Comprehensive Heart Failure Center, University Hospital Würzburg, Am Schwarzenberg 15, A15, 97078 Würzburg, Germany.
Institute of Experimental Biomedicine, University Hospital Würzburg, Josef-Schneider-Str. 2, D16, 97080 Würzburg, Germany.
Cardiovasc Res. 2023 May 2;119(3):772-785. doi: 10.1093/cvr/cvac113.
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.
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.
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.
巨噬细胞在缺血性心脏修复中具有关键的双重作用，因为它们既能促进组织愈合，又能造成损伤。在梗死的心脏中，多种组织驻留和单核细胞衍生的巨噬细胞亚群共存，但它们的确切身份、时间动态以及调节其获得离散状态的机制尚未完全了解。为了解决这个问题，我们使用多模态单细胞免疫谱分析，结合靶向细胞耗竭和巨噬细胞命运图谱，精确绘制实验性心肌梗死后单核细胞/巨噬细胞的转化。
我们对急性心肌梗死小鼠的循环和心脏免疫细胞进行了单细胞转录组和细胞表面标志物谱分析，并整合了梗死前和梗死后 1、3、5、7 和 11 天获得的单细胞转录组。我们使用 CCR2+单核细胞耗竭的互补策略和组织驻留巨噬细胞的命运图谱，确定了心脏巨噬细胞群体的起源。梗死心脏的巨噬细胞景观由单核细胞衍生的细胞主导，这些细胞包括两种被定义为 Isg15hi 和 MHCII+Il1b+的促炎细胞群，以及非炎症性 Trem2hi 细胞。Trem2hi 巨噬细胞在缺血区观察到，但在远程存活心肌中未观察到，并且由两个亚群组成，依次定位于心脏，定义为 Trem2hiSpp1hi 单核细胞-巨噬细胞中间产物，和完全分化的 Trem2hiGdf15hi 巨噬细胞。心脏 Trem2hi 巨噬细胞与代谢疾病小鼠模型中发现的“脂质相关巨噬细胞”具有相似性，并且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具有保守特征。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，巨噬细胞通过凋亡细胞吞噬作用获得 Trem2hi 特征。
我们的工作提供了缺血性心脏中单核细胞/巨噬细胞转化的全面图谱，为进一步研究如何利用这些细胞促进缺血性心脏修复提供了有价值的资源。
