Delivery of MicroRNA-126 by Apoptotic Bodies Induces CXCL12-Dependent Vascular Protection
Delivery of MicroRNA-126 by Apoptotic Bodies Induces CXCL12-Dependent Vascular Protection
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DOI：
10.1126/scisignal.2000610
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发表时间：
2009-12-08
影响因子：
7.3
通讯作者：
Weber, Christian
中科院分区：
文献类型：
--
作者：
Zernecke, Alma;Bidzhekov, Kiril;Weber, Christian
细胞凋亡是胚胎发生和出生后细胞稳态的关键过程，涉及称为凋亡小体的膜微泡的脱落。在对组织损伤的反应中，CXC趋化因子CXCL 12及其受体CXCR 4对抗细胞凋亡并募集祖细胞。在这里，我们表明，内皮细胞衍生的凋亡小体在动脉粥样硬化过程中产生，并传递旁分泌警报信号，受体血管细胞，触发生产CXCL 12。CXCL 12的产生是由microRNA-126（miR-126）介导的，其在凋亡小体中富集并抑制G蛋白（异三聚体三磷酸鸟苷结合蛋白）信号传导16（G蛋白偶联受体（GPCR）信号传导的抑制剂）的调节剂的功能。这使得CXCR 4（一种GPCR）能够触发一个自动调节反馈回路，增加CXCL 12的产生。给予凋亡小体或miR-126限制动脉粥样硬化，促进Sca-1（+）祖细胞的掺入，并赋予不同小鼠动脉粥样硬化模型斑块稳定性的特征。这项研究强调了microRNA在健康和疾病中的功能，这些功能可能扩展到其他形式的组织修复或稳态过程中祖细胞的招募。
Apoptosis is a pivotal process in embryogenesis and postnatal cell homeostasis and involves the shedding of membranous microvesicles termed apoptotic bodies. In response to tissue damage, the CXC chemokine CXCL12 and its receptor CXCR4 counteract apoptosis and recruit progenitor cells. Here, we show that endothelial cell-derived apoptotic bodies are generated during atherosclerosis and convey paracrine alarm signals to recipient vascular cells that trigger the production of CXCL12. CXCL12 production was mediated by microRNA-126 (miR-126), which was enriched in apoptotic bodies and repressed the function of regulator of G protein (heterotrimeric guanosine triphosphate-binding protein) signaling 16, an inhibitor of G protein-coupled receptor (GPCR) signaling. This enabled CXCR4, a GPCR, to trigger an autoregulatory feedback loop that increased the production of CXCL12. Administration of apoptotic bodies or miR-126 limited atherosclerosis, promoted the incorporation of Sca-1(+) progenitor cells, and conferred features of plaque stability on different mouse models of atherosclerosis. This study highlights functions of microRNAs in health and disease that may extend to the recruitment of progenitor cells during other forms of tissue repair or homeostasis.