Exosomes secreted by hiPSC-derived cardiac cells improve recovery from myocardial infarction in swine
Exosomes secreted by hiPSC-derived cardiac cells improve recovery from myocardial infarction in swine
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DOI：
10.1126/scitranslmed.aay1318
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发表时间：
2020-09-16
影响因子：
17.1
通讯作者：
Zhang, Jianyi
中科院分区：
文献类型：
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作者：
Gao, Ling;Wang, Lu;Zhang, Jianyi
心肌梗死（MI）的细胞疗法治疗部分地由移植细胞分泌的外泌体介导。因此，我们比较了心肌细胞（CM; 1000万），内皮细胞（EC; 500万）和平滑肌细胞（SMC; 500万）的混合物的治疗效果，这些细胞来源于人诱导多能干细胞（hiPSC），或从三种细胞类型中提取的外泌体，在MI后的猪中。雌性猪接受假手术;梗塞而不治疗（MI组）;或梗塞并用hiPSC-CM、hiPSC-EC和hiPSC-SMC治疗（MI +细胞组）;用来自给予MI +细胞组的相同剂量的细胞的均质化片段（MI + Fra组）;或用从hiPSC-CM：hiPSC-EC：hiPSC-SMC的2：1：1混合物提取的外来体（7.5mg）治疗（MI + Exo组）。将细胞和外泌体注射到损伤的心肌中。在体外，外泌体促进EC管形成和小鼠主动脉环的微血管发芽，并通过减少细胞凋亡、维持细胞内钙稳态和增加腺苷5 '-三磷酸来保护hiPSC-CM。在体内，心肌梗死后4周，MI + Cell、MI + Fra和MI + Exo组的左心室射血分数、室壁应力、心肌生物能量学、心肌肥厚、瘢痕大小、细胞凋亡和梗死区域血管生成的测量结果均优于MI组。MI、MI + Cell和MI + Exo组动物的惊厥事件频率相似。因此，由hiPSC衍生的心脏细胞分泌的外泌体改善了心肌恢复而不增加致炎性并发症的频率，并且可以为心肌损伤提供非细胞治疗选择。
Cell therapy treatment of myocardial infarction (MI) is mediated, in part, by exosomes secreted from transplanted cells. Thus, we compared the efficacy of treatment with a mixture of cardio-myocytes (CMs; 10 million), endothelial cells ( ECs; 5 million), and smooth muscle cells (SMCs; 5 million) derived from human induced pluripotent stem cells ( hiPSCs), or with exosomes extracted from the three cell types, in pigs after MI. Female pigs received sham surgery; infarction without treatment (MI group); or infarction and treatment with hiPSC-CMs, hiPSC-ECs, and hiPSC-SMCs ( MI + Cell group); with homogenized fragments from the same dose of cells administered to the MI + Cell group (MI + Fra group); or with exosomes (7.5 mg) extracted from a 2:1:1 mixture of hiPSC-CMs:hiPSC-ECs:hiPSC- SMCs (MI + Exo group). Cells and exosomes were injected into the injured myocardium. In vitro, exosomes promoted EC tube formation and microvessel sprouting from mouse aortic rings and protected hiPSC-CMs by reducing apoptosis, maintaining intracellular calcium homeostasis, and increasing adenosine 5'-triphosphate. In vivo, measurements of left ventricular ejection fraction, wall stress, myocardial bioenergetics, cardiac hypertrophy, scar size, cell apoptosis, and angiogenesis in the infarcted region were better in the MI + Cell, MI + Fra, and MI + Exo groups than in the MI group 4 weeks after infarction. The frequencies of arrhythmic events in animals from the MI, MI + Cell, and MI + Exo groups were similar. Thus, exosomes secreted by hiPSC-derived cardiac cells improved myocardial recovery without increasing the frequency of arrhythmogenic complications and may provide an acellular therapeutic option for myocardial injury.