells; molecular biology; metabolism; biophysics; bioengineering; computational modeling and systems analysis; electrophysiology; pharmacology and physiology. Papers are encouraged with both basic and translational approaches. The journal is directed not only to basic scientists but also to clinical cardiologists who wish to follow the rapidly advancing frontiers of basic knowledge of the heart and circulation.
期刊最新文献
Exercise training attenuates cardiac dysfunction induced by excessive sympathetic activation through an AMPK-KLF4-FMO2 axis. Different effects of cardiomyocyte contractile activity on transverse and axial tubular system luminal content dynamics. Editorial Board Macrophages in the infarcted heart acquire a fibrogenic phenotype, expressing matricellular proteins, but do not undergo fibroblast conversion Cardiac macrophages and fibroblasts: A synergistic partnership without cellular transition
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