Abstract 1417: Stem Cell Based Gene Transfer of GATA4 Fused with Cell Penetrating Peptide VP22 for Cardiac Repair
We have recently demonstrated that GATA4 fused with cell penetrating peptide VP22 is an efficacious strategy for delivering a cardiac transcription factor to the myocardium in ischemic cardiomyopathy. We have similarly demonstrated that the delivery of SDF-1 to the heart soon after myocardial infarction (MI) leads to stem cell recruitment and preservation of cardiac myocytes. We hypothesized that by combining VP22:GATA4 and SDF-1 delivery to the myocardium we could recruit stem cells to the heart and force their differentiation following MI. We used the infusion of genetically modified mesenchymal stem cells (MSC) to deliver the SDF-1 and VP22:GATA4 to the heart after MI. MSCs isolated from bone marrow and stably transduced with Lentiviral VP22:GATA4 or SDF-1 were infused through tail vein one week after LAD ligation in Lewis rat model. Experimental groups consisted of Saline, Control MSC, SDF-1 MSC, VP22:GATA4 MSC or combined VP22:GATA4 and SDF-1 MSC. In each situation 2 million MSC were infused, but no more than 1 million of any specific genetically modified MSC was infused. Ejection fraction was quantified by echocardgraphy 2 and 6 weeks after cell infusion. At 2 w after cell infusion we observed a 23 ± 1% and 40 ± 5% improvements in ejection fraction of MSC and SDF-1 groups relative to saline controls. We observed a 23 ± 4% decline in function in the VP22:GATA4 group and no improvement in the combination group. At 6 weeks after cell infusion, we observed no significant improvements in the MSC group and a 47 ± 10% and a 20 ± 4% improvements in the SDF-1 and combo groups, the function in the VP22:GATA4 group improved to have no significant difference compared to saline control. Intravenous infusion of MSC can be used to deliver natural and chimeric proteins to the myocardial tissue following MI. The initial decline in function in those animals that received VP22:GATA4 expressing MSC suggest that forced induction of cardiac differentiation soon after MI may have detrimental effects on myocardial tissue leading to increased cardiac myocyte death and adverse remodeling. These findings have implications in strategies being developed to induce myocardial regeneration soon after MI.