Abstract 21125: Long-Term Outcome of Administration of Hypoxia-Preconditioned Mesenchymal Stem Cells After Acute Myocardial Infarction in Nonhuman Primate Angiogenesis Persist for at Least 17 Months

Abstract

Rationale: Hypoxia preconditioning (HP) could improve the effectiveness of bone marrow mesenchymal stem cells (MSCs) for cardiac repair. However, the long-term (>1 year) effects, potential arrhythmogenic complications of transplanted HP-MSCs are unknown. Objective: The present study was designed to assess the long term (17 months) outcome of HP-MSCs administration for the treatment of myocardial infarction (MI) in a small scale (N=10), nonhuman primate (Cynomolgous monkeys) investigation. Methods and Results: MSCs were engineered to express green fluorescent protein (GFP), cultured under ambient oxygen or 0.5% oxygen (HP-MSCs) for 24 hours and then delivered into the infarcted hearts of Cynomolgus monkeys (1X10 7 cells per heart). 17 months later, HP-MSCs-treated monkeys tended to exhibited smaller scars, along with improvement of global left ventricular function. No ventricular arrhythmia were observed. It is worth mentioning that HP-MSCs transplantation triggered a prolonged response of angiogenesis, resulting in increased density of endothelial cells (CD31 POS cells) and smooth muscle cells (SMA POS cells) for 17 months. However, HP failed to enhance the long-term retention of transplanted cells in the injured heart (No GFP POS cells were detected), indicating that the paracrine actions were the pivotal mechanisms of HP. Therefore, we further evaluated the therapeutic effects of exosomes, the major paracrine components, for the cardiac repair, and found that monkey HP-MSCs-derived exosomes injection displayed equivalent beneficial angiogenesis with HP-MSC per se administration for the treatment of MI in mice model. Conclusions: The beneficial effects of HP-MSCs on cardiac repair tended to be sustained for at least 17 months in non-human primates without increasing the occurrence of arrhythmogenic complications. This is the first report that administration of HP-MSCs in the heart induces angiogenesis via exosome secretion that persist for at least 17 months which support the safety and feasibility of HP-MSCs therapy.