Allogeneic Mesenchymal Stromal Cells Overexpressing Mutant Human Hypoxia‐Inducible Factor 1‐α (HIF1‐α) in an Ovine Model of Acute Myocardial Infarction

Abstract

Background Bone marrow mesenchymal stromal cells ( BMMSC s) are cardioprotective in acute myocardial infarction ( AMI ) because of release of paracrine angiogenic and prosurvival factors. Hypoxia‐inducible factor 1‐α ( HIF 1‐α), rapidly degraded during normoxia, is stabilized during ischemia and upregulates various cardioprotective genes. We hypothesized that BMMSC s engineered to overexpress mutant, oxygen‐resistant HIF 1‐α would confer greater cardioprotection than nontransfected BMMSC s in sheep with AMI . Methods and Results Allogeneic BMMSC s transfected with a minicircle vector encoding mutant HIF 1‐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 BMMSC s ( BMMSC ; n=6) displayed less infarct size limitation and percent LVEF improvement, whereas in placebo‐treated animals (n=6), neither parameters changed over time. HIF 1‐α‐transfected BMMSC s ( BMMSC ‐ HIF ) induced angio‐/arteriogenesis and decreased apoptosis by HIF 1‐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 . Conclusions 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 HIF 1‐mediated overexpression of paracrine factors and enhanced retention of injected cells. Given the safety of the minicircle vector and the feasibility of BMMSC s for allogeneic application, this treatment may be potentially useful in the clinic.