title: Allogeneic Mesenchymal Stromal Cells Overexpressing Mutant Human Hypoxia-Inducible Factor 1-α (HIF1-α) in an Ovine Model of Acute Myocardial Infarction.
abstract: Bone marrow mesenchymal stromal cells (BMMSCs) are cardioprotective in acute myocardial infarction (AMI) because of release of paracrine angiogenic and prosurvival factors. Hypoxia-inducible factor 1-α (HIF1-α), rapidly degraded during normoxia, is stabilized during ischemia and upregulates various cardioprotective genes. We hypothesized that BMMSCs engineered to overexpress mutant, oxygen-resistant HIF1-α would confer greater cardioprotection than nontransfected BMMSCs in sheep with AMI.
  
  
  
  Allogeneic BMMSCs transfected with a minicircle vector encoding mutant HIF1-α (BMMSC-HIF) were injected in the peri-infarct of sheep (n=6) undergoing coronary occlusion. Over 2 months, infarct volume measured by cardiac magnetic resonance (CMR) imaging decreased by 71.7±1.3% (P<0.001), and left ventricular (LV) percent ejection fraction (%EF) increased near 2-fold (P<0.001) in the presence of markedly decreased end-systolic volume. Sheep receiving nontransfected BMMSCs (BMMSC; n=6) displayed less infarct size limitation and percent LVEF improvement, whereas in placebo-treated animals (n=6), neither parameters changed over time. HIF1-α-transfected BMMSCs (BMMSC-HIF) induced angio-/arteriogenesis and decreased apoptosis by HIF1-mediated overexpression of erythropoietin, inducible nitrous oxide synthase, vascular endothelial growth factor, and angiopoietin-1. Cell tracking using paramagnetic iron nanoparticles in 12 additional sheep revealed enhanced long-term retention of BMMSC-HIF.
  
  
  
  Intramyocardial delivery of BMMSC-HIF reduced infarct size and improved LV systolic performance compared to BMMSC, attributed to increased neovascularization and cardioprotective effects induced by HIF1-mediated overexpression of paracrine factors and enhanced retention of injected cells. Given the safety of the minicircle vector and the feasibility of BMMSCs for allogeneic application, this treatment may be potentially useful in the clinic.
authors.affiliation: Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMETTYB), Universidad Favaloro-CONICET, Buenos Aires, Argentina Departamento de Fisiología, Facultad de Ciencias Médicas, Universidad Favaloro, Buenos Aires, Argentina.
authors.forename: Anna P
authors.initials: AP
authors.lastname: Hnatiuk
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA.
authors.forename: Sang-Ging
authors.initials: SG
authors.lastname: Ong
authors.affiliation: Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMETTYB), Universidad Favaloro-CONICET, Buenos Aires, Argentina Departamento de Fisiología, Facultad de Ciencias Médicas, Universidad Favaloro, Buenos Aires, Argentina.
authors.forename: Fernanda D
authors.initials: FD
authors.lastname: Olea
authors.affiliation: Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMETTYB), Universidad Favaloro-CONICET, Buenos Aires, Argentina Departamento de Fisiología, Facultad de Ciencias Médicas, Universidad Favaloro, Buenos Aires, Argentina.
authors.forename: Paola
authors.initials: P
authors.lastname: Locatelli
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA.
authors.forename: Johannes
authors.initials: J
authors.lastname: Riegler
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA.
authors.forename: Won Hee
authors.initials: WH
authors.lastname: Lee
authors.affiliation: St George's, University of London, United Kingdom.
authors.forename: Cheng Hao
authors.initials: CH
authors.lastname: Jen
authors.affiliation: Departmento de Cardiología, Hospital Universitario de la Foundación Favaloro, Buenos Aires, Argentina.
authors.forename: Andrea
authors.initials: A
authors.lastname: De Lorenzi
authors.affiliation: Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMETTYB), Universidad Favaloro-CONICET, Buenos Aires, Argentina Departamento de Fisiología, Facultad de Ciencias Médicas, Universidad Favaloro, Buenos Aires, Argentina.
authors.forename: Carlos S
authors.initials: CS
authors.lastname: Giménez
authors.affiliation: Departmento de Patología, Facultad de Ciencias Médicas, Universidad Favaloro, Buenos Aires, Argentina.
authors.forename: Rubén
authors.initials: R
authors.lastname: Laguens
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Wu
authors.affiliation: Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMETTYB), Universidad Favaloro-CONICET, Buenos Aires, Argentina Departamento de Fisiología, Facultad de Ciencias Médicas, Universidad Favaloro, Buenos Aires, Argentina crottogini@favaloro.edu.ar.
authors.forename: Alberto
authors.initials: A
authors.lastname: Crottogini
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005434:Flow Cytometry; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism / Q000502:physiology*; D015151:Immunoblotting; D008279:Magnetic Resonance Imaging; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000473:pathology / Q000628:therapy*; D012756:Sheep
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit
keywords: angiogenesis; growth substances; myocardial infarction