miRNA-148a–containing GMSC-derived EVs modulate Treg/Th17 balance via IKKB/NF-κB pathway and treat a rheumatoid arthritis model
Jingrong Chen, Xiaoyi Shi, Yanan Deng, Junlong Dang, Yan Liu, Jun Zhao, Rongzhen Liang, Donglan Zeng, Wenbin Wu, Yiding Xiong, Jia Yuan, Ye Chen, Julie Wang, Weidong Lin, Xiangfang Chen, Weishan Huang, Nancy Olsen, Yunfeng Pan, Qingling Fu, Song Guo Zheng
Jingrong Chen, Xiaoyi Shi, Yanan Deng, Junlong Dang, Yan Liu, Jun Zhao, Rongzhen Liang, Donglan Zeng, Wenbin Wu, Yiding Xiong, Jia Yuan, Ye Chen, Julie Wang, Weidong Lin, Xiangfang Chen, Weishan Huang, Nancy Olsen, Yunfeng Pan, Qingling Fu, Song Guo Zheng
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Research Article Stem cells

miRNA-148a–containing GMSC-derived EVs modulate Treg/Th17 balance via IKKB/NF-κB pathway and treat a rheumatoid arthritis model

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.

Authors

Jingrong Chen, Xiaoyi Shi, Yanan Deng, Junlong Dang, Yan Liu, Jun Zhao, Rongzhen Liang, Donglan Zeng, Wenbin Wu, Yiding Xiong, Jia Yuan, Ye Chen, Julie Wang, Weidong Lin, Xiangfang Chen, Weishan Huang, Nancy Olsen, Yunfeng Pan, Qingling Fu, Song Guo Zheng

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Figure 8

GMSC-derived EVs protect against inflamed synovial fibroblast–mediated humanized animal model.

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GMSC-derived EVs protect against inflamed synovial fibroblast–mediated h...
(A) Schematic experimental set-up for RASF-mediated humanized animal model. In the first operation, SCID mice were implanted with a cartilage-sponge complex under the left flank skin (primary implant). After 2 weeks, individual 5 × 105 CM-DiI-labeled RASFs, 2 × 106 GMSCs, and/or 100 μg GMSC-EVs were injected into the cartilage-sponge complex, and the implant was inserted into a s.c. space in the right flank skin (contralateral implant). (B and C) At day 60, the primarily and contralateral cartilages were collected, and the mean fluorescence intensity (MFI) of CM-DiI–labeled RASFs in primarily cartilages were quantified using ImageJ software to evaluate the invasiveness of contralateral RASFs after treatment with GMSCs or GMSC-EVs. Scale bars = 500 μm. (D and E) The contralateral and primary cartilages were collected and subjected to H&E staining to assess the invasiveness scores of inflammatory cells and the destruction of cartilages. The red arrows indicated the lesions of cartilage destruction caused by RASFs. Scale bars = 200 μm. Statistical significance was assessed by 1-way ANOVA with Dunnett multiple-comparison test in B–E. Data are mean ± SD, n = 5–6 mice. ****P < 0.0001.