Exosomes isolated from human cardiosphere-derived cells attenuate pressure overload-induced right ventricular dysfunction

Objectives: Cardiosphere-derived cell (CDC) transplantation has been shown to attenuate right ventricular (RV) dysfunction in patients with hypoplastic left heart syndrome. However, live cell transplantation requires complex handling protocols that may limit its use. Exosomes are protein and nucleic acid-containing nanovesicles secreted by many cell types, including stem cells, which have been shown to exert a cardioprotective effect comparable with whole cells following myocardial injury. We therefore sought to evaluate 3 human CDC-derived exosome preparations in a juvenile porcine model of acute pressure-induced RV dysfunction. Methods: Twenty immunocompetent juvenile Yorkshire pigs (7-10 kg) underwent pulmonary arterial banding followed by intramyocardial test agent administration: control (n = 6), XO-1 (n = 4), XO-2 (n = 5), and XO-3 (n = 5). Animals were monitored for 28 days postoperatively with periodic phlebotomy and echocardiography, followed by extensive postmortem gross and histopathologic analysis. Results: All animals survived the banding operation. One died suddenly on postoperative day 1; another was excluded due to nonstandard response to banding. Of the remaining animals, there were no clinical concerns. RV fractional area change was improved in the XO-1 and XO-2 groups relative to controls at postoperative day 28. On histologic analysis, exosome-treated groups exhibited decreased cardiomyocyte hypertrophy with respect to controls. Conclusions: Human CDC-derived exosome administration was associated with significant preservation of RV systolic function in the setting of acute pressure overload. Such acellular preparations may prove superior to whole cells and may represent a novel therapeutic approach to clinical myocardial injury.