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Abstract
Mesenchymal stromal cells (MSCs) are multipotent cells, immunomodulatory stem cells that are currently used for regenerative medicine and treatment of a number of inflammatory diseases, thanks to their ability to significantly influence tissue microenvironments through the secretion of large variety of soluble factors. Recently, several groups have reported the presence of extracellular vesicles (EVs) within MSC secretoma, showing their beneficial effect in different animal models of disease. Here, we used a standardized methodological approach to dissect the immunomodulatory effects exerted by MSC-derived EVs on unfractionated peripheral blood mononuclear cells and purified T, B and NK cells. We describe here for the first time: i. direct correlation between the degree of EV-mediated immunosuppression and EV uptake by immune effector cells, a phenomenon further amplified following MSC priming with inflammatory cytokines; ii. induction in resting MSCs of immunosuppressive properties towards T cell proliferation through EVs obtained from primed MSCs, without any direct inhibitory effect towards T cell division. Our conclusion is that the use of reproducible and validated assays is not only useful to characterize the mechanisms of action of MSC-derived EVs, but is also capable of justifying EV potential use as alternative cell-free therapy for the treatment of human inflammatory diseases.
Highlights
It has been suggested that extracellular vesicles (EVs) can mediate the paracrine mechanism of Mesenchymal stromal cells (MSCs), playing a role in tissue repair and immune regulation[26]
The therapeutic effects of EVs have been investigated in different disease models, including cardiovascular diseases, acute kidney injury, and liver or lung injuries, where the injection of EVs resulted in an improvement of tissue damage and inflammation[34,35,36,37,38,39]
Some recent reports suggested the role of MSC-derived EVs in immunomodulation of different immunosuppressive towards effector cells (IECs); for instance, EVs co-cultured with unfractionated peripheral blood mononuclear cells (PBMCs) inhibited B cell proliferation and immunoglobulin release[40,41], but non-univocal effects were observed on T cell proliferation[42]
Summary
It has been suggested that extracellular vesicles (EVs) can mediate the paracrine mechanism of MSCs, playing a role in tissue repair and immune regulation[26]. Some recent reports suggested the role of MSC-derived EVs in immunomodulation of different IECs; for instance, EVs co-cultured with unfractionated peripheral blood mononuclear cells (PBMCs) inhibited B cell proliferation and immunoglobulin release[40,41], but non-univocal effects were observed on T cell proliferation[42]. We focused our attention on the EV-mediated interactions between resting or inflammatory primed MSCs and different IECs, either as unfractionated PBMCs or purified-T, -B and -NK cells, with the aim of quantifying the modulatory effect of EVs by using the standardized immunological assays normally employed to characterize MSC functions[43]. We identified the presence of miRNA-155 and miRNA-146 within MSC-derived EVs, suggesting a potential role in their immunomodulatory activities
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