Intracellular osteopontin potentiates the immunosuppressive activity of mesenchymal stromal cells.

IF 7.1 2区 医学 Q1 CELL & TISSUE ENGINEERING
Wanlin Yang, Min Jin, Yuting Gu, Xiaonan Zhao, Lingqiao Zhu, Shan He, Hui Wang, Xinyuan Ding, Bei Wang, Tingwang Jiang, Yichuan Xiao, Guoqiang Zhou, Jiefang Huang, Yanyun Zhang
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引用次数: 0

Abstract

Introduction: Mesenchymal stromal cell (MSC)-based cell therapy is a promising approach for various inflammatory disorders based on their immunosuppressive capacity. Osteopontin (OPN) regulates several cellular functions including tissue repair, bone metabolism and immune reaction. However, the biological function of OPN in regulating the immunosuppressive capacity of MSCs remains elusive.

Objectives: This study aims to highlight the underlying mechanism of the proinflammatory cytokines affect the therapeutic ability of MSCs through OPN.

Methods: MSCs in response to the proinflammatory cytokines were collected to determine the expression profile of OPN. In vitro T-cell proliferation assays and gene editing were performed to check the role and mechanisms of OPN in regulating the immunosuppressive capacity of MSCs. Inflammatory disease mouse models were established to evaluate the effect of OPN on improving MSC-based immunotherapy.

Results: We observed that OPN, including its two isoforms iOPN and sOPN, was downregulated in MSCs upon proinflammatory cytokine stimulation. Interestingly, iOPN, but not sOPN, greatly enhanced the immunosuppressive activity of MSCs on T-cell proliferation and thus alleviated the inflammatory pathologies of hepatitis and colitis. Mechanistically, iOPN interacted with STAT1 and mediated its deubiquitination, thereby inducing the master immunosuppressive mediator inducible nitric oxide synthase (iNOS) in MSCs. In addition, iOPN expression was directly downregulated by activated STAT1, which formed a negative feedback loop to restrain MSC immunosuppressive capacity.

Conclusion: Our findings demonstrated that iOPN expression modulation in MSCs is a novel strategy to improve MSC-based immunotherapy.

细胞内骨质素可增强间充质基质细胞的免疫抑制活性。
导言:基于间充质干细胞(MSC)的免疫抑制能力,以间充质干细胞为基础的细胞疗法是治疗各种炎症性疾病的一种很有前景的方法。骨营养素(OPN)调节多种细胞功能,包括组织修复、骨代谢和免疫反应。然而,OPN 在调节间充质干细胞免疫抑制能力方面的生物学功能仍未确定:本研究旨在揭示促炎细胞因子通过 OPN 影响间充质干细胞治疗能力的内在机制:方法:收集对促炎细胞因子做出反应的间充质干细胞,以确定 OPN 的表达谱。进行体外T细胞增殖试验和基因编辑,以检测OPN在调节间充质干细胞免疫抑制能力中的作用和机制。建立了炎症性疾病小鼠模型,以评估OPN对改善基于间充质干细胞的免疫疗法的影响:结果:我们观察到,在促炎细胞因子刺激下,间充质干细胞中的OPN(包括其两种异构体iOPN和sOPN)被下调。有趣的是,iOPN(而非 sOPN)大大增强了间充质干细胞对 T 细胞增殖的免疫抑制活性,从而缓解了肝炎和结肠炎的炎症病变。从机理上讲,iOPN 与 STAT1 相互作用并介导其去泛素化,从而诱导间充质干细胞中的主要免疫抑制介质诱导型一氧化氮合酶(iNOS)。此外,iOPN的表达被活化的STAT1直接下调,这形成了一个负反馈环,抑制了间充质干细胞的免疫抑制能力:我们的研究结果表明,调节间充质干细胞中 iOPN 的表达是改善间充质干细胞免疫疗法的一种新策略。
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来源期刊
Stem Cell Research & Therapy
Stem Cell Research & Therapy CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
13.20
自引率
8.00%
发文量
525
审稿时长
1 months
期刊介绍: Stem Cell Research & Therapy serves as a leading platform for translational research in stem cell therapies. This international, peer-reviewed journal publishes high-quality open-access research articles, with a focus on basic, translational, and clinical research in stem cell therapeutics and regenerative therapies. Coverage includes animal models and clinical trials. Additionally, the journal offers reviews, viewpoints, commentaries, and reports.
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