! The Therapeutic Potential of Mesenchymal Stem/Stromal Cell-Derived Extracellular Vesicles

Following the discoveries that human mesenchymal stem or stromal cells (MSC) contain multilineage differentiation potentials and can modulate immune responses, more than 500 clinical trials have been registered at the NIH to test for the therapeutic potentials of MSC in various diseases. In contrast to the initial hypothesis that MSCs mediate their therapeutic effects by intercalating into affected tissues, novel results suggest that they exert their therapeutic impacts in a paracrine rather than in a cellular manner. To this end, extracellular vesicles (EV), like exosomes and microvesicles, have been found to mediate at least a proportion of the MSCs' therapeutic functions. EV are considered to be extracellular organelles which mediate intercellular communication processes very specifically, also between cells at distance sites. EV are formed by almost all cell types and have been detected in all body liquids. Depending on their origin, they contain specific mixtures of lipids, proteins and non-coding RNAs. As non-self-replicating units which can be sterilized by filtration, EVs provide a number of advantages over cellular therapeutics. In addition to a variety of different preclinical models, EVs harvested from MSC-conditioned media have been administered in an individual treatment attempt to a steroid-refractory Graft-versus-Host Disease (GvHD) patient. Positive therapeutic effects, but no side effects were observed in all preclinical models tested so far as well as in the GvHD patient. Thus, MSC-EVs appear to be a promising new tool in immune therapy and in regenerative medicine.