Exosomes from mesenchymal stem cells overexpressing MIF enhance myocardial repair
Exosomes from mesenchymal stem cells overexpressing MIF enhance myocardial repair
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间充质干细胞过度表达 MIF 的外泌体增强心肌修复
DOI：
10.1002/jcp.29456
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发表时间：
2020-01-20
影响因子：
5.6
通讯作者：
Zhang, Fengxiang
中科院分区：
文献类型：
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作者：
Liu, Xiaolin;Li, Xin;Zhang, Fengxiang
越来越多的证据表明，间充质干细胞(MSC)来源的外切体(Exo)介导了心肌梗死(MI)后的心脏修复。巨噬细胞移动抑制因子(MIF)是一种促炎细胞因子，在调节细胞动态平衡方面发挥着重要作用。本研究旨在探讨高表达MIF的骨髓间充质干细胞(BM-MSCs)体外分泌对心肌梗死大鼠的心脏保护作用。将MIF表达载体转入BM-MSCs。分别从BM-MSCs和MIF-BM-MSCs的培养上清液中分离外周血细胞。用MitoTracker染色观察新生小鼠心肌细胞线粒体的形态。用脱氧核苷酸转移酶介导的dUTP缺口末端标记法检测NRCM的凋亡。将BM-MSC-exo和MIF-BM-MSC-exo肌肉注射到心肌梗死大鼠模型的梗死灶周围。超声心动图评价大鼠心功能。MIF-BM-MSCs的MIF表达明显高于BM-MSCs。BM-MSC-exo和MIF-BM-MSC-exo均表达CD63和CD81。在缺氧/血清剥夺(H/SD)条件下，MIF-BM-MSC-exo组较BM-MSC-exo组通过激活腺苷5‘-单磷酸活化蛋白激酶信号通路减少线粒体断裂和细胞凋亡。注射BM-MSC-exo或MIF-BM-MSC-exo可显著恢复心肌梗死大鼠的心功能。与BM-MSC-exo相比，注射MIF-BM-MSC-exo可增强心功能，减少心脏重塑，减少心肌细胞线粒体碎裂、活性氧生成和细胞凋亡。本研究揭示了MIF-BM-MSC-exo治疗心肌梗死的新机制，为心血管疾病的治疗提供了新的策略。
Accumulating evidence has shown that mesenchymal stem cell (MSC)-derived exosomes (exo) mediate cardiac repair following myocardial infarction (MI). Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, plays a critical role in regulating cell homeostasis. This study aimed to investigate the cardioprotective effects of exo secreted from bone marrow-MSCs (BM-MSCs) overexpressing MIF in a rat model of MI. MIF plasmid was transducted in BM-MSCs. Exo were isolated from the supernatants of BM-MSCs and MIF-BM-MSCs, respectively. The morphology of mitochondria in neonatal mice cardiomyocytes (NRCMs) was determined by MitoTracker staining. The apoptosis of NRCMs was examined by deoxynucleotidyl transferase-mediated dUTP nick end-labeling. BM-MSC-exo and MIF-BM-MSC-exo were intramuscularly injected into the peri-infarct region in a rat model of MI. The heart function of rats was assessed by echocardiography. The expression of MIF was greatly enhanced in MIF-BM-MSCs compared with BM-MSCs. Both BM-MSC-exo and MIF-BM-MSC-exo expressed CD63 and CD81. NRCMs treated with MIF-BM-MSC-exo exhibited less mitochondrial fragmentation and cell apoptosis under hypoxia/serum deprivation (H/SD) challenge than those treated with BM-MSC-exo via activating adenosine 5 '-monophosphate-activated protein kinase signaling. Moreover, these effects were partially abrogated by Compound C. Injection of BM-MSC-exo or MIF-BM-MSC-exo greatly restored heart function in a rat model of MI. Compared with BM-MSC-exo, injection of MIF-BM-MSC-exo was associated with enhanced heart function, reduced heart remodeling, less cardiomyocyte mitochondrial fragmentation, reactive oxygen species generation, and apoptosis. Our study reveals a new mechanism of MIF-BM-MSC-exo-based therapy for MI and provides a novel strategy for cardiovascular disease treatment.