Abstract 19379: Failure of Regenerative Cell-Based Therapy to Stimulate Coronary Collateral Growth in a Rat Model of Metabolic Syndrome

Nearly 30-40% of patients with coronary disease show little or no coronary collateral growth and have a poorer prognosis than those with well-developed collaterals. Stem cell therapies hold promise for stimulating vascular growth in the heart, but most results to date have been modest. Perhaps stem cell survival and differentiation are compromised by the oxidative environment occurring in cardiovascular disease. To test this, we determined if cell-based regenerative therapies stimulate coronary collateral growth in a rat model characterized by oxidative stress and poor coronary collateralization. Previously we found that induced vascular progenitor cells (iVPCs) were the best cell type (compared to MSCs and iPS cells) to stimulate coronary collateral growth in lean (LN) rats (10-day repetitive ischemia [RI] protocol). Using the RI protocol, iVPCs were implanted intramuscularly in the heart of Zucker Obese Fatty (ZOF) rats. Coronary collateral flow was significantly increased by iVPCs in LN but not in ZOF (Figure 1), suggesting that under oxidative stress, iVPCs fail to induce coronary collateral growth. To understand why iVPCs did not stimulate collateral growth in ZOF rats, we mimicked conditions of oxidative stress and mitochondrial DNA damage in ZOF rats (previously observed in our lab) by treating the cells with H 2 O 2 (100 µM or 800 µM) for 2 hrs followed by 100 µM 4-Nitroquinoline 1-oxide for 1 hr. These stressors decreased viability of iVPCs by 19.8% and 62.7% (high and low H 2 O 2 ; p<0.05; MTT assay) and decreased the expression of stemness lineage markers for SSEA1, CD133, and c-kit by 79%, 84% and 67%, respectively (real-time PCR). These data indicate that oxidative stress in ZOF rats compromises cell survival and stemness of the implanted iVPCs, limiting their regenerative potential. Our results suggest that consideration of adjunctive therapies to improve cell survival and regenerative capacity is important in cell-based therapies for vascular disease.