Myocardial reparative functions of exosomes from mesenchymal stem cells are enhanced by hypoxia treatment of the cells via transferring microRNA-210 in an nSMase2-dependent way.
Myocardial reparative functions of exosomes from mesenchymal stem cells are enhanced by hypoxia treatment of the cells via transferring microRNA-210 in an nSMase2-dependent way.
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通过以 nSMase2 依赖性方式转移 microRNA-210 对细胞进行缺氧处理，增强间充质干细胞外泌体的心肌修复功能
DOI：
10.1080/21691401.2017.1388249
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发表时间：
2018-12
期刊：
影响因子：
--
通讯作者：
Yu H
中科院分区：
文献类型：
--
作者：
Zhu J;Lu K;Zhang N;Zhao Y;Ma Q;Shen J;Lin Y;Xiang P;Tang Y;Hu X;Chen J;Zhu W;Webster KA;Wang J;Yu H
缺氧处理可增强间充质干细胞（MSCs）的旁分泌作用。本研究旨在探究缺氧处理的间充质干细胞分泌的外泌体（ExoH）在心肌修复方面是否优于常氧处理的间充质干细胞分泌的外泌体（ExoN）。将小鼠骨髓来源的间充质干细胞在缺氧或常氧条件下培养24小时，然后将条件培养基中的外泌体心肌内注射到C57BL / 6小鼠的梗死心脏中。ExoH显著提高了生存率，减小了瘢痕面积，并使心脏功能得到更好的恢复。与ExoN相比，ExoH使梗死心脏的血管密度增加、心肌细胞（CMs）凋亡减少、纤维化减轻，且心脏祖细胞募集增多。微小核糖核酸（microRNA）分析显示，ExoH中的microRNA - 210（miR - 210）水平明显高于ExoN。将miR - 210模拟物转染到内皮细胞（ECs）和心肌细胞中，产生了与ExoH类似的生物学效应。间充质干细胞的缺氧处理增加了中性鞘磷脂酶2（nSMase2）的表达，该酶对外泌体分泌至关重要。抑制nSMase2的活性会导致miR - 210分泌减少，并消除ExoH的有益作用。总之，缺氧培养增强了间充质干细胞及其分泌的外泌体中miR - 210和nSMase2的活性，这至少部分解释了缺氧处理细胞来源的外泌体增强的心脏保护作用。
Abstract Hypoxia treatment enhances paracrine effect of mesenchymal stem cells (MSCs). The aim of this study was to investigate whether exosomes from hypoxia-treated MSCs (ExoH) are superior to those from normoxia-treated MSCs (ExoN) for myocardial repair. Mouse bone marrow-derived MSCs were cultured under hypoxia or normoxia for 24 h, and exosomes from conditioned media were intramyocardially injected into infarcted heart of C57BL/6 mouse. ExoH resulted in significantly higher survival, smaller scar size and better cardiac functions recovery. ExoH conferred increased vascular density, lower cardiomyocytes (CMs) apoptosis, reduced fibrosis and increased recruitment of cardiac progenitor cells in the infarcted heart relative to ExoN. MicroRNA analysis revealed significantly higher levels of microRNA-210 (miR-210) in ExoH compared with ExoN. Transfection of a miR-210 mimic into endothelial cells (ECs) and CMs conferred similar biological effects as ExoH. Hypoxia treatment of MSCs increased the expression of neutral sphingomyelinase 2 (nSMase2) which is crucial for exosome secretion. Blocking the activity of nSMase2 resulted in reduced miR-210 secretion and abrogated the beneficial effects of ExoH. In conclusion, hypoxic culture augments miR-210 and nSMase2 activities in MSCs and their secreted exosomes, and this is responsible at least in part for the enhanced cardioprotective actions of exosomes derived from hypoxia-treated cells.
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