Abstract
Immune-mediated diseases are characterized by abnormal activity of the immune system. The cytochalasin B-induced membrane vesicles (CIMVs) are innovative therapeutic instruments. However, the immunomodulating activity of human mesenchymal stem cell (MSC)-derived CIMVs (CIMVs-MSCs) remains unknown. Therefore, we sought to investigate the immunological properties of CIMVs-MSCs and evaluate their effect on human peripheral blood mononuclear cells (PBMCs). We found that CIMVs-MSCs are primarily uptaken by monocytes and B-cells. Additionally, we demonstrated that CIMVs-MSCs inhibit phytohemagglutinin (PHA)-induced proliferation of PBMCs, with more pronounced effect on T-lymphocytes expansion as compared to that of B-cells. In addition, activation of T-helpers (CD4+CD25+), B-cells (CD19+CD25+), and T-cytotoxic lymphocytes (CD8+CD25+) was also significantly suppressed by CIMVs-MSCs. Additionally, CIMVs-MSCs decreased secretion of epidermal growth factor (EGF) and pro-inflammatory Fractalkine in a population of PBMCs, while the releases of FGF-2, G-CSF, anti-inflammatory GM-CSF, MCP-3, anti-inflammatory MDC, anti-inflammatory IL-12p70, pro-inflammatory IL-1b, and MCP-1 were increased. We analyzed the effect of CIMVs-MSCs on an isolated population of CD4+ and CD8+ T-lymphocytes and demonstrated their different immune response and cytokine secretion. Finally, we observed that no xenogeneic nor allogeneic transplantation of CIMVs induced an immune response in mice. Our data suggest that CIMVs-MSCs have immunosuppressive properties, are potential agents for immunomodulating treatment, and are worthy of further investigation.
Highlights
Immune-mediated diseases such as autoimmune diseases, allergies and graft-versus-host reaction are serious healthcare challenges worldwide
For the first time, we report that CD14+ (99.5 ± 0.26%) and CD20+ (69.43 ± 9.52%) cells are preferably uptaken by cytochalasin B-induced membrane vesicles (CIMVs)-Mesenchymal stem cell (MSC), while a lower CIMVs uptake was found in CD8+ (35.6 ± 3.83) and CD56+ (30.26 ± 3.44) cells, and even the smallest amount of CIMVs was detected in CD4+ (14.5 ± 4.42) (Figure 3)
We found that CIMVs-MSCs induced the secretion of FGF-2, G-CSF, IL-12p70, and MCP-1 in both CD4+ and CD8+ cells, which could explain our observation of an increased production of these cytokines in whole peripheral blood mononuclear cells (PBMCs)
Summary
Immune-mediated diseases such as autoimmune diseases, allergies and graft-versus-host reaction are serious healthcare challenges worldwide. Current treatment strategies of these diseases have multiple weaknesses and deficiencies, urging the development of innovative immune-modulation therapeutics. Mesenchymal stem cell (MSC)-based therapies are an effective approach for a range of immune-mediated diseases, including chronic autoimmune urticaria, multiple sclerosis, Crohn’s disease, rheumatoid arthritis, systemic lupus erythematosus, and many others [1]. It is believed that the therapeutic efficacy is mediated by the paracrine action of extracellular vesicles (EVs) released by MSCs [3]. A cell-free treatment approach using EVs was suggested as an alternative and demonstrated better biodistribution as well as no risk of carcinogenesis or blood vessels occlusion [2,4]. Human MSC-derived EVs have been used in two clinical cases where significant improvements of symptoms were demonstrated [7,8]
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