Abstract P002: Pim-1 Engineering of Human CPCs Increases Their Ability to Repair the Heart After Myocardial Infarction
Rationale: The efficiency of adoptively transferred human cardiac stem cells to repair damaged myocardium is extremely limited. There is an urgent need to improve the potency of human stem cells to engraft, proliferate and differentiate into cardiac phenotypes before launching them as viable therapeutic tool in clinics.
Objective: Demonstrate that Pim-1 engineering of human cardiac stem cells (hCPCs) can improve their long term persistence in the damaged myocardium associated with significant augmentation of cardiac function.
Methods and Results: hCPCs positive for the putative stem cell marker c-kit were isolated from heart biopsy samples from patients undergoing Left Ventricular Assist Device (LVAD) implantation. hCPCs were engineered to express Pim-1-GFP, a fused GFP version of the kinase by using a lentivirus expression system. Pim-1 engineering of hCPCs significantly increased their viability, proliferation and metabolic activity. Conversely, treatment with a Pim-1 specific inhibitor quercetagetin completely abrogated the observed proliferative response. Pim-1 engineered hCPCs were transplanted in immunocompromised mice with myocardial infarction to evaluate functional competency of the cells. Animals receiving Pim-1 CPCs showed increased hemodynamic performance as evidenced by dp/dt, LVEDP and LVDP measurements 10 weeks after transplantation. Cardiac function demonstrated sustained improvement even after 20 weeks of transplantation in Pim-1 CPC transplanted animals compared to control cell transplanted group. Concurrent with enhanced cardiac function, animals having Pim-1 CPCs demonstrated increased cellular engraftment, persistence and proliferation of human CPCs. In particular, a greater number of c-kit+ cells, improved vasculature and reduced infarct size were observed.
Conclusion: Genetic engineering of human CPCs with Pim-1 enhances their ability to repair damaged myocardium. Ex vivo gene delivery to enhance survival, proliferation and regeneration in damaged myocardium has emerged as a viable option addressing current limitations associated with stem cell therapy.
- © 2011 by American Heart Association, Inc.