Extracellular vesicles (EVs) offer a new approach for treatment of diseases and immunotherapy. EVs have already demonstrated their immunomodulatory properties: in the treatment of sepsis1, EVs lowered the level of inflammatory mediators. In the treatment of GVHD2, EVs reduced the level TNF-a, IL-2 and IFN-y. Finally in auto-immune diseases3, EVs inhibited the migration of inflammatory cells and reduced the level of inflammatory mediators. In clinical studies, EVs have shown their immunomodulatory properties in the treatment of COVID-19 by downregulating the cytokine storm4, but also in chronic kidney disease (CKD) where a significant increase in anti-inflammatory mediators and an improvement of kidney function was observed5. Though, depending on the cell of origin, EVs can exert immunostimulatory or immunosuppressive activities.6 As an example, EVs from macrophages infected with mycobacterium contained pro-inflammatory molecules, inducing the secretion of pro-inflammatory cytokines.7 EVs derived from tumor cells have immunosuppressive activities, allowing cells to escape the immune system.8 EVs secreted by dendritic cells can express major histocompability complex (MHC) and co-stimulatory molecules, triggering anti-tumor responses.9
Immunomodulatory properties of MSCs are partially mediated by secreted EVs. Thus, the action of EVs from stem cells is mainly described as immunosuppressive and regulatory, with direct effects on various immune cells through diverse factors such as PD-1, TGF- β, PGE2 or IDO. These effects have been described on the transplantation of islets of Langerhans10, the polarization of macrophages into M2 anti-inflammatory in a rat model of vascular graft, or through the regulation of anti-inflammatory and inflammatory cytokines in a model of neuronal regeneration.11 Nonetheless, the characterization of MSC’s secretome shows the simultaneous presence of pro and anti-inflammatory proteins. 12–14
The immunomodulatory action of MSC derived EVs can vary depending on many factors. The cell source, even between different MSCs of adipose tissue, umbilical cord or bone marrow15, the state of the cell and passage16, the production method16, and the downstream process such as isolation, concentration, and EV purification are many existing factors which can impact the immunomodulatory activity of EVs. Notably, some production methods can increase the immunomodulatory activity, such as hypoxia17 or cell priming.18,19
Despite all these differences, data indicate that EVs derived from MSCs has potential for the treatment of immunological diseases. Nevertheless, in order to develop a successful and effective immunotherapy, more studies are needed to clarify the mechanism of action of EVs and standardization of isolation and characterization of EVs.20
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