Therapeutic effects of CTLA4Ig-overexpressing mesenchymal stem cell-derived extracellular vesicles in a mouse model of rheumatoid arthritis
Abstract Background Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by cartilage damage and bone erosion. Current pharmacological treatments often fail to repair damaged tissues and may cause severe immune-related side effects. Moreover, some patients exhibit inadequate respo...
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| Language: | English |
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BMC
2025-07-01
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| Series: | Stem Cell Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13287-025-04524-x |
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| author | Eun Wha Choi I-Rang Lim Ji Hong Park Jiwoo Song Bongkum Choi Sungjoo Kim |
| author_facet | Eun Wha Choi I-Rang Lim Ji Hong Park Jiwoo Song Bongkum Choi Sungjoo Kim |
| author_sort | Eun Wha Choi |
| collection | DOAJ |
| description | Abstract Background Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by cartilage damage and bone erosion. Current pharmacological treatments often fail to repair damaged tissues and may cause severe immune-related side effects. Moreover, some patients exhibit inadequate responses to existing therapies. This study evaluated the therapeutic potential of extracellular vesicles (EV) derived from immortalized mesenchymal stem cells (iMSCs) overexpressing cytotoxic T lymphocyte-associated antigen-4 immunoglobulin fusion protein (CTLA4Ig) (CT-EV) compared with iMSC-derived EVs (ASC-EV). Methods Following EV characterization and in vitro functional assessments, collagen-induced arthritis (CIA) model mice (n = 10/group) were treated with Dulbecco’s phosphate-buffered saline (dPBS, 150 µL, twice weekly; Group C), ASC-EV (derived from the culture supernatant of 2 × 106 iMSCs/150 µL of dPBS, twice weekly; Group E), CT-EV (derived from the culture supernatant of 2 × 106 CTLA4Ig-overexpressing iMSCs/150 µL of dPBS, twice weekly; Group CT), or methotrexate (3 mg/kg, three times per week; Group M). A normal control group received dPBS (150 µL, twice weekly; Group N). Results CT-EV showed a significant increase in EV quantity and the production of CTLA4, transforming growth factor β1, and interleukin (IL)-1 receptor antagonist compared with ASC-EV. In mitogen-stimulated immune cells from CIA mice, CT-EV significantly reduced IL-6, IL-10, and Regulated upon Activation, Normal T cell Expressed and Presumably Secreted (RANTES) levels. Administration of both ASC-EV and CT-EV led to a decrease in macrophage proportions and an increase in T helper type 2 cells and serum IL-4 levels. Furthermore, CT-EV treatment resulted in additional reductions in anti-CII antibody levels, C-telopeptide II concentrations, and the proportion of CD138⁺ cells, thereby contributing to cartilage protection. Conclusions CT-EV demonstrated superior therapeutic effects compared with ASC-EV in the CIA model, highlighting its potential as an effective treatment strategy for RA. |
| format | Article |
| id | doaj-art-4aca51a599fb4e0da41e7e324014cf68 |
| institution | Kabale University |
| issn | 1757-6512 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Stem Cell Research & Therapy |
| spelling | doaj-art-4aca51a599fb4e0da41e7e324014cf682025-08-20T04:01:53ZengBMCStem Cell Research & Therapy1757-65122025-07-0116111810.1186/s13287-025-04524-xTherapeutic effects of CTLA4Ig-overexpressing mesenchymal stem cell-derived extracellular vesicles in a mouse model of rheumatoid arthritisEun Wha Choi0I-Rang Lim1Ji Hong Park2Jiwoo Song3Bongkum Choi4Sungjoo Kim5Department of Veterinary Clinical Pathology, College of Veterinary Medicine, Institute of Veterinary Science, Kangwon National UniversityDepartment of Veterinary Clinical Pathology, College of Veterinary Medicine, Institute of Veterinary Science, Kangwon National UniversityDepartment of Veterinary Clinical