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miRNA-148a-containing GMSC-derived EVs modulate Treg/Th17 balance via IKKB/NF-κB pathway and treat a rheumatoid arthritis model.
- Source :
-
JCI insight [JCI Insight] 2024 Apr 23; Vol. 9 (10). Date of Electronic Publication: 2024 Apr 23. - Publication Year :
- 2024
-
Abstract
- Mesenchymal stem cells (MSCs) have demonstrated potent immunomodulatory properties that have shown promise in the treatment of autoimmune diseases, including rheumatoid arthritis (RA). However, the inherent heterogeneity of MSCs triggered conflicting therapeutic outcomes, raising safety concerns and limiting their clinical application. This study aimed to investigate the potential of extracellular vesicles derived from human gingival mesenchymal stem cells (GMSC-EVs) as a therapeutic strategy for RA. Through in vivo experiments using an experimental RA model, our results demonstrate that GMSC-EVs selectively homed to inflamed joints and recovered Treg and Th17 cell balance, resulting in the reduction of arthritis progression. Our investigations also uncovered miR-148a-3p as a critical contributor to the Treg/Th17 balance modulation via IKKB/NF-κB signaling orchestrated by GMSC-EVs, which was subsequently validated in a model of human xenograft versus host disease (xGvHD). Furthermore, we successfully developed a humanized animal model by utilizing synovial fibroblasts obtained from patients with RA (RASFs). We found that GMSC-EVs impeded the invasiveness of RASFs and minimized cartilage destruction, indicating their potential therapeutic efficacy in the context of patients with RA. Overall, the unique characteristics - including reduced immunogenicity, simplified administration, and inherent ability to target inflamed tissues - position GMSC-EVs as a viable alternative for RA and other autoimmune diseases.
- Subjects :
- Humans
Animals
Mice
I-kappa B Kinase metabolism
Signal Transduction
Disease Models, Animal
Gingiva cytology
Gingiva metabolism
Gingiva pathology
Gingiva immunology
Male
Fibroblasts metabolism
Arthritis, Rheumatoid therapy
Arthritis, Rheumatoid immunology
Arthritis, Rheumatoid metabolism
Th17 Cells immunology
Th17 Cells metabolism
MicroRNAs genetics
MicroRNAs metabolism
NF-kappa B metabolism
T-Lymphocytes, Regulatory immunology
T-Lymphocytes, Regulatory metabolism
Mesenchymal Stem Cells metabolism
Mesenchymal Stem Cells immunology
Extracellular Vesicles metabolism
Extracellular Vesicles transplantation
Subjects
Details
- Language :
- English
- ISSN :
- 2379-3708
- Volume :
- 9
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- JCI insight
- Publication Type :
- Academic Journal
- Accession number :
- 38652539
- Full Text :
- https://doi.org/10.1172/jci.insight.177841