在体外使用三种多发性硬化症疾病调节疗法对炎性少突胶质祖细胞进行药理调节。

IF 8.3 2区 材料科学 Q1 MATERIALS SCIENCE, MULTIDISCIPLINARY ACS Applied Materials & Interfaces Pub Date : 2024-07-01 DOI:10.1016/j.neurot.2024.e00379
Larissa Jank , Riley B. Catenacci , Veronica Minney , Danny Galleguillos , Peter A. Calabresi
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引用次数: 0

摘要

针对多发性硬化症的促进髓鞘再生疗法的临床前研究往往忽视了与疾病相关的炎症环境的影响。众所周知,γ干扰素(IFN-γ)会抑制少突胶质祖细胞(OPC)的分化,并诱导最近描述的以表达主要组织相容性复合体(MHC)分子为特征的免疫OPC(iOPC)表型。我们测试了克拉利宾(CDB)、富马酸二甲酯(DMF)和干扰素-β(IFN-β)(治疗多发性硬化症的现有抗炎疗法)对 IFN-γ 诱导的 iOPC 形成和 OPC 分化受阻的影响。与之前的报告一致,我们证明 IFN-β 和 DMF 可抑制 OPC 的增殖,而 CDB 则没有影响。在体外测试的生理浓度下,没有一种药物表现出细胞毒性作用。在分化试验中,无论是在炎症条件下还是在基础条件下,没有一种药物能促进分化。为了研究药物对 iOPC 的影响,我们使用从 MHC 报告小鼠体内分离的细胞,通过活细胞成像技术在体外监测 MHC 的表达。IFN-β 抑制了 MHC II 类的诱导,而 DMF 则抑制了 I 类和 II 类的诱导。CDB 对 MHC 诱导没有影响。我们的结论是,在炎症条件下,促进增殖和分化以及抑制 iOPC 诱导可能需要不同的治疗策略,而且必须保持平衡才能实现最大修复。我们的体外 MHC 筛选试验可用于不同类型的细胞,以测试候选药物和疾病相关刺激的效果。
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Pharmacological modulation of inflammatory oligodendrocyte progenitor cells using three multiple sclerosis disease modifying therapies in vitro

Preclinical studies of pro-remyelinating therapies for multiple sclerosis tend to neglect the effect of the disease-relevant inflammatory milieu. Interferon-gamma (IFN-γ) is known to suppress oligodendrocyte progenitor cell (OPC) differentiation and induce a recently described immune OPC (iOPC) phenotype characterized by expression of major histocompatibility complex (MHC) molecules. We tested the effects of cladribine (CDB), dimethylfumarate (DMF), and interferon-beta (IFN-β), existing anti-inflammatory therapies for MS, on the IFN-γ-induced iOPC formation and OPC differentiation block. In line with previous reports, we demonstrate that IFN-β and DMF inhibit OPC proliferation, while CDB had no effect. None of the drugs exhibited cytotoxic effects at the physiological concentrations tested in vitro. In a differentiation assay, none of the drugs were able to promote differentiation, under inflammatory or basal conditions. To study drug effects on iOPCs, we monitored MHC expression in vitro with live cell imaging using cells isolated from MHC reporter mice. IFN-β suppressed induction of MHC class II, and DMF led to suppression of both class I and II. CDB had no effect on MHC induction. We conclude that promoting proliferation and differentiation and suppressing iOPC induction under inflammatory conditions may require separate therapeutic strategies and must be balanced for maximal repair. Our in vitro MHC screening assay can be leveraged across cell types to test the effects of drug candidates and disease-related stimuli.

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来源期刊
ACS Applied Materials & Interfaces
ACS Applied Materials & Interfaces 工程技术-材料科学:综合
CiteScore
16.00
自引率
6.30%
发文量
4978
审稿时长
1.8 months
期刊介绍: ACS Applied Materials & Interfaces is a leading interdisciplinary journal that brings together chemists, engineers, physicists, and biologists to explore the development and utilization of newly-discovered materials and interfacial processes for specific applications. Our journal has experienced remarkable growth since its establishment in 2009, both in terms of the number of articles published and the impact of the research showcased. We are proud to foster a truly global community, with the majority of published articles originating from outside the United States, reflecting the rapid growth of applied research worldwide.
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