title: 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.
abstract: OBJECTIVE
  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 μg HGF and 2 to 8 μg 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.
authors: The Stem Cell and Regenerative Biology Unit (BioStem), RISES, Liverpool John Moores University, Liverpool, UK.
authors: Georgina M
authors: GM
authors: Ellison
authors: Daniele
authors: D
authors: Torella
authors: Santo
authors: S
authors: Dellegrottaglie
authors: Claudia
authors: C
authors: Perez-Martinez
authors: Armando
authors: A
authors: Perez de Prado
authors: Carla
authors: C
authors: Vicinanza
authors: Saranya
authors: S
authors: Purushothaman
authors: Valentina
authors: V
authors: Galuppo
authors: Claudio
authors: C
authors: Iaconetti
authors: Cheryl D
authors: CD
authors: Waring
authors: Andrew
authors: A
authors: Smith
authors: Michele
authors: M
authors: Torella
authors: Carlos
authors: C
authors: Cuellas Ramon
authors: Jose Manuel
authors: JM
authors: Gonzalo-Orden
authors: Valter
authors: V
authors: Agosti
authors: Ciro
authors: C
authors: Indolfi
authors: Manuel
authors: M
authors: Galiñanes
authors: Felipe
authors: F
authors: Fernandez-Vazquez
authors: Bernardo
authors: B
authors: Nadal-Ginard
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D003331:Coronary Vessels / Q000166:cytology / Q000502:physiology*; D004359:Drug Therapy, Combination; D005260:Female; D017228:Hepatocyte Growth Factor / Q000008:administration & dosage* / Q000502:physiology; D006801:Humans; D007269:Injections, Intra-Arterial; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage* / Q000502:physiology; D009203:Myocardial Infarction / Q000473:pathology* / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D013552:Swine
chemical_list: C066855:HGF protein, human; D017228:Hepatocyte Growth Factor; D007334:Insulin-Like Growth Factor I