Mesenchymal stem cell-derived exosomes increase ATP levels, decrease oxidative stress and activate PI3K/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury
Mesenchymal stem cell-derived exosomes increase ATP levels, decrease oxidative stress and activate PI3K/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury
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DOI：
10.1016/j.scr.2013.01.002
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发表时间：
2013-05-01
影响因子：
1.2
通讯作者：
de Kleijn, Dominique P.
中科院分区：
文献类型：
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作者：
Arslan, Fatih;Lai, Ruenn Chai;de Kleijn, Dominique P.
我们以前已经确定外泌体作为间充质干细胞分泌的旁分泌因子。最近，我们发现再灌注损伤的关键特征，即ATP/NADH的损失，增加的氧化应激和细胞死亡是由缺血/再灌注心肌中的蛋白质组缺陷所支持的，并且可以通过外泌体中的蛋白质来改善。为了在体内测试该假设，小鼠（C57 B16/J）经历30分钟缺血，随后再灌注（I/R损伤）。在再灌注前5分钟施用纯化的外泌体或盐水。与盐水治疗相比，外泌体使梗死面积减少了45%。Langendorff实验显示，完整但未裂解的外泌体增强了缺血/再灌注心肌的活力。外泌体处理的动物在28天随访期间表现出左心室几何形状和收缩性能的显著保留。再灌注后1小时内，外泌体治疗增加了缺血/再灌注心脏中ATP和NADH的水平，降低了氧化应激，增加了磷酸化Akt和磷酸化GSK-3 β，并减少了磷酸化c-JNK。随后，局部和全身炎症反应在再灌注后24小时显著减少。总之，我们的研究表明，完整的外泌体恢复生物能量学，减少氧化应激和激活促生存信号传导，从而增强心肌I/R损伤后的心脏功能和几何形状。因此，间充质干细胞来源的外泌体是心肌梗死再灌注治疗的潜在辅助剂。(c)2013爱思唯尔有限公司版权所有。
We have previously identified exosomes as the paracrine factor secreted by mesenchymal stem cells. Recently, we found that the key features of reperfusion injury, namely loss of ATP/NADH, increased oxidative stress and cell death were underpinned by proteomic deficiencies in ischemic/reperfused myocardium, and could be ameliorated by proteins in exosomes. To test this hypothesis in vivo, mice (C57Bl6/J) underwent 30 min ischemia, followed by reperfusion (I/R injury). Purified exosomes or saline was administered 5 min before reperfusion. Exosomes reduced infarct size by 45% compared to saline treatment. Langendorff experiments revealed that intact but not lysed exosomes enhanced viability of the ischemic/reperfused myocardium. Exosome treated animals exhibited significant preservation of left ventricular geometry and contractile performance during 28 days follow-up. Within an hour after reperfusion, exosome treatment increased levels of ATP and NADH, decreased oxidative stress, increased phosphorylated-Akt and phosphorylated-GSK-3 beta, and reduced phosphorylated-c-JNK in ischemic/reperfused hearts. Subsequently, both local and systemic inflammation were significantly reduced 24 h after reperfusion. In conclusion, our study shows that intact exosomes restore bioenergetics, reduce oxidative stress and activate pro-survival signaling, thereby enhancing cardiac function and geometry after myocardial I/R injury. Hence, mesenchymal stem cell-derived exosomes are a potential adjuvant to reperfusion therapy for myocardial infarction. (c) 2013 Elsevier B.V. All rights reserved.