Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction
Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction
复制标题
DOI：
10.1038/s41590-019-0363-8
复制
发表时间：
2019-01-01
影响因子：
30.5
通讯作者：
Epelman, Slava
中科院分区：
文献类型：
--
作者：
Dick, Sarah A.;Macklin, Jillian A.;Epelman, Slava
巨噬细胞促进心肌梗死后的损伤和修复，但在混合人群中的区分功能仍然具有挑战性。在这里，我们使用命运作图、联体共生和单细胞转录组学来证明在稳态下，TIMD 4（+）LYVE 1（+）MHC-II（lo）CCR 2（-）驻留的心脏巨噬细胞自我更新，血液单核细胞输入可忽略不计。单核细胞部分取代了TIMD 4（-）LYVE 1（-）MHC-II（hi）CCR 2（-）巨噬细胞，并完全取代了TIMD 4（-）LYVE 1（-）MHC（-）II（hi）CCR 2（+）巨噬细胞，揭示了单核细胞对功能不同的巨噬细胞亚群的贡献的层次结构。缺血性损伤减少了TIMD 4（+）和TIMD 4（-）驻留巨噬细胞的丰度，而CCR 2（+）单核细胞衍生的巨噬细胞在梗死组织内采用多种细胞命运，包括那些几乎无法与驻留巨噬细胞区分的细胞。募集的巨噬细胞不表达TIMD 4，突出了TIMD 4在没有命运作图的情况下追踪驻留巨噬细胞亚组的能力。尽管存在这种相似性，但使用基于Cx 3cr 1的系统对驻留巨噬细胞进行诱导性消耗导致心脏功能受损，并主要在梗死周围区域内促进不良重塑，揭示了驻留心脏巨噬细胞的非冗余心脏保护作用。
Macrophages promote both injury and repair after myocardial infarction, but discriminating functions within mixed populations remains challenging. Here we used fate mapping, parabiosis and single-cell transcriptomics to demonstrate that at steady state, TIMD4(+)LYVE1(+)MHC-II(lo)CCR2(-) resident cardiac macrophages self-renew with negligible blood monocyte input. Monocytes partially replaced resident TIMD4(-)LYVE1(-)MHC-II(hi)CCR2(-) macrophages and fully replaced TIMD4(-)LYVE1(-)MHC(-)II(hi)CCR2(+) macrophages, revealing a hierarchy of monocyte contribution to functionally distinct macrophage subsets. Ischemic injury reduced TIMD4(+) and TIMD4(-) resident macrophage abundance, whereas CCR2(+) monocyte-derived macrophages adopted multiple cell fates within infarcted tissue, including those nearly indistinguishable from resident macrophages. Recruited macrophages did not express TIMD4, highlighting the ability of TIMD4 to track a subset of resident macrophages in the absence of fate mapping. Despite this similarity, inducible depletion of resident macrophages using a Cx3cr1-based system led to impaired cardiac function and promoted adverse remodeling primarily within the peri-infarct zone, revealing a nonredundant, cardioprotective role of resident cardiac macrophages.