A Large-Scale Investigation of Hypoxia-Preconditioned Allogeneic Mesenchymal Stem Cells for Myocardial Repair in Nonhuman Primates: Paracrine Activity Without Remuscularization.
A Large-Scale Investigation of Hypoxia-Preconditioned Allogeneic Mesenchymal Stem Cells for Myocardial Repair in Nonhuman Primates: Paracrine Activity Without Remuscularization.
复制标题
缺氧预条件同种异体间充质干细胞对非人灵长类心肌修复的大规模研究
DOI：
10.1161/circresaha.115.307516
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发表时间：
2016-03-18
影响因子：
20.1
通讯作者：
Wang J
中科院分区：
文献类型：
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作者：
Hu X;Xu Y;Zhong Z;Wu Y;Zhao J;Wang Y;Cheng H;Kong M;Zhang F;Chen Q;Sun J;Li Q;Jin J;Li Q;Chen L;Wang C;Zhan H;Fan Y;Yang Q;Yu L;Wu R;Liang J;Zhu J;Wang Y;Jin Y;Lin Y;Yang F;Jia L;Zhu W;Chen J;Yu H;Zhang J;Wang J
补充数字内容可在文本中找到。移植骨髓间充质干细胞（MSCs）用于心脏修复的有效性有限；因此，优化干细胞心肌治疗的策略是必要的。本研究旨在验证我们的中心假设，即在一项大规模（N=49）、长期（9个月）的非人灵长类动物（猕猴）研究中，缺氧预处理MSCs （HP-MSCs）比在环境氧水平下培养的MSCs更有效地治疗心肌损伤。设计MSCs表达绿色荧光蛋白，在环境氧或0.5%氧（HP-MSCs）下培养24小时，然后在食蟹猴梗死心脏中进行检测（1×107细胞/心脏）。缺氧预处理增加了培养的间充质干细胞中几种促生存/促血管生成因子的表达，心肌梗死后第90天，HP-MSCs处理的猴子梗死面积和左心室功能的测量结果明显优于对照组处理的猴子；正常培养的骨髓间充质干细胞处理猴子的功能改善不显著。HP-MSCs移植还与心肌细胞增殖、血管密度、心肌糖摄取和移植细胞植入增加以及内源性细胞凋亡减少有关，但未增加致心律失常并发症的发生。缺氧预处理提高了MSCs移植治疗非人灵长类动物心肌梗死的有效性，而不会增加致心律失常并发症的发生，这表明HP-MSCs移植的未来临床试验是有必要的。
Supplemental Digital Content is available in the text. The effectiveness of transplanted bone marrow mesenchymal stem cells (MSCs) for cardiac repair has been limited; thus, strategies for optimizing stem-cell–based myocardial therapy are needed. The present study was designed to test our central hypothesis that hypoxia-preconditioned MSCs (HP-MSCs) are more effective than MSCs cultured under ambient oxygen levels for the treatment of myocardial injury in a large-scale (N=49), long-term (9 months), nonhuman primate (Cynomolgous monkeys) investigation. MSCs were engineered to express green fluorescent protein, cultured under ambient oxygen or 0.5% oxygen (HP-MSCs) for 24 hours and then tested in the infarcted hearts of Cynomolgus monkeys (1×107 cells per heart). Hypoxia preconditioning increased the expression of several prosurvival/proangiogenic factors in cultured MSCs, and measurements of infarct size and left-ventricular function at day 90 after myocardial infarction were significantly more improved in monkeys treated with HP-MSCs than in monkeys treated with the control vehicle; functional improvements in normal cultured bone marrow mesenchymal stem cells–treated monkeys were not significant. HP-MSCs transplantation was also associated with increases in cardiomyocyte proliferation, vascular density, myocardial glucose uptake, and engraftment of the transplanted cells and with declines in endogenous cell apoptosis, but did not increase the occurrence of arrhythmogenic complications. Hypoxia preconditioning improved the effectiveness of MSCs transplantation for the treatment of myocardial infarction in nonhuman primates without increasing the occurrence of arrhythmogenic complications, which suggests that future clinical trials of HP-MSCs transplantation are warranted.