From the Smidt Heart Institute (G.d.C., E.J., W.L., K.L., E.M.), Cedars-Sinai Medical Center, Los Angeles, CA.
Northwestern University, Chicago, IL (M.D., E.B.T.).
Arterioscler Thromb Vasc Biol. 2019 Oct;39(10):2082-2096. doi: 10.1161/ATVBAHA.119.313115. Epub 2019 Aug 22.
Extracellular vesicles secreted by cardiosphere-derived cells (CDC) polarize macrophages toward a distinctive phenotype with enhanced phagocytic capacity (M). These changes underlie cardioprotection by CDC 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 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. CDC exposure induces sustained MerTK expression in M through extracellular vesicle transfer of microRNA-26a (via suppression of ); the cardioprotective response is lost in animals deficient in MerTK. Single-cell RNA-sequencing revealed phagocytic pathway activation in M, with increased expression of complement factor , a phagocytosis facilitator.
Together, these data demonstrate that extracellular vesicle modulation of MerTK and C1qa expression leads to enhanced macrophage efferocytosis and cardioprotection.
心肌球衍生细胞（CDC）分泌的细胞外囊泡将巨噬细胞极化为具有增强吞噬能力（M）的独特表型。这些变化是由 CDC 和其亲本细胞介导的心脏保护作用的基础，特别是在心肌梗死后减轻无复流现象，但机制尚不清楚。在这里，我们检验了这样一个假设，即 M 特别有效地清除死亡细胞的碎片（即细胞凋亡），以减轻心肌梗死后的不可逆损伤。方法和结果：用骨髓来源的巨噬细胞进行体外细胞凋亡吞噬试验，以及体内心肌梗死转基因啮齿动物模型，证明 M 能增强凋亡细胞的清除。CDC 暴露通过 microRNA-26a（通过抑制 ）的细胞外囊泡转移在 M 中诱导持续的 MerTK 表达；在 MerTK 缺陷的动物中，这种心脏保护反应消失。单细胞 RNA 测序显示 M 中吞噬途径的激活，补体因子 的表达增加，这是一种吞噬促进剂。
这些数据表明，细胞外囊泡对 MerTK 和 C1qa 表达的调节导致巨噬细胞吞噬作用增强和心脏保护。
