KMID : 0620920230550030665
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Experimental & Molecular Medicine 2023 Volume.55 No. 3 p.665 ~ p.679
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Mesenchymal stem cell-derived extracellular vesicles subvert Th17 cells by destabilizing ROR¥ãt through posttranslational modification
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Jung Sun-Young
Lee Sun-Ho Kim Hyun-Je Kim Su-Eon Moon Ji-Hwan Chung Hyun-Woo Kang Seong-Jun Park Chung-Gyu
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Abstract
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Mesenchymal stem cell (MSC)-derived small extracellular vesicles (MSC-sEVs) are known to exert immunosuppressive functions. This study showed that MSC-sEVs specifically convert T helper 17 (Th17) cells into IL-17 low-producer (ex-Th17) cells by degrading RAR-related orphan receptor ¥ãt (ROR¥ãt) at the protein level. In experimental autoimmune encephalomyelitis (EAE)-induced mice, treatment with MSC-sEVs was found to not only ameliorate clinical symptoms but also to reduce the number of Th17 cells in draining lymph nodes and the central nervous system. MSC-sEVs were found to destabilize ROR¥ãt by K63 deubiquitination and deacetylation, which was attributed to the EP300-interacting inhibitor of differentiation 3 (Eid3) contained in the MSC-sEVs. Small extracellular vesicles isolated from the Eid3 knockdown MSCs by Eid3-shRNA failed to downregulate ROR¥ãt. Moreover, forced expression of Eid3 by gene transfection was found to significantly decrease the protein level of ROR¥ãt in Th17 cells. Altogether, this study reveals the novel immunosuppressive mechanisms of MSC-sEVs, which suggests the feasibility of MSC-sEVs as an attractive therapeutic tool for curing Th17-mediated inflammatory diseases.
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KEYWORD
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Mesenchymal stem cells, T cells
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