Exosomes derived from mesenchymal stem cells attenuate the progression of atherosclerosis in ApoE-/- mice via miR-let7 mediated infiltration and polarization of M2 macrophage
Exosomes derived from mesenchymal stem cells attenuate the progression of atherosclerosis in ApoE-/- mice via miR-let7 mediated infiltration and polarization of M2 macrophage
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DOI：
10.1016/j.bbrc.2019.02.005
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发表时间：
2019-03-19
影响因子：
3.1
通讯作者：
Li, Gang
中科院分区：
文献类型：
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作者：
Li, Jiangbing;Xue, Hao;Li, Gang
动脉粥样硬化是血管系统的慢性炎症性疾病。源自间充质干细胞（MSC）的外泌体发挥免疫调节和免疫抑制作用；然而，MSCs-外泌体给药对动脉粥样硬化的影响尚不清楚。在这里，我们的 ApoE(-/-) 小鼠被喂食高脂肪饮食，并接受 MSC 外泌体静脉注射 12 周。尾静脉注射后，MSCs-外泌体能够迁移到动脉粥样硬化斑块并选择性地定居在巨噬细胞附近。 MSCs-外泌体治疗减少了 ApoE(-/-) 小鼠的动脉粥样硬化斑块面积，并大大减少了斑块中巨噬细胞的浸润，将诱导的巨噬细胞极化向 M2 相关。在体外，MSCs-外泌体处理显着抑制 LPS 诱导的 M1 标记物表达，同时增加巨噬细胞中 M2 标记物的表达。此外，发现 miR-let7 家族在 MSC 外泌体中高度富集。在 ApoE(-/-) 小鼠的主动脉根部发现内源性 miR-let7 表达，MSC 外泌体治疗进一步上调 miR-let7 水平。此外，在体外，抑制1.1937细胞中的miR-let7可分别通过IGF2BP1和HMGA2途径显着抑制迁移和M2极化。我们的研究表明，MSC-性小体通过 miR-let7/HMGA2/NF-kappa B 途径改善 ApoE(-/-) 中的动脉粥样硬化并促进斑块中的 M2 巨噬细胞极化。此外，MSCs-外泌体通过斑块中的 miR-let7/IGF2BP1/PTEN 通路抑制巨噬细胞浸润。这一发现扩展了我们对间充质干细胞-外泌体影响动脉粥样硬化斑块炎症的认识，并提供了预防动脉粥样硬化的潜在方法。来自间充质干细胞的外泌体有望作为治疗剂来降低冠状动脉疾病的残余风险。 (C) 2019 Elsevier Inc. 保留所有权利。
Atherosclerosis is a chronic inflammatory disease of the vasculature. Exosomes derived from mesenchymal stem cells (MSCs) exert immunomodulatory and immunosuppressive effects; however, the MSCs-exosomes administration on atherosclerosis was unknown. Here, our ApoE(-/-) mice were fed a high-fat diet and received intravenous injections of exosomes from MSCs for 12 weeks. After tail-vein injection, MSCs-exosomes were capable of migrating to atherosclerotic plaque and selectively taking up residence near macrophages. MSCs-exosomes treatment decreased the atherosclerotic plaque area of ApoE(-/-) mice and greatly reduced the infiltration of macrophages in the plaque, associating induced macrophage polarization towards M2. In vitro, MSCs-exosomes treatment markedly inhibited LPS-induced M1 markers expression, while increased M2 markers expression in macrophages. Moreover, miR-let7 family was found to be highly enriched in MSCs-exosomes. Endogenous miR-let7 expression was found in the aortic root of ApoE(-/-) mice, and MSCs-exosomes treatment further up-regulated miR-let7 levels. In addition, inhibition of miR-let7 in 1.1937 cells significantly inhibited the migration and M2 polarization via IGF2BP1 and HMGA2 pathway respectively in vitro. Our study demonstrates that MSC-sexosomes ameliorated atherosclerosis in ApoE(-/-) and promoted M2 macrophage polarization in the plaque through miR-let7/HMGA2/NF-kappa B pathway. In addition, MSCs-exosomes suppressed macrophage infiltration via miR-let7/IGF2BP1/PTEN pathway in the plaque. This finding extends our knowledge on MSCs-exosomes affect inflammation in atherosclerosis plaque and provides a potential method to prevent the atherosclerosis. Exosomes from MSCs hold promise as therapeutic agents to reduce the residual risk of coronary artery diseases. (C) 2019 Elsevier Inc. All rights reserved.