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Enhanced Immunosuppressive Capability of Mesenchymal Stem Cell-derived Small Extracellular Vesicles with High Expression of CD73 in Experimental Autoimmune Uveitis

Duan, Y;Chen, X;Shao, H;Li, Y;Zhang, Z;Li, H;Zhao, C;Xiao, H;Wang, J;Zhang, X;

Background: Autoimmune uveitis is an inflammatory disease triggered by an aberrant immune response. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) are emerging as potential therapeutic agents for this condition. CD73, an ectoenzyme present on MSC-sEVs, is involved in mitigating inflammation by converting extracellular adenosine monophosphate into adenosine. We hypothesize that the inhibitory effect of MSC-sEVs on experimental autoimmune uveitis (EAU) could be partially attributed to the surface expression of CD73.

Methods: To investigate novel therapeutic approaches for autoimmune uveitis, we performed lentiviral transduction to overexpress CD73 on the surface of MSC-sEVs, yielding CD73-enriched MSC-sEVs (sEVs-CD73). Mice with IRBP-induced EAU were grouped randomly and treated with 50 μg MSC-sEVs, vector infected MSC-sEVs, sEVs-CD73 or PBS via single tail vein injection. We evaluated the clinical and histological features of the induced mice and analyzed the proportion and functional capabilities of T helper cells. Furthermore, T-cells were co-cultured with various MSC-sEVs in vitro, and we quantified the resulting inflammatory response to assess the potential therapeutic benefits of sEVs-CD73.

Results: Compared to MSC-sEVs, sEVs-CD73 significantly alleviates EAU, leading to reduced inflammation and diminished tissue damage. Treatment with sEVs-CD73 results in a decreased proportion of Th1 cells in the spleen, draining lymph nodes, and eyes, accompanied by an increased proportion of Treg cells. In vitro assays further reveal that sEVs-CD73 inhibit T-cell proliferation, suppress Th1 cells differentiation, and enhance Treg cells proportion.

Conclusion: Over-expression of CD73 on MSC-sEVs enhanced their immunosuppressive effects in EAU, indicating that sEVs-CD73 have the potential as an efficient immunotherapeutic agent for autoimmune uveitis.