Systemic delivery of large-scale manufactured Wharton’s Jelly mesenchymal stem cell-derived extracellular vesicles improves cardiac function after myocardial infarction

Abstract

Introduction: Cardiovascular disease and myocardial infarction are leading causes of morbidity and mortality in aged populations. Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) are under evaluation as a therapeutic option for the treatment of myocardial infarction. Aim: This study aimed to develop a large-scale manufacturing procedure to harvest clinical-grade EVs required for the translation of EVs to the clinic. Methods and Results: We compared the efficiency of large scale MSC-derived EV production and characterized EV miRNA cargo using the Quantum bioreactor with either fetal bovine serum or human platelet lysate (PLT)-containing expansion media. We tested the potency of the EV products in a murine model of acute myocardial infarction. Our results demonstrate an advantage of the Quantum bioreactor as a large-scale platform for EV production using PLT media; however, both media produced EVs with similar effects in vivo. The systemic delivery of EV products improved cardiac function following myocardial infarctions as indicated by a significant improvement in ejection fraction as well as parameters of cardiac performance, afterload, contractility and lusitropy. Conclusion: These findings have important implications for scale-up strategies of EVs and will facilitate clinical trials for their clinical evaluation. One sentence summary: Large scale manufacturing of MSC-derived EVs is feasible and when delivered systemically, improves cardiac function after myocardial infarction.