Abstract 17836: The Regenerative Capacity of Explant-derived Cardiac Stem Cells Inversely Correlates With Patient Risk for Future Cardiac Events

Abstract

Background: Although recent trials have demonstrated that cardiac-derived cell products repair damaged myocardium, the influence of age and medical co-morbidities is unknown. Therefore we investigated the effect of medical comorbidities on the functional activity of human explant-derived cardiac stem cells (EDCs). Methods/Results: Human EDCs were cultured from atrial appendages obtained during cardiac surgery. The Long Term Stratification model (LTS) was chosen as the best means of discriminating between patients with few or extensive comorbidities. Increasing LTS score demonstrated a moderate negative correlation with: 1) EDC conditioned media HUVEC tubule formation (R 2 =0.53; r=-4±1, p=0.003), 2) transwell recruitment of circulating angiogenic cells (R 2 =0.48; r=-15±5, p=0.016), 3) decreased echocardiographic ejection fraction (R 2 =0.64, r=-0.7±0.2, p=0.003) and increasing scar burden (R 2 =0.59, r=-0.5±0.2, p=0.04) 3 weeks after myocardial injection of EDCs into a SCID mouse model of myocardial infarction. These effects may be attributable to LTS score dependent decreases in SDF-1 (R 2 =0.33; r=-0.2±0.1, p=0.02) or exosome (R 2 =0.59; r=-2.4±0.8X10 7 , p=0.02) content within conditioned media. Interestingly, the most abundant cytokine in EDC conditioned media (IL-6) demonstrated a positive correlation with increasing LTS scores (R 2 =0.33, r=1.2±0.5, p=0.03). Lentiviral mediated knock down of IL-6 (IL-6KD) by EDCs suggests that IL-6 supports therapeutic regeneration as intra-myocardial injection of IL-6 KD EDCs from low (<3) and high (>5) LTS score patients reduced improvements in ejection fraction by 1.4±0.1 fold (p≤0.05) while increasing scar burden by 1.3±0.1 fold (p≤0.05). Immunohistochemistry demonstrated that IL-6KD reduced newly generated BrdU+ myocytes (p=0.03 vs. scramble treated EDCs) while promoting the persistence of maladaptive myofibroblasts (p=0.01 vs. scramble treated EDCs). Conclusions: The regenerative performance of the earliest cell population cultured from human tissue declines with accumulating medical co-morbidities. This effect is associated with diminished production of pro-cardiogenic cytokines and exosomes while IL-6 plays a novel pivotal role in EDC-mediated repair of damaged myocardium.