Abstract 15044: Cardiac Explant-derived Cells From Aged Donors With Ischemic Cardiomyopathy Demonstrate Impaired Cell Survival and Therapeutic Regeneration

Abstract

Background: While cardiac stem cells are emerging as a promising therapy for ischemic cardiomyopathy (ICM), the influence of advanced donor age and ICM on the regenerative performance of these cells are unknown. Hypothesis: Advanced donor age and a history of ICM combine to limit the regenerative performance of explant-derived cells (EDCs) through altered cell functions which reflects fundamental changes in the molecular signature of aged ischemic EDCs. Methods and Results: EDCs were cultured from myocardial biopsies of young (8 weeks; n=40) and old (52 weeks; n=36) C57/BL6 mice 4 weeks after randomization to sham or experimental myocardial infraction (MI; ejection fraction 28±2%, p=0.24 effect of donor age). Although advanced donor age was associated with reduced telomere length, aging alone had negligible effects on EDCs. In contrast, EDCs sourced from aged ICM donors showed reduced cardiomyogenic differentiation (i.e., greater propensity to adopt an endothelial or smooth muscle lineage), cytokine production (reduced angiogenin, angiopoietin-1 and VEGF), pro-angiogenic capacity (1.2±0.03 fold less tubules formed; p=0.02), reactive oxygen species metabolism (1.8±0.3 fold greater reactive oxygen species, p=0.04; 1.9±0.1 fold less superoxide dismutase activity, p<0.01; 2.4±0.3 fold less glutathione peroxidase activity, p<0.01), and apoptosis resistance (1.5±0.1 fold greater; p=0.02) as compared to young ICM EDCs. With the exception of 1.6±0.1 fold greater production of IL-6 (p=0.04), ICM did not influence young EDCs. Transplantation of EDCs from aged ICM donors into aged recipients 1 week after MI provided lesser degrees of cell-mediated cardiac repair (3±1 vs. 8±1% change in LVEF from baseline to 21 days post CSC transplant after transplant of young ICM EDCs; p<0.01). Finally, transcriptome comparison of ICM EDCs showed aging promoted the differential expression of 145 genes (≥2 fold change; false discovery rate ≤0.05) which modify many of the pathways responsible for effective cell cycle control and DNA damage/repair. Conclusions: EDCs from aged donors with a history of ICM demonstrate an attenuated capacity for cardiac repair that reflects differential expression of transcripts suggestive of impaired cell cycle control and repair.