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

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

卷:58

Article

Ellison, Georgina M.^1,2  Torella, Daniele^1,2  Dellegrottaglie, Santo³  Perez-Martinez, Claudia^4,5,6  Perez de Prado, Armando^4,5,6  Vicinanza, Carla^1,2  Purushothaman, Saranya¹  Galuppo, Valentina²  Iaconetti, Claudio²  Waring, Cheryl D.¹  Smith, Andrew¹  Torella, Michele⁹  Cuellas Ramon, Carlos^4,5,6  Manuel Gonzalo-Orden, Jose^4,5,6  Agosti, Valter²  Indolfi, Ciro²  Galinanes, Manuel^7,8  Fernandez-Vazquez, Felipe^4,5,6  Nadal-Ginard, Bernardo¹ 

[1] Liverpool John Moores Univ, Stem Cell & Regenerat Biol Unit BioStem, RISES, Liverpool L3 3AF, Merseyside, England

[2] Magna Graecia Univ Catanzaro, Dept Med, I-88100 Catanzaro, Italy

[3] Univ Naples Federico 2, Div Cardiol, Naples, Italy

[4] Univ Leon, IBIOMED, E-24071 Leon, Spain

[5] Univ Leon, Fdn Invest Sanitaria Leon, E-24071 Leon, Spain

[6] Hosp Univ Leon, Leon, Spain

[7] Univ Autonoma Barcelona, Univ Hosp Vall dHebron, Dept Cardiac Surg, Area Cor, E-08193 Barcelona, Spain

[8] Univ Autonoma Barcelona, Univ Hosp Vall dHebron, Res Inst, E-08193 Barcelona, Spain

[9] Univ Naples 2, Dept Cardiothorac & Resp Sci, Naples, Italy

关键词: cardiac magnetic resonance imaging;    cardiac stem cells;    growth factors;    myocardial infarction;    myocardial regeneration;   

DOI  :  10.1016/j.jacc.2011.05.013

来源: Elsevier

【 摘 要 】

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

【 授权许可】

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