Endogenous Cardiac Stem Cell Activation by Insulin-Like Growth Factor-1/Hepatocyte Growth Factor Intracoronary Injection Fosters Survival and Regeneration of the Infarcted Pig Heart
Endogenous Cardiac Stem Cell Activation by Insulin-Like Growth Factor-1/Hepatocyte Growth Factor Intracoronary Injection Fosters Survival and Regeneration of the Infarcted Pig Heart
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DOI：
10.1016/j.jacc.2011.05.013
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发表时间：
2011-08-23
影响因子：
24
通讯作者：
Nadal-Ginard, Bernardo
中科院分区：
文献类型：
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作者：
Ellison, Georgina M.;Torella, Daniele;Nadal-Ginard, Bernardo
本研究的目的是通过临床上适用的冠状动脉内注射方案在与人类疾病相关的猪心肌梗死（MI）模型中测试胰岛素样生长因子（IGF）-1/肝细胞生长因子（HGF）激活驻留的内源性猪心脏干/祖细胞（epCSCs）并促进心肌修复的能力。心脏干/祖细胞（CSC）移植以及心肌内注射特异性生长因子原位激活可导致急性心肌梗死（AMI）后心肌再生。经皮冠状动脉造影左前降支闭塞。在冠状动脉再灌注后30分钟，通过梗死相关动脉以单剂量（范围为0.5至2 μ g HGF和2至8 μ g IGF-1）共同施用IGF-1和HGF。结果IGF-1/HGF激活c-kit阳性CD 45阴性的epCSCs，并促进其向肌细胞分化。IGF-1/HGF以剂量依赖性方式改善心肌细胞存活，并减少纤维化和心肌细胞反应性肥大。在AMI后21天和60天，它显著增加c-kit阳性-CD 45阴性epCSC数量，并促进梗死和梗死周围/边缘区域新心肌（肌细胞和微血管）的生成。结论在与人类疾病相关的AMI动物模型中，冠状动脉内注射IGF-1/HGF是一种减少病理性心脏重构、诱导心肌再生和改善心室功能的实用而有效的策略。（J Am科尔心脏病学杂志2011; 58：977-86）（C）美国心脏病学会基金会2011年
Objectives The purpose of this study was to test the ability of insulin-like growth factor (IGF)-1/hepatocyte growth factor (HGF) to activate resident endogenous porcine cardiac stem/progenitor cells (epCSCs) and to promote myocardial repair through a clinically applicable intracoronary injection protocol in a pig model of myocardial infarction (MI) relevant to human disease.Background In rodents, cardiac stem/progenitor cell (CSC) transplantation as well as in situ activation through intramyocardial injection of specific growth factors has been shown to result in myocardial regeneration after acute myocardial infarction (AMI).Methods Acute MI was induced in pigs by a 60-min percutaneous transluminal coronary angiography left anterior descending artery occlusion. The IGF-1 and HGF were co-administered through the infarct-related artery in a single dose (ranging from 0.5 to 2 mu g HGF and 2 to 8 mu g IGF-1) 30 min after coronary reperfusion. Pigs were sacrificed 21 days later for dose-response relationship evaluation by immunohistopathology or 2 months later for cardiac function evaluation by cardiac magnetic resonance imaging.Results The IGF-1/HGF activated c-kit positive-CD45 negative epCSCs and increased their myogenic differentiation in vitro. The IGF-1/HGF, in a dose-dependent manner, improved cardiomyocyte survival, and reduced fibrosis and cardiomyocyte reactive hypertrophy. It significantly increased c-kit positive-CD45 negative epCSC number and fostered the generation of new myocardium (myocytes and microvasculature) in infarcted and peri-infarct/border regions at 21 and 60 days after AMI. The IGF-1/HGF reduced infarct size and improved left ventricular function at 2 months after AMI.Conclusions In an animal model of AMI relevant to the human disease, intracoronary administration of IGF-1/HGF is a practical and effective strategy to reduce pathological cardiac remodeling, induce myocardial regeneration, and improve ventricular function. (J Am Coll Cardiol 2011; 58: 977-86) (C) 2011 by the American College of Cardiology Foundation