Abstract 15228: Manganese-Enhanced MRI (MEMRI) Determines the Mechanistic Efficacy of Exosome Therapy in a Porcine Myocardial Infarction Model

Abstract

Introduction: Transplantation of exosomes from mesenchymal stem cells (MSCs) and induced pluripotent stem cell derived cardiomyocytes (iCMs) improves heart function after myocardial infarction (MI). However, imaging methods have not been established to assess the mechanism of these treatments. Contrast imaging with gadolinium delayed-enhancement MRI (DEMRI) allows non-specific quantification of myocardial fibrosis. In contrast, MEMRI demonstrates active uptake of manganese into intracellular space by the viable cardiomyocytes via L-type calcium channel. MEMRI delineates the level of cellular metabolism and identifies the recovery of the injured but viable cardiomyocytes in the peri-infarct region (PIR). Hypothesis: MEMRI reflects the mechanistic efficacy of cell therapy. Methods: Yorkshire swine were subject to percutaneous proximal left anterior descending artery occlusion for 1 hour. Ten 500ul injections containing 5 x 10 11 exosomes isolated from MSCs and iCMs were delivered transendocardially to the PIR. Four weeks after injury, left ventricular ejection fraction (LVEF), and myocardial scar/viability were measured. DEMRI and MEMRI delineated the PIR to quantify the effects of exosomes. Results: The LVEF of PBS (control), MSC-exosome, and iCM-exosome groups was 18.66% ± 4.23, 27.46% ± 6.16, and 29.5% ± 3.96*, respectively (*p<0.05). The % contrast enhancement by DEMRI over total LV volume were 29.38% ± 4.86, 28.76% ± 5.02, and 29.58% ± 5.55, respectively. Meanwhile, the % contrast nulling (CN, non-viable) by MEMRI were 20.51% ± 3.86, 9.53% ± 1.99, and 7.31% ± 2.62*, respectively (*p<0.01). mRNA seq of the porcine myocardium and subsequent gene ontology and KEGG analyses demonstrated significant differential gene expression of iCM-exosome group related to calcium regulation (adenylate cyclase 7, 3.30-fold change) and sarcoplasmic reticulum calcium ion transport (chemokine receptor 5, 3.15-fold change). Conclusions: The % CN reduction of MEMRI reflects improved cardiomyocyte metabolism and calcium handing by exosome therapy. The underlying mechanism and functional improvement are identified by MEMRI.