Exosomes secreted by cardiosphere-derived cells reduce scarring, attenuate adverse remodelling, and improve function in acute and chronic porcine myocardial infarction
Exosomes secreted by cardiosphere-derived cells reduce scarring, attenuate adverse remodelling, and improve function in acute and chronic porcine myocardial infarction
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DOI：
10.1093/eurheartj/ehw240
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发表时间：
2017-01-14
影响因子：
39.3
通讯作者：
Marban, Eduardo
中科院分区：
文献类型：
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作者：
Gallet, Romain;Dawkins, James;Marban, Eduardo
目的心脏球源性细胞(CDCs)的再生需要自然分泌的纳米囊泡，称为外体，而外体在啮齿类动物中模拟CDCs的益处。然而，外显体还没有在翻译上逼真的大动物模型中进行研究。方法和结果在急性心肌梗死(AMI)和恢复期心肌梗死(CMI)模型中，猪通过冠状动脉内(IC)或开胸心肌内(IM)注射人CDC外切体(或载体)。冠脉内无复流面积和梗塞面积(IS)在冠脉内无效，IM外体从80+/-5%降至61+/-12%(P=0.001)，并保留了左心室射血分数(LVEF)。在一项关于CMI的随机安慰剂对照研究中，心肌梗死(MI)后4周的猪接受了经皮注射赋形剂(n=6)或CDC外切体(n=6)。治疗前和治疗后1个月的磁共振成像(MRI)显示，外渗体(而不是赋形剂)保留了LV容量和LVEF(-0.1+/-2.2%vs.-5.4+/-3.6%，P=0.01)，同时减少了瘢痕大小。结论心肌球源性细胞外渗体可减少心肌梗死和心肌梗死后的心肌肥厚，减少瘢痕形成，阻止不良重构，改善左心室射血分数。虽然从概念上讲，Exosome作为心肌梗死的无细胞治疗剂很有吸引力，但它的缺点是IM递送是必要的。
Aims Naturally secreted nanovesicles known as exosomes are required for the regenerative effects of cardiosphere-derived cells (CDCs), and exosomes mimic the benefits of CDCs in rodents. Nevertheless, exosomes have not been studied in a translationally realistic large-animal model. We sought to optimize delivery and assess the efficacy of CDC-secreted exosomes in pig models of acute (AMI) and convalescent myocardial infarction (CMI).Methods and results In AMI, pigs received human CDC exosomes (or vehicle) by intracoronary (IC) or open-chest intramyocardial (IM) delivery 30 min after reperfusion. No-reflowarea and infarct size (IS) were assessed histologically at 48 h. Intracoronary exosomes were ineffective, but IM exosomes decreased IS from 80 +/- 5% to 61 +/- 12% (P = 0.001) and preserved left ventricular ejection fraction (LVEF). In a randomized placebo-controlled study of CMI, pigs 4 weeks post-myocardial infarction (MI) underwent percutaneous IM delivery of vehicle (n = 6) or CDC exosomes (n = 6). Magnetic resonance imaging (MRI) performed before and 1 month after treatment revealed that exosomes (but not vehicle) preserved LV volumes and LVEF (-0.1 +/- 2.2% vs. -5.4 +/- 3.6%, P = 0.01) while decreasing scar size. Histologically, exosomes decreased LV collagen content and cardiomyocyte hypertrophy while increasing vessel density.Conclusion Cardiosphere-derived cell exosomes delivered IM decrease scarring, halt adverse remodelling and improve LVEF in porcine AMI and CMI. While conceptually attractive as cell-free therapeutic agents for myocardial infarction, exosomes have the disadvantage that IM delivery is necessary.