Mesenchymal stem cell-derived extracellular vesicles subvert Th17 cells by destabilizing RORγt through posttranslational modification

• Published in: Experimental & molecular medicine 2023, 55(0), , pp.665-679
• Main Authors: Jung, Sunyoung, Lee, Sunho, Kim, Hyun Je, Kim, Sueon, Moon, Ji Hwan, Chung, Hyunwoo, Kang, Seong-Jun, Park, Chung-Gyu
• Format: Article
• Language: English
• Subjects: 13/100; 13/109; 13/31; 13/51; 14/19; 38/77; 631/250/1619/554; 631/532/2074; 64/60; Animals; Autoimmune diseases; Biomedical and Life Sciences; Biomedicine; Cell activation; Cell Differentiation - genetics; Central nervous system; Deacetylation; Encephalomyelitis, Autoimmune, Experimental; Experimental allergic encephalomyelitis; Extracellular vesicles; Extracellular Vesicles - metabolism; Helper cells; Immunotherapy; Inflammatory diseases; Interleukin 17; Lymph nodes; Lymphocytes T; Medical Biochemistry; Membrane vesicles; Mesenchymal stem cells; Mesenchymal Stem Cells - metabolism; Mice; Molecular Medicine; Nuclear Receptor Subfamily 1, Group F, Member 3 - genetics; Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism; Protein Processing, Post-Translational; Psoriasis; Stem Cells; Th17 Cells; Transfection; 생화학
• ISSN: 2092-6413; 1226-3613; 2092-6413
• DOI: 10.1038/s12276-023-00949-7

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 γt (RORγt) 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 RORγt 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 RORγt. Moreover, forced expression of Eid3 by gene transfection was found to significantly decrease the protein level of RORγt 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. Autoimmune disease: Stem cell vesicles have therapeutic potential Tiny membrane-bound vesicles derived from certain stem cells could provide effective therapy for a range of autoimmune conditions. Adult or mesenchymal stem cells (MSCs) in the bone marrow, fat, and other tissues have shown promise in immunotherapy which is associated with the secretion of biomolecule-laden structures known as extracellular vesicles. Chung-Gyu Park, Seoul National University, South Korea, and colleagues have now helped clarify a likely therapeutic mechanism. The authors showed marked relief of symptoms in a mouse model of autoimmune disease upon treatment with MSC-derived vesicles and linked this effect to reduced levels of immune cells known as TH17 cells. Further analysis revealed that these vesicles selectively suppress the production and activation of TH17 cells, which generally play a prominent role in exacerbating various autoimmune diseases including lupus and psoriasis.