Characterization, Preconditioning, Safety, and Other Issues of MSC-Derived EVs and Secretome

Recently, a growing number of scientific research and clinical studies have demonstrated the potential of extracellular vesicles (EVs) secreted by cells of different types for treating various diseases. It was shown that most frequently, substances and molecules excreted by the cells exert therapeutic or other effects, and not the cells themselves. Their cargo is wrapped in membrane envelopes, allowing it to survive for a longer time and find targets in organs and tissues as well as overcome various barriers, including the blood-brain barrier. EVs from mesenchymal stromal (stem) cells (MSCs) have attracted particular interest, as MSCs possess immunomodulatory and tissue-repairing properties per se. However, their clinical use is severely limited due to the frequent lack of efficiency in clinical trials, as well as existing risks of tumorigenesis and pulmonary embolism. EVs isolated from MSCs may help circumvent these problems, but their composition and properties, like those of their progenitors, vary significantly between batches, owing to donor characteristics and cell culture conditions. EVs from immortalized MSCs offer greater potential for repeatability and uniformity but raise the question of whether cell immortalization products enter EVs and are transferred to target cells and/or affect them. This review examines the most recent data on preconditioning techniques for MSC-derived EVs, EV characterization, large-scale manufacturing, storage, and the use of EVs from immortalized MSCs, including their characteristics and therapeutic properties, with a special emphasis on safety issues.