Mechanism of Enhanced MerTK-Dependent Macrophage Efferocytosis by Extracellular Vesicles
Mechanism of Enhanced MerTK-Dependent Macrophage Efferocytosis by Extracellular Vesicles
复制标题
DOI：
10.1161/atvbaha.119.313115
复制
发表时间：
2019-10-01
影响因子：
8.7
通讯作者：
Marban, Eduardo
中科院分区：
文献类型：
--
作者：
de Couto, Geoffrey;Jaghatspanyan, Ervin;Marban, Eduardo
目的：心球源性细胞（CDCev）分泌的细胞外囊泡使巨噬细胞极化为具有增强吞噬能力的独特表型（M-CDCev）。这些变化是CDCev和母体CDC的心脏保护作用的基础，显著减弱了心肌梗死后的无复流现象，但机制尚不清楚。在这里，我们测试了M-CDCev在清除垂死细胞碎片（即红细胞增多症）以减轻心肌梗死后不可逆损伤方面特别有效的假设。方法和结果：骨髓源性巨噬细胞的体外巨噬细胞吞噬试验和心肌梗死的体内转基因啮齿动物模型证明了M-CDCev增强的凋亡细胞清除。CDCev暴露通过microRNA-26 a的细胞外囊泡转移（通过抑制Adam 17）诱导M-CDCev中持续的MerTK表达;在MerTK缺陷的动物中丧失了心脏保护反应。单细胞RNA测序显示，吞噬途径激活M-CDCev，与补体因子C1 qa，吞噬促进剂的表达增加。结论：总之，这些数据表明，MerTK和C1 qa表达的细胞外囊泡调节导致增强的巨噬细胞吞噬和心脏保护。
Objective: Extracellular vesicles secreted by cardiosphere-derived cells (CDCev) polarize macrophages toward a distinctive phenotype with enhanced phagocytic capacity (M-CDCev). These changes underlie cardioprotection by CDCev and by the parent CDCs, notably attenuating the no-reflow phenomenon following myocardial infarction, but the mechanisms are unclear. Here, we tested the hypothesis that M-CDCev are especially effective at scavenging debris from dying cells (ie, efferocytosis) to attenuate irreversible damage post-myocardial infarction. Approach and Results: In vitro efferocytosis assays with bone marrow-derived macrophages, and in vivo transgenic rodent models of myocardial infarction, demonstrate enhanced apoptotic cell clearance with M-CDCev. CDCev exposure induces sustained MerTK expression in M-CDCev through extracellular vesicle transfer of microRNA-26a (via suppression of Adam17); the cardioprotective response is lost in animals deficient in MerTK. Single-cell RNA-sequencing revealed phagocytic pathway activation in M-CDCev, with increased expression of complement factor C1qa, a phagocytosis facilitator. Conclusions: Together, these data demonstrate that extracellular vesicle modulation of MerTK and C1qa expression leads to enhanced macrophage efferocytosis and cardioprotection.