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.

IF 4.5 3区医学 Q2 CELL & TISSUE ENGINEERING Stem Cell Reviews and Reports Pub Date : 2024-12-02 DOI:10.1007/s12015-024-10827-y

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

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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.

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载Mir-29-3p的人脐带间充质干细胞衍生外泌体通过抑制CD4+ T细胞中IL-22的表达来靶向AhR改善幼年特发性关节炎

背景：青少年特发性关节炎（JIA）是儿童最常见的慢性炎症性风湿病之一。人脐带间充质干细胞（HUCMSCs）来源的外泌体（HUCMSCs- exos）参与自身免疫性疾病。本研究探讨了HUCMSC-Exos通过递送miR-29-3p抑制IL-22在CD4+ T细胞中的表达，靶向AhR改善JIA的机制。方法：建立胶原诱导关节炎（CIA）小鼠模型，分别用HUCMSCs-Exos和miR-29-3p antagomir治疗小鼠。采用JIA患者CD4+ T细胞进行细胞实验。通过组织病理学染色、透射电镜（TEM）、免疫组织化学、CCK-8实验、流式细胞术、Western blotting、实时荧光定量PCR、酶联免疫吸附实验（ELISA）、激光共聚焦显微镜和荧光素酶实验来阐明其作用机制。结果JIA-CD4+ T细胞IL-22表达升高，miR-29-3p水平降低，而HUCMSCs-Exos显著抑制JIA患者CD4+ T细胞IL-22表达，miR-29a-3p、miR-29b-3p、miR-29c-3p水平升高。与转染miR-29-3p mimic或miR-29-3p inhibitor的HUCMSCs共培养后，CD4+ T细胞中miR-29a-3p、miR-29b-3p、miR-29c-3p、AhR和IL-22的表达显著逆转。在体内实验中，HUCMSCs-Exos通过传递miR-29-3p来抑制AhR、IL-22、IL-22R1、MMP3和MMP13的表达，从而改善了CIA小鼠。此外，HUCMSCs-Exos还传递靶向AhR表达的miR-29-3p，通过减轻关节炎滑膜成纤维细胞激活来抑制JIA-CD4 + T细胞中的IL-22。结论：载miR-29-3p的HUCMSCs-Exos通过抑制CD4+ T细胞中IL-22的表达，靶向AhR改善JIA，为JIA的治疗提供科学依据。

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来源期刊

Stem Cell Reviews and Reports 医学-细胞生物学

CiteScore

9.30

自引率

4.20%

发文量

审稿时长

3 months

期刊介绍： The purpose of Stem Cell Reviews and Reports is to cover contemporary and emerging areas in stem cell research and regenerative medicine. The journal will consider for publication: i) solicited or unsolicited reviews of topical areas of stem cell biology that highlight, critique and synthesize recent important findings in the field. ii) full length and short reports presenting original experimental work. iii) translational stem cell studies describing results of clinical trials using stem cells as therapeutics. iv) papers focused on diseases of stem cells. v) hypothesis and commentary articles as opinion-based pieces in which authors can propose a new theory, interpretation of a controversial area in stem cell biology, or a stem cell biology question or paradigm. These articles contain more speculation than reviews, but they should be based on solid rationale. vi) protocols as peer-reviewed procedures that provide step-by-step descriptions, outlined in sufficient detail, so that both experts and novices can apply them to their own research. vii) letters to the editor and correspondence. In order to facilitate this exchange of scientific information and exciting novel ideas, the journal has created five thematic sections, focusing on: i) the role of adult stem cells in tissue regeneration; ii) progress in research on induced pluripotent stem cells, embryonic stem cells and mechanism governing embryogenesis and tissue development; iii) the role of microenvironment and extracellular microvesicles in directing the fate of stem cells; iv) mechanisms of stem cell trafficking, stem cell mobilization and homing with special emphasis on hematopoiesis; v) the role of stem cells in aging processes and cancerogenesis.