Effects of Mesenchymal Stem Cell-Derived Exosomes on Experimental Autoimmune Uveitis

Abstract

We previously demonstrated that mesenchymal stem cells (MSCs) ameliorated experimental autoimmune uveoretinitis (EAU) in rats. Recently, MSC-derived exosomes (MSC-Exo) were thought to carry functions of MSCs. In this study, we tested the effect of local administration of human MSC-Exo on established EAU in the same species. Rats with EAU induced by immunization with interphotoreceptor retinol-binding protein 1177–1191 peptide were treated by periocular injections of increasing doses of MSC-Exo starting at the disease onset for 7 consecutive days. The in vitro effects of MSC-Exo on immune cell migration and responder T cell proliferation were examined by chemotactic assays and lymphocyte proliferation assays, respectively. We found that MSC-Exo greatly reduced the intensity of ongoing EAU as their parent cells by reducing the infiltration of T cell subsets, and other inflammatory cells, in the eyes. Furthermore, the chemoattractive effects of CCL2 and CCL21 on inflammatory cells were inhibited by MSC-Exo. However, no inhibitory effect of MSC-Exo on IRBP-specific T cell proliferation was observed. These results suggest that MSC-Exo effectively ameliorate EAU by inhibiting the migration of inflammatory cells, indicating a potential novel therapy of MSC-Exo for uveitis.

Engineering mesenchymal stem cells to improve their exosome efficacy and yield for cell‐free therapy

“…They can ameliorate liver fibrosis, exert protective effects against acute liver injury and may enhance the anti-tumour effect against hepatocellular carcinoma [18]. MSC-exosomes have also been found to inhibit the migration of inflammatory cells, thus providing a benefit for the autoimmune disease uveitis [33]. Plenty of studies have shown their therapeutic use; however, one caveat is that the generated exosomes are not a uniform population [34,35].…”

“…First, the purity of the exosomes must be established based off the isolation method. Polymeric precipitation of the exosomes would require some further purification [18,32] or the ultracentrifugation of exosomes may need some additional filtering [33]. Different isolation or purification methods can also yield heterogeneous MSC-exosomes, making it difficult to compare proteomic studies between them.…”

Immunoregulatory Effects of Stem Cell-Derived Extracellular Vesicles on Immune Cells

“…GM-CSF, granulocyte-macrophage colony-stimulating factor. (47) or prevent the migration of pro-inflammatory M1 macrophages through interaction with chemokine ligands expressed on other tissues and cells (28,41,42,47) (Table 1). In addition, as reported by a study, SC-EVs downregulate the production of IL-23 and IL-22 and upregulate anti-inflammatory prostaglandin E2 (PGE2) by indirectly repressing the function of T helper type 17 (Th17) cell or by inducing conversion of Th17 cells into regulatory T cells (Tregs) (102).…”

Recent advances of exosomes in immune-mediated eye diseases

“…The mixed lymphocyte reaction assay indicated that these MSC-Exos performed a significant inhibitory effect on the T cell proliferation and Th1 and Th17 development [60]. However, in another experimental study focused on EAU, human umbilical cord-derived MSC-Exos (hUC-MSC-Exos) failed to suppress the proliferation of conA-stimulated T cells, but effectively inhibited inflammatory cell migration [61]. In vitro results from our group showed that hUC-MSC-Exos had only a slight suppressive effect on interphotoreceptor retinoid-binding protein (IRBP)-specific Th17 responses, while they significantly inhibited DCdriven Th17 responses through the modulation of DCderived Th17-polarizing cytokines IL-1β, IL-6, and IL-23.…”