Microvesicles derived from mesenchymal stem cells: potent organelles for induction of tolerogenic signaling.

Generation and maintenance of immunological tolerance is a pivotal aim in the field of autoimmunity. Regulatory molecules of Programmed Death Ligand-1 (PD-L1), galectin-1 and TGF-β are described as key mediators of peripheral tolerance that actively suppress auto-reactive cells and inhibit their mediated tissue damages. Accordingly, biological intervention in host immune system for induction of peripheral tolerance is pivot to many of the recent studies. Mesenchymal stem cell-derived microvesicles (MVs) are viewed as potential mediators to shed peripheral tolerance toward auto-reactive cells via bearing of tolerogenic molecules. Here, MVs were isolated from mesenchymal stem cell (MSC) cultures' conditioned medium. They were explored for the expression of PD-L1, galectin-1 and membrane bound TGF-β through flow cytometry. The immunoregulatory effects of MVs on splenic mononuclear cells (MNCs) derived from experimental autoimmune encephalomyelitis (EAE) affected mice were investigated using MTT assay, ELISA and flow cytometry. MVs derived from MSCs expressed PD-L1, galecin-1 and membrane-bound TGF-β. MVs exhibited the potential to inhibit auto-reactive lymphocyte proliferation and also the potency to promote them to secret anti-inflammatory cytokines of IL-10 and TGF-β. Interestingly, inducing inflammatory setting on MSCs, revealed the enhancing regulatory effects of MVs via increased expression of some regulatory molecules, specifically PD-L1 and TGF-β. Induction of tolerogenic signaling, promotion of CD4+ CD25+ Foxp3+ regulatory T cells generation and apoptotic activity towards activated T cells are shown to be possible mechanisms involved in MV-mediated regulation. Recent study suggests MSC-derived MVs as potent organelles for induction of peripheral tolerance and modulation of immune responses.