Abstract 415: Electrical Stimulation of Pediatric Cardiac-derived c-kit ⁺ Progenitor Cells Improves Retention and Cardiac Function in Right Ventricular Heart Failure

Nearly 1% of babies born in the US will be diagnosed with a congenital heart defect (CHD). While surgical therapy has improved survival, many of these children go on to develop right ventricular heart failure (RVHF). The emergence of cardiovascular regenerative medicine as a potential therapeutic strategy for pediatric HF has provided new avenues for treatment with a focus on repairing or regenerating the diseased myocardium to restore cardiac function. While primarily tried using adult cells and adult disease models, stem cell therapy is relatively untested in the pediatric population. Cardiac-derived c-kit + progenitor cells (CPCs) have been widely studied as a cell-based therapy for cardiac pathologies; however, unless these cells are extracted at a very young age their therapeutic efficacy has been shown to be diminished. Finding novel ways to enhance the reparative potential of these cells is thus of critical significance. We previously reported pediatric CPCs (isolated from patients between 1-5 years of age) respond to electrical stimulation (ES) by initiating intracellular calcium oscillations. Here, we investigate the ability of ES to enhance the retention and therapeutic function of pediatric CPCs in an animal model of RVHF. Human CPCs isolated from pediatric patients were exposed to chronic ES and implanted into the RV myocardium of rats. Cardiac function and cellular retention analysis showed electrically stimulated CPCs (ES-CPCs) were retained in the heart at a significantly higher level and longer time than control CPCs and also significantly improved right ventricular functional parameters. ES also induced upregulation of extracellular matrix and adhesion genes, such as integrins β1 and β5, and significantly increased in vitro survival and adhesion of cells. Lastly, we show that ES induces CPCs to release higher levels of reported pro-reparative factors in vitro, including angiogenin, FGF, HGF, and VEGF. These findings suggest electrical stimulation can be utilized to increase the retention, survival, and therapeutic effect of human c- kit + progenitor cells. Furthermore, our insights into the mechanisms of increased retention and paracrine function of ES-CPCs can have implications on a variety of cell-based therapies.