title: Combined administration of mesenchymal stem cells overexpressing IGF-1 and HGF enhances neovascularization but moderately improves cardiac regeneration in a porcine model.
abstract: BACKGROUND
  Insulin-like growth factor 1 (IGF-1) and hepatocyte growth factor (HGF) are among the most promising growth factors for promoting cardiorepair. Here, we evaluated the combination of cell- and gene-based therapy using mesenchymal stem cells (MSC) genetically modified to overexpress IGF-1 or HGF to treat acute myocardial infarction (AMI) in a porcine model.
  
  
  METHODS
  Pig MSC from adipose tissue (paMSC) were genetically modified for evaluation of different therapeutic strategies to improve AMI treatment. Three groups of infarcted Large White pigs were compared (I, control, non-transplanted; II, transplanted with paMSC-GFP (green fluorescent protein); III, transplanted with paMSC-IGF-1/HGF). Cardiac function was evaluated non-invasively using magnetic resonance imaging (MRI) for 1 month. After euthanasia and sampling of the animal, infarcted areas were studied by histology and immunohistochemistry.
  
  
  RESULTS
  Intramyocardial transplant in a porcine infarct model demonstrated the safety of paMSC in short-term treatments. Treatment with paMSC-IGF-1/HGF (1:1) compared with the other groups showed a clear reduction in inflammation in some sections analyzed and promoted angiogenic processes in ischemic tissue. Although cardiac function parameters were not significantly improved, cell retention and IGF-1 overexpression was confirmed within the myocardium.
  
  
  CONCLUSIONS
  The simultaneous administration of IGF-1- and HGF-overexpressing paMSC appears not to promote a synergistic effect or effective repair. The combined enhancement of neovascularization and fibrosis in paMSC-IGF-1/HGF-treated animals nonetheless suggests that sustained exposure to high IGF-1 + HGF levels promotes beneficial as well as deleterious effects that do not improve overall cardiac regeneration.
authors.affiliation: Jesús Usón Minimally Invasive Surgery Center, Cáceres, Spain.|Department of Cardiovascular Development and Repair, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Gómez-Mauricio
authors.affiliation: Department of Cardiovascular Development and Repair, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.|Cardiovascular Area, CIMUS, Instituto de Investigación Sanitaria, University of Santiago de Compostela, Santiago de Compostela, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Moscoso
authors.affiliation: Jesús Usón Minimally Invasive Surgery Center, Cáceres, Spain.
authors.forename: María-Fernanda
authors.initials: MF
authors.lastname: Martín-Cancho
authors.affiliation: Jesús Usón Minimally Invasive Surgery Center, Cáceres, Spain.
authors.forename: Verónica
authors.initials: V
authors.lastname: Crisóstomo
authors.affiliation: Department of Cardiovascular Development and Repair, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.|ICREC (Heart Failure and Cardiac Regeneration) Research Program, Health Sciences Research Institute Germans Trias i Pujol (IGTP), Badalona, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Prat-Vidal
authors.affiliation: Jesús Usón Minimally Invasive Surgery Center, Cáceres, Spain.
authors.forename: Claudia
authors.initials: C
authors.lastname: Báez-Díaz
authors.affiliation: Jesús Usón Minimally Invasive Surgery Center, Cáceres, Spain.
authors.forename: Francisco M
authors.initials: FM
authors.lastname: Sánchez-Margallo
authors.affiliation: Department of Cardiovascular Development and Repair, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain. abernad@cnb.csic.es.|Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), Darwin 3 (Campus UAM Cantoblanco), 28049, Madrid, Spain. abernad@cnb.csic.es.
authors.forename: Antonio
authors.initials: A
authors.lastname: Bernad
mesh_terms: D000818:Animals; D064987:Cell- and Tissue-Based Therapy; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D015870:Gene Expression; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic; D012038:Regeneration / Q000502:physiology; D013552:Swine; D019076:Transgenes
chemical_list: D049452:Green Fluorescent Proteins; D017228:Hepatocyte Growth Factor; D007334:Insulin-Like Growth Factor I
keywords: Acute myocardial infarction; Cell therapy; Gene therapy; HGF; IGF-1; Mesenchymal stem cells; Porcine model