Pathology, College of Veterinary Medicine, Institute of Veterinary Science, Kangwon National UniversityBioanalysis Center, GenNBio IncBioanalysis Center, GenNBio IncGenNBio IncAbstract Background Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by cartilage damage and bone erosion. Current pharmacological treatments often fail to repair damaged tissues and may cause severe immune-related side effects. Moreover, some patients exhibit inadequate responses to existing therapies. This study evaluated the therapeutic potential of extracellular vesicles (EV) derived from immortalized mesenchymal stem cells (iMSCs) overexpressing cytotoxic T lymphocyte-associated antigen-4 immunoglobulin fusion protein (CTLA4Ig) (CT-EV) compared with iMSC-derived EVs (ASC-EV). Methods Following EV characterization and in vitro functional assessments, collagen-induced arthritis (CIA) model mice (n = 10/group) were treated with Dulbecco’s phosphate-buffered saline (dPBS, 150 µL, twice weekly; Group C), ASC-EV (derived from the culture supernatant of 2 × 106 iMSCs/150 µL of dPBS, twice weekly; Group E), CT-EV (derived from the culture supernatant of 2 × 106 CTLA4Ig-overexpressing iMSCs/150 µL of dPBS, twice weekly; Group CT), or methotrexate (3 mg/kg, three times per week; Group M). A normal control group received dPBS (150 µL, twice weekly; Group N). Results CT-EV showed a significant increase in EV quantity and the production of CTLA4, transforming growth factor β1, and interleukin (IL)-1 receptor antagonist compared with ASC-EV. In mitogen-stimulated immune cells from CIA mice, CT-EV significantly reduced IL-6, IL-10, and Regulated upon Activation, Normal T cell Expressed and Presumably Secreted (RANTES) levels. Administration of both ASC-EV and CT-EV led to a decrease in macrophage proportions and an increase in T helper type 2 cells and serum IL-4 levels. Furthermore, CT-EV treatment resulted in additional reductions in anti-CII antibody levels, C-telopeptide II concentrations, and the proportion of CD138⁺ cells, thereby contributing to cartilage protection. Conclusions CT-EV demonstrated superior therapeutic effects compared with ASC-EV in the CIA model, highlighting its potential as an effective treatment strategy for RA.https://doi.org/10.1186/s13287-025-04524-xAutoimmune diseasesCTLA4IgCollagen-induced arthritisExtracellular vesiclesMesenchymal stem cellRheumatoid arthritis |
| spellingShingle | Eun Wha Choi I-Rang Lim Ji Hong Park Jiwoo Song Bongkum Choi Sungjoo Kim Therapeutic effects of CTLA4Ig-overexpressing mesenchymal stem cell-derived extracellular vesicles in a mouse model of rheumatoid arthritis Stem Cell Research & Therapy Autoimmune diseases CTLA4Ig Collagen-induced arthritis Extracellular vesicles Mesenchymal stem cell Rheumatoid arthritis |
| title | Therapeutic effects of CTLA4Ig-overexpressing mesenchymal stem cell-derived extracellular vesicles in a mouse model of rheumatoid arthritis |
| title_full | Therapeutic effects of CTLA4Ig-overexpressing mesenchymal stem cell-derived extracellular vesicles in a mouse model of rheumatoid arthritis |
| title_fullStr | Therapeutic effects of CTLA4Ig-overexpressing mesenchymal stem cell-derived extracellular vesicles in a mouse model of rheumatoid arthritis |
| title_full_unstemmed | Therapeutic effects of CTLA4Ig-overexpressing mesenchymal stem cell-derived extracellular vesicles in a mouse model of rheumatoid arthritis |
| title_short | Therapeutic effects of CTLA4Ig-overexpressing mesenchymal stem cell-derived extracellular vesicles in a mouse model of rheumatoid arthritis |
| title_sort | therapeutic effects of ctla4ig overexpressing mesenchymal stem cell derived extracellular vesicles in a mouse model of rheumatoid arthritis |
| topic | Autoimmune diseases CTLA4Ig Collagen-induced arthritis Extracellular vesicles Mesenchymal stem cell Rheumatoid arthritis |
| url | https://doi.org/10.1186/s13287-025-04524-x |
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