Abstract 593: Efficacy Of Induced Pluripotent Stem Cell-derived Endothelial Cell Therapy Is Impaired By Chronic Nicotine Exposure In A Murine Model Of Peripheral Artery Disease

Abstract

Treatment strategies for peripheral artery disease (PAD) remain limited due to the many challenges of surgical intervention. Stem cell therapy offer a promising option, but barriers exist to their clinical translatability. Among these barriers include lifestyle choices like nicotine use that may influence the efficacy of stem cell therapy. The objective of this study aims to examine the efficacy of iPSC-EC therapy for treatment of PAD in mice with prior chronic exposure to nicotine. We hypothesize that chronic nicotine exposure negatively affects the therapeutic potential of implanted iPSC-ECs in a murine model of PAD. Immunocompromised (NSG) mice were implanted with an osmotic pump for controlled exposed to nicotine or saline (control) for 28 days. Cotinine levels confirmed plasma nicotine presence. After 28 days of nicotine or saline exposure, the mice underwent induction of hindlimb ischemia and before receiving an injection of 10 6 iPSC-ECs. A second dose of cells were injected to the ischemic limb on day 7 post-surgery. All mice were monitored for blood perfusion recovery using laser Doppler spectroscopy imaging. At day 14 post-surgery, mice were euthanized, and the gastrocnemius muscle was harvested for histological analysis. The results show that the average cotinine concentration in sera was ~200 ng/mL, which is within physiological range for a tobacco user. Blood perfusion recovery at day 14 showed that nicotine treated groups have impaired perfusion recovery, compared to control mice treated with saline. This finding was supported by histological analysis of capillary density showing decreased angiogenesis in the nicotine group after iPSC-EC therapy. In conclusion, nicotine exposure was associated with poorer blood perfusion recovery after iPSC-EC therapy, compared to control saline exposure, suggesting that chronic nicotine exposure may have adverse effects on the efficacy of iPSC-EC therapy for treatment of PAD.