No abstract

Mesenchymal stromal cells (MSCs) are cardioprotective in acute myocardial infarction (AMI). Besides, we have shown that intramyocardial injection of plasmid-VEGF(165) (pVEGF) in ovine AMI reduces infarct size and improves left ventricular (LV) function. We thus hypothesized that MSCs overexpressing VEGF(165) (MSCs-pVEGF) would afford greater cardioprotection than non-modified MSCs or pVEGF alone. Sheep underwent an anteroapical AMI and, 1 week later, received intramyocardial MSCs-pVEGF in the infarct border. One month post treatment, infarct size (magnetic resonance) decreased by 31% vs pre-treatment. Of note, myocardial salvage occurred predominantly at the subendocardium, the myocardial region displaying the largest contribution to systolic performance. Consistently, LV ejection fraction recovered to almost its baseline value because of marked decrease in end-systolic volume. None of these effects were observed in sheep receiving non-transfected MSCs or pVEGF. Although myocardial retention of MSCs decreased steeply over time, the treatment induced significant capillary and arteriolar proliferation, which reduced subendocardial fibrosis. We conclude that in ovine AMI, allogeneic VEGF-overexpressing MSCs induce subendocardial myocardium salvage through microvascular proliferation, reducing infarct size and improving LV function more than non-transfected MSCs or the naked plasmid. Importantly, the use of a plasmid rather than a virus allows for repeated treatments, likely needed in ischemic heart disease.

BackgroundBone 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.Methods and ResultsAllogeneic 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.ConclusionsIntramyocardial 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.