Human Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes Loaded Mir-29-3p Targets AhR to Improve Juvenile Idiopathic Arthritis via Inhibiting the Expression of IL-22 in CD4+ T Cell

Xinyi Wei; Kunpeng Sui; Yuanyuan Peng; Sha Li; Yu Fang; Zhi Chen; Xiao Du; Xue Xie; Haiming Tang; QiuYue Wen; JingWei Li; Meilin He; Qin Cheng; Wei Zhang

doi:10.1007/s12015-024-10827-y

Human Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes Loaded Mir-29-3p Targets AhR to Improve Juvenile Idiopathic Arthritis via Inhibiting the Expression of IL-22 in CD4⁺ T Cell

Stem Cell Rev Rep. 2024 Dec 2. doi: 10.1007/s12015-024-10827-y. Online ahead of print.

Authors

Xinyi Wei^#¹, Kunpeng Sui^#¹, Yuanyuan Peng^#¹, Sha Li¹, Yu Fang¹, Zhi Chen¹, Xiao Du¹, Xue Xie¹, Haiming Tang¹, QiuYue Wen¹, JingWei Li¹, Meilin He¹, Qin Cheng¹, Wei Zhang²

Affiliations

¹ Pediatric Immunology and Rheumatology Department, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China.
² Pediatric Immunology and Rheumatology Department, School of Medicine, Chief Physician, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, No.1617, Riyue Avenue, Qingyang District, Chengdu, Sichuan, China. gczhangwei@uestc.edu.cn.

^# Contributed equally.

PMID: 39621151
DOI: 10.1007/s12015-024-10827-y

Abstract

Background: Juvenile idiopathic arthritis (JIA) is one of the most common chronic inflammatory rheumatic diseases in children. Human umbilical cord mesenchymal stem cells (HUCMSCs)-derived exosomes (HUCMSCs-Exos) are involved in autoimmune diseases. This study investigates the mechanism of HUCMSC-Exos in improving JIA by targeting AhR through delivery of miR-29-3p to inhibit IL-22 expression in CD4⁺ T cells.

Methods: Collagen induced arthritis (CIA) mouse model was established, and mice were treated with HUCMSCs-Exos and miR-29-3p antagomir, respectively. CD4⁺ T cells from JIA patients were used for cell experiments. The mechanism was elucidated by histopathological staining, transmission electron microscopy (TEM), immunohistochemistry, CCK-8 assay, flow cytometry, Western blotting, real-time PCR, and enzyme-linked immunosorbent assay (ELISA), laser confocal microscopy, and luciferase assay.

Result: JIA-CD4⁺ T cells showed higher expression of IL-22 and lower the levels of miR-29-3p, while HUCMSCs-Exos significantly inhibited the expression of IL-22 and increased the levels of miR-29a-3p, miR-29b-3p, and miR-29c-3p in CD4⁺ T cells from JIA patients. The expression of miR-29a-3p, miR-29b-3p, miR-29c-3p, AhR, and IL-22 in CD4⁺ T cells was significantly reversed when co-cultured with HUCMSCs transfected with miR-29-3p mimic or miR-29-3p inhibitor. In vivo experiment, HUCMSCs-Exos ameliorated CIA mice by delivering miR-29-3p to inhibit AhR, IL-22, IL-22R1, MMP3, and MMP13 expression. Furthermore, HUCMSCs-Exos also deliver miR-29-3p targeting AhR expression to inhibit IL-22 in JIA-CD4 + T cells through alleviating arthritic synovial fibroblast activation.

Conclusion: HUCMSCs-Exos loaded miR-29-3p targets AhR to improve JIA via inhibiting the expression of IL-22 in CD4⁺ T cell, which provides a scientific basis for the treatment of JIA.

Keywords: Exosomes; Human umbilical cord mesenchymal stem cells; Interleukin-22; Juvenile idiopathic arthritis; MiR-29-3p/AhR.

Abstract

Grants and funding