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.

A novel approach for large-scale manufacturing of small extracellular vesicles from bone marrow-derived mesenchymal stromal cells using a hollow fiber bioreactor

“…MSC expansion with hollow fiber bioreactors such as the Quantum system of Terumo BCT has already been implemented for several cell-based applications ( Nold et al, 2013 ; Rojewski et al, 2013 ; Hanley et al, 2014 ; Lechanteur et al, 2014 ; Barckhausen et al, 2016 ; Haack-Sorensen et al, 2016 ; Lambrechts et al, 2016 ; Haack-Sorensen et al, 2018 ; Mizukami et al, 2018 ; Frank et al, 2019 ; Mennan et al, 2019 ; Lisini et al, 2020 ; Vymetalova et al, 2020 ; Cocce et al, 2021 ; Haberle et al, 2021 ; Mendt et al, 2021 ). However, only few studies investigated the use of hollow fiber bioreactor-based systems for the production of MSC-derived sEVs ( Mendt et al, 2018 ; Cao et al, 2020 ; Yan and Wu, 2020 ; Gobin et al, 2021 ; Bellio et al, 2022 ). In addition, Witwer et al highlighted the urgent need to investigate the impact of bioreactor-based production processes on sEV characteristics ( Witwer et al, 2019 ).…”

Mitochondrial Transfer/Transplant in Skin: Reducing ROS Damage, Enhancing Proliferation and Wound Healing

“…Mice BM MSCs and broblasts were cultured in high glucose Dulbecco's modi ed Eagle's medium (DMEM, Item: 12430-054) supplemented with 1% penicillin/streptomycin solution (PS; 10,000 U/mL and 10,000 µg/mL, respectively, Item: 17-0602E), 1% L-glutamine (200 mM), 25 mM HEPES, (all from Gibco; Cascade Biologics, Portland, OR, USA) and 10% Foetal Bovine Serum, Quali ed (FBS) (Item 10437-028, GIBCO; Cascade Biologics, Portland, OR, USA). Human WJ MSCs, isolated from the umbilical cord of healthy and full-term infants and characterized as previously described 27 , were donated by Maria Ines Mitrani and AssureImmune, Inc. in Miami. Cells were grown in a medium composed of 20% FBS and 1% penicillin/streptomycin in α-MEM from Gibco or 5% PLT max (Millcreek), heparin, and 1% penicillin/streptomycin.…”

Stem Cell-Derived Extracellular Vesicles in the Treatment of Cardiovascular Diseases

“…Experimental data also suggest that SCEVs have a therapeutic capacity upon established injury to the myocardium. Indeed, using EVs of Wharton’s Jelly-derived MSCs in a murine myocardial infarction model, significant improvements in the ejection fraction and cardiac output and reduced infarct size were reported [ 139 ]. Current experimental data indicate that the myocardial repair capacity of SCEVs is mediated by multiple, possibly parallel, underlying mechanisms.…”