Aims Macrophages have a critical and dual role in post-ischaemic cardiac repair, as they can foster both tissue healing and damage. Multiple subsets of tissue resident and monocyte-derived macrophages coexist in the infarcted heart, but their precise identity, temporal dynamics, and the mechanisms regulating their acquisition of discrete states are not fully understood. To address this, we used multi-modal single-cell immune profiling, combined with targeted cell depletion and macrophage fate mapping, to precisely map monocyte/macrophage transitions after experimental myocardial infarction. Methods and results We performed single-cell transcriptomic and cell-surface marker profiling of circulating and cardiac immune cells in mice challenged with acute myocardial infarction, and integrated single-cell transcriptomes obtained before and at 1, 3, 5, 7, and 11 days after infarction. Using complementary strategies of CCR2+ monocyte depletion and fate mapping of tissue resident macrophages, we determined the origin of cardiac macrophage populations. The macrophage landscape of the infarcted heart was dominated by monocyte-derived cells comprising two pro-inflammatory populations defined as Isg15hi and MHCII+Il1b+, alongside non-inflammatory Trem2hi cells. Trem2hi macrophages were observed in the ischaemic area, but not in the remote viable myocardium, and comprised two subpopulations sequentially populating the heart defined as Trem2hiSpp1hi monocyte-to-macrophage intermediates, and fully differentiated Trem2hiGdf15hi macrophages. Cardiac Trem2hi macrophages showed similarities to ‘lipid-associated macrophages’ found in mouse models of metabolic diseases and were observed in the human heart, indicating conserved features of this macrophage state across diseases and species. Ischaemic injury induced a shift of circulating Ly6Chi monocytes towards a Chil3hi state with granulocyte-like features, but the acquisition of the Trem2hi macrophage signature occurred in the ischaemic tissue. In vitro, macrophages acquired features of the Trem2hi signature following apoptotic-cell efferocytosis. Conclusion Our work provides a comprehensive map of monocyte/macrophage transitions in the ischaemic heart, constituting a valuable resource for further investigating how these cells may be harnessed and modulated to promote post-ischaemic heart repair.

中文翻译：

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实验性心肌梗死中单核细胞来源的巨噬细胞多样性的动力学

目标 巨噬细胞在缺血后心脏修复中具有关键的双重作用，因为它们可以促进组织愈合和损伤。组织驻留和单核细胞来源的巨噬细胞的多个子集共存于梗塞心脏中，但它们的确切身份、时间动态以及调节它们获得离散状态的机制尚不完全清楚。为了解决这个问题，我们使用多模态单细胞免疫分析，结合靶向细胞耗竭和巨噬细胞命运图谱，以精确映射实验性心肌梗死后的单核细胞/巨噬细胞转变。方法和结果 我们对受到急性心肌梗死攻击的小鼠的循环和心脏免疫细胞进行了单细胞转录组学和细胞表面标记物分析，并整合了在 1、3、5、1、3 和 梗死后7、11天。使用 CCR2+ 单核细胞耗竭和组织驻留巨噬细胞命运图谱的互补策略，我们确定了心脏巨噬细胞群的起源。梗塞心脏的巨噬细胞景观以单核细胞衍生细胞为主，包括两个促炎细胞群，定义为 Isg15hi 和 MHCII + Il1b +，以及非炎性 Trem2hi 细胞。在缺血区域观察到 Trem2hi 巨噬细胞，但在远处存活的心肌中没有观察到，并且包含两个亚群，这些亚群依次填充心脏，定义为 Trem2hiSpp1hi 单核细胞到巨噬细胞中间体，以及完全分化的 Trem2hiGdf15hi 巨噬细胞。心脏 Trem2hi 巨噬细胞显示出与代谢疾病小鼠模型中发现的“脂质相关巨噬细胞”的相似性，并在人类心脏中观察到，表明这种巨噬细胞状态在疾病和物种中的保守特征。缺血性损伤诱导循环 Ly6Chi 单核细胞向具有粒细胞样特征的 Chil3hi 状态转变，但 Trem2hi 巨噬细胞特征的获得发生在缺血组织中。在体外，巨噬细胞在凋亡细胞胞吐作用后获得了 Trem2hi 特征。结论 我们的工作提供了缺血心脏中单核细胞/巨噬细胞转变的综合图谱，构成了进一步研究如何利用和调节这些细胞以促进缺血后心脏修复的宝贵资源。但 Trem2hi 巨噬细胞特征的获得发生在缺血组织中。在体外，巨噬细胞在凋亡细胞胞吐作用后获得了 Trem2hi 特征。结论 我们的工作提供了缺血心脏中单核细胞/巨噬细胞转变的综合图谱，构成了进一步研究如何利用和调节这些细胞以促进缺血后心脏修复的宝贵资源。但 Trem2hi 巨噬细胞特征的获得发生在缺血组织中。在体外，巨噬细胞在凋亡细胞胞吐作用后获得了 Trem2hi 特征。结论 我们的工作提供了缺血心脏中单核细胞/巨噬细胞转变的综合图谱，构成了进一步研究如何利用和调节这些细胞以促进缺血后心脏修复的宝贵资源。