Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): CRC1425 - DFG Introduction Resident macrophages account for 5% of the cells in the healthy heart. In response to cardiac injury, monocytes infiltrate and differentiate into recruited macrophages complementing the original resident macrophage population, and together orchestrate cardiac remodeling. We aim to identify the extent to which macrophage origin, tissue location and type of cardiac injury determine macrophage phenotypes in ischemic and non-ischemic cardiac injuries over time. Results and methods We use a reporter mouse line CX3CR1Yfp CreER/+:R26tdT/+ to visualize and quantify fluxes of resident and recruited macrophages and their respective localizations within the heart following ischemia and reperfusion (I/R) injury and pressure overload after transversal aortic constriction (TAC), respectively. Interestingly, macrophage numbers peaked during the first week post-surgery in both the local/acute and the global/continuous injury models. Initially, recruited macrophages outnumbered the resident macrophage pool within the infarct area but ultimately reached a near 1:1 equilibrium at 4 weeks post I/R injury. In the remote myocardium the 1:1 equilibrium established already during the first week. In TAC-injured hearts, the 1:1 ratio of recruited and resident hearts also established within the first week post-surgery and persisted up to 8 weeks of follow-up even as cardiac function deteriorated. In the infarct, recruited macrophages showed increased cytokine synthesis, defensive response, and cell adhesion pathways during the first week after injury. Many inflammatory pathways remained activated up to day 28 post MI despite simultaneous activation of the anti-inflammatory response. Formerly resident macrophages and their progeny also mounted an immune response throughout the healing process. Unexpectedly, by day 28 post MI when a stable scar had formed, resident and recruited macrophage population transcriptomes converted onto a common, pro-inflammatory steady state phenotype, that differed from their originally divergent gene expression profiles in the healthy heart by over one thousand genes. In the remote zone, however, resident macrophages maintained cellular homeostasis function, unlike recruited macrophages that retained an inflammatory program. Following TAC surgery, transcriptional profiles remained differentially regulated at all time points tested, where recruited subset induced immune response and resident macrophages upregulated tissue remodeling genes. Conclusion Ischemic and non-ischemic cardiac injuries induce a transient peak of monocyte recruitment and macrophage differentiation in and around cardiac lesions which lead to a permanent integration of recruited monocyte-derived macrophages into the pool of tissue resident macrophages – albeit at different paces. The type of injury and macrophage localization within the changing tissue microenvironment determine partial or complete override of ontogenic cell programs.

中文翻译：

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心脏损伤后巨噬细胞转录组的变化取决于病变类型，而不是其个体发生性质


资金致谢 资金来源类型： 公共补助金 – 仅国家预算。主要资金来源：CRC1425 - DFG 简介 常驻巨噬细胞占健康心脏细胞的 5%。为了应对心脏损伤，单核细胞渗透并分化为募集的巨噬细胞，补充原始驻留巨噬细胞群，并共同协调心脏重塑。我们的目的是确定随着时间的推移，巨噬细胞起源、组织位置和心脏损伤类型在多大程度上决定缺血性和非缺血性心脏损伤中的巨噬细胞表型。结果和方法 我们使用报告小鼠系 CX3CR1Yfp CreER/+:R26tdT/+ 来可视化和量化驻留和招募的巨噬细胞的通量及其在缺血再灌注 (I/R) 损伤和横主动脉后压力超负荷后各自在心脏内的定位分别是收缩（TAC）。有趣的是，在局部/急性和整体/持续损伤模型中，巨噬细胞数量在术后第一周达到峰值。最初，募集的巨噬细胞数量超过了梗塞区域内的常驻巨噬细胞池，但最终在 I/R 损伤后 4 周达到接近 1:1 的平衡。在远端心肌中，第一周就已经建立了 1:1 平衡。在 TAC 损伤的心脏中，在术后第一周内就建立了 1:1 的募集心脏和驻留心脏的比例，并且即使心脏功能恶化，该比例也能持续长达 8 周的随访时间。在梗塞中，受伤后第一周内，募集的巨噬细胞表现出细胞因子合成、防御反应和细胞粘附途径增加。 尽管同时激活了抗炎反应，但许多炎症通路在心肌梗死后第 28 天仍保持激活状态。以前驻留的巨噬细胞及其后代也在整个愈合过程中产生了免疫反应。出乎意料的是，到心肌梗死后第 28 天，当稳定的疤痕形成时，驻留和招募的巨噬细胞群转录组转化为常见的促炎稳态表型，这与健康心脏中最初不同的基因表达谱有 1000 多个基因的不同。然而，在偏远地区，常驻巨噬细胞维持细胞稳态功能，这与保留炎症程序的招募巨噬细胞不同。 TAC 手术后，转录谱在所有测试时间点都保持差异性调节，其中招募的子集诱导免疫反应，驻留巨噬细胞上调组织重塑基因。结论 缺血性和非缺血性心脏损伤会导致心脏病变内部和周围的单核细胞募集和巨噬细胞分化出现短暂的峰值，从而导致募集的单核细胞衍生的巨噬细胞永久整合到组织驻留巨噬细胞池中——尽管速度不同。变化的组织微环境中的损伤类型和巨噬细胞定位决定了个体细胞程序的部分或完全覆盖。