Abstract 16665: Intracoronary Administration of Neonatal Cardiac Mesenchymal Cells Promotes Cardiac Functional Recovery in a Porcine Model of Acute Myocardial Infarction

Abstract

Background: The strong regenerative potential of neonatal mesenchymal stem cells (nMSCs) in animal MI models when compared to adult MSCs have been attributed to their paracrine secretions. This study determines the therapeutic potential of nMSC-based therapies in a translationally relevant animal large model. Methods: Yorkshire Pigs underwent a 60-minute coronary occlusion followed by reperfusion. Pigs were randomized for intracoronary administration of 10 million nMSCs (n=4), 20 million nMSCs (n=4), 2 mg/kg of TCM (n=4), 10 million nMSCs plus 2 mg/kg TCM (n=5), or placebo (n=4). The infarct size was quantified 48 hours post-infarction. Separate (10 million nMSCs plus 2 mg TCM treated and control) groups were allowed to survive for 28 days, and cardiac MRI (cMR) was performed on post- operative days 7 and 28. Results: After 48hrs, increasing the dose of nMSCs (20 million vs 10 million nMSCs) showed more decrease in infarct size (74+0.03% vs 83.2+0.05%, p =0.25). 2 mg TCM reduced the infarct size in comparison to control (60.8+ 0.09% vs 91+0.03%, p= 0.02). Combination of 10 million nMSCs plus 2 mg TCM achieved the greater reduction of infarct size from 91+ 0.03% to 56+0.02% ( p =0.0002). At 28 days, infarct percent mass to the left ventricle mass was significantly smaller in the combination of 10 million nMSCs and 2mg TCM than control group (3.98+1.7 % vs 13.63 + 3.9%, p =0.003). These combination treated animals showed an increase in stroke volume (+ 10 mL vs - 1.7 mL, p= 0.002) and preserved LV dimensions and ejection fraction by day 28 as compared to day 7. None of the treatment groups showed any end-organ damage. The infarct zone for treated animals showed enhanced angiogenesis and reduced fibrosis, inflammation and apoptosis. Anti-apoptotic signaling molecules related to MAPK pathway are being investigated. Conclusions: Intracoronary infusion of nMSCs-TCM is safe, promotes the strongest cardiac and vascular regeneration by decreasing scar and improving LV function in pigs after AMI. These results provide the rationale for a subsequent translation of a combination allogenic product of nMSCs-TCM to clinical trials.