Safety and Feasibility for Pediatric Cardiac Regeneration Using Epicardial Delivery of Autologous Umbilical Cord Blood-Derived Mononuclear Cells Established in a Porcine Model System

Congenital heart diseases (CHDs) requiring surgical palliation mandate new treatment strategies to optimize long-term outcomes. Despite the mounting evidence of cardiac regeneration, there are no long-term safety studies of autologous cell-based transplantation in the pediatric setting. We aimed toestablishaporcinepipelinetoevaluatethefeasibilityandlong-termsafetyofautologousumbilical cord blood mononuclear cells (UCB-MNCs) transplanted into the right ventricle (RV) of juvenile porcine hearts. Piglets were born by caesarean section to enable UCB collection. Upon meeting release criteria, 12 animals were randomized in a double-blinded fashion prior to surgical delivery of test article(n=6)orplacebo(n=6).TheUCB-MNC(3310 6 cellsperkilogram)orcontrol(dimethylsulfoxide, 10%) products were injected intramyocardially into the RV under direct visualization. The cohorts were monitored for 3 months after product delivery with assessments of cardiac performance, rhythm, and serial cardiac biochemical markers, followed by terminal necropsy. No mortalities were associated with intramyocardial delivery of UCB-MNCs or placebo. Two animals from the placebo group developed local skin infection after surgery that responded to antibiotic treatment. Electrophysiological assessments revealed no arrhythmias in either group throughout the 3-month study. Twoanimalsin thecell-therapy grouphadtransient, subclinical dysrhythmia intheperioperativeperiod, likely because of an exaggerated response to anesthesia. Overall, this study demonstrated that autologousUCB-MNCscanbesafelycollectedandsurgicallydeliveredinapediatricsetting.Thesafety profile establishes the foundation for cell-based therapy directed at the RV of juvenile hearts and aims to accelerate cell-based therapies toward clinical trials for CHD. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:195–206