iNOS Activity Is Required for the Therapeutic Effect of Mesenchymal Stem Cells in Experimental Systemic Sclerosis
iNOS Activity Is Required for the Therapeutic Effect of Mesenchymal Stem Cells in Experimental Systemic Sclerosis
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DOI：
10.3389/fimmu.2018.03056
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发表时间：
2018-12-21
影响因子：
7.3
通讯作者：
Noel, Daniele
中科院分区：
文献类型：
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作者：
Maria, Alexandre T. J.;Rozier, Pauline;Noel, Daniele
目的：纤维化是系统性硬化症（SSc）的一个标志，SSc是一种难治性疾病，目前仍在寻求创新的治疗策略。在新的抗纤维化方法中，基于间充质基质/干细胞（MSC）的治疗似乎很有前途。以前，我们报道了MSC在SSc实验模型中的抗纤维化作用，通过各种机制（组织重塑，免疫调节，抗氧化防御）。由于免疫调节是一个关键的机制，MSC的治疗效果，我们研究了与MSC免疫抑制特性的关键分子的具体作用，并假设这些分子的MSC缺陷将是有效减少纤维化SSc.Methods：SSc诱导6周每日皮内注射次氯酸盐（HOCI）在小鼠中。从野生型小鼠（WT）或IL 1 RA、IL 6或iNOS敲除小鼠（分别为IL 1 RA（-/-）、IL 6（-/-）或iNOS（-/-）MSC）的骨髓中分离MSC。在第21天，接种小鼠接受2.5 × 105 MSC静脉输注。结果：IL 1 RA（-/-）和IL 6（-/-）MSC具有与WT MSC相似的抗纤维化作用，皮肤厚度减少，胶原沉积减少。相反，iNOS（-/-）MSC不发挥抗纤维化功能，如通过与未处理的HOCI-SSc小鼠相似的皮肤厚度进展所示。与WT MSC相比，iNOS（-/-）MSC保持了一些免疫抑制和组织重塑的属性，但失去了他们的能力，以减少氧化应激HOCI-SSc mice.Conclusion：我们的研究突出了至关重要的作用，iNOS，其活性所需的MSC在实验SSc的抗纤维化特性，特别强调NO相关的抗氧化功能。
Objectives: Fibrosis is a hallmark of systemic sclerosis (SSc), an intractable disease where innovative strategies are still being sought. Among novel anti-fibrotic approaches, mesenchymal stromal/stem cell (MSC)-based therapy appears promising. Previously, we reported anti-fibrotic effects of MSC in an experimental model of SSc, through various mechanisms (tissue remodeling, immunomodulation, anti-oxidant defense). Since immunomodulation is a pivotal mechanism for MSC therapeutic effects, we investigated the specific role of critical molecules associated with MSC immunosuppressive properties and hypothesized that MSC defective for these molecules would be less effective in reducing fibrosis in SSc.Methods: SSc was induced by 6-week daily intradermal injections of hypochlorite (HOCI) in mice. MSC were isolated from the bone marrow of wild type mice (WT) or mice knockout for IL1RA, IL6, or iNOS (IL1RA(-/-), IL6(-/-), or iNOS(-/-) MSC, respectively). Treated-mice received 2.5 x 10(5) MSC intravenous infusion at d21. Skin thickness, histological and biological parameters were evaluated in skin and blood at d42.Results: IL1RA(-/-) and IL6(-/-) MSC exerted similar anti-fibrotic properties as WT MSC, with a reduction of skin thickness together with less collagen deposition. Conversely, iNOS(-/-) MSC did not exert anti-fibrotic functions as shown by a similar skin thickness progression as non-treated HOCI-SSc mice. Compared with WT MSC, iNOS(-/-) MSC kept some immunosuppressive and tissue remodeling properties, but lost their capacity to reduce oxidative stress in HOCI-SSc mice.Conclusion: Our study highlights the crucial role of iNOS, whose activity is required for the anti-fibrotic properties of MSC in experimental SSc, with a special emphasis on NO-related anti-oxidant functions.