Institute of Biomedical Sciences, Fudan University, 200032, Shanghai, China.
Department of Cardiology, Zhongshan Hospital, Fudan University. Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 200032, Shanghai, PR China.
Cell Death Dis. 2019 May 29;10(6):422. doi: 10.1038/s41419-019-1667-1.
The role of M1 macrophages (M1M)-derived exosomes in the progression of neointimal hyperplasia remains unclear now. Using a transwell co-culture system, we demonstrated that M1M contributed to functional change of vascular smooth muscle cell (VSMC). We further stimulated VSMCs with exosomes isolated from M1M. Our results demonstrated that these exosomes could be taken up by VSMCs through macropinocytosis. Using a microRNA array assay, we identified that miR-222 originated from M1M-derived exosomes triggered the functional changes of VSMCs. In addition, we confirmed that miR-222 played a key role in promoting VSMCs proliferation and migration by targeting Cyclin Dependent Kinase Inhibitor 1B (CDKN1B) and Cyclin Dependent Kinase Inhibitor 1C (CDKN1C) in vitro. In vivo, M1M-derived exosomes significantly aggravated neointima formation following carotid artery ligation injury and wire injury and these effects were partly abolished by miR-222 inhibitor 2'OMe-miR-222. Our findings thus suggest that exosomes derived from M1M could aggravate neointimal hyperplasia through delivering miR-222 into VSMCs. Future studies are warranted to validate if the post-injury vascular neointimal hyperplasia and restenosis could be attenuated by inhibiting miR-222.
现在尚不清楚 M1 巨噬细胞（M1M）衍生的外泌体在新生内膜增生中的作用。通过 Transwell 共培养系统，我们证明 M1M 有助于血管平滑肌细胞（VSMC）的功能变化。我们进一步用从 M1M 分离的外泌体刺激 VSMC。我们的结果表明，这些外泌体可以通过巨胞饮作用被 VSMC 摄取。通过 microRNA 阵列分析，我们确定了源自 M1M 衍生外泌体的 miR-222 触发了 VSMC 的功能变化。此外，我们通过体外靶向细胞周期蛋白依赖性激酶抑制剂 1B（CDKN1B）和细胞周期蛋白依赖性激酶抑制剂 1C（CDKN1C）证实，miR-222 通过靶向 Cyclin Dependent Kinase Inhibitor 1B（CDKN1B）和 Cyclin Dependent Kinase Inhibitor 1C（CDKN1C）在体外发挥关键作用促进 VSMC 的增殖和迁移。在体内，M1M 衍生的外泌体在颈总动脉结扎损伤和线损伤后显著加重新生内膜形成，而 miR-222 抑制剂 2'OMe-miR-222 部分消除了这些作用。因此，我们的研究结果表明，M1M 衍生的外泌体可以通过将 miR-222 递送到 VSMC 中来加重新生内膜增生。有必要进行进一步的研究来验证抑制 miR-222 是否可以减轻损伤后血管新生内膜增生和再狭窄。
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