Overexpression of soluble RAGE in mesenchymal stem cells enhances their immunoregulatory potential for cellular therapy in autoimmune arthritis.
Overexpression of soluble RAGE in mesenchymal stem cells enhances their immunoregulatory potential for cellular therapy in autoimmune arthritis.
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DOI：
10.1038/srep35933
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发表时间：
2016-11-02
影响因子：
4.6
通讯作者：
Cho ML
中科院分区：
文献类型：
--
作者：
Park MJ;Lee SH;Moon SJ;Lee JA;Lee EJ;Kim EK;Park JS;Lee J;Min JK;Kim SJ;Park SH;Cho ML
间充质干细胞(MSCs)是类风湿性关节炎(RA)细胞治疗的诱导剂。晚期糖基化终末产物受体(RAGE)是内源性炎症配体的模式识别受体。可溶性RAGE(SRAGE)是RAGE的一种截断形式，起着诱饵和抗炎分子的作用。本研究的目的是确定SRAGE是否具有治疗作用，以及在RA实验模型中高表达SRAGE的MSCs(SRAGE-MSCs)的作用机制。人脂肪组织来源的骨髓间充质干细胞(Ad-hMSCs)经DNA转染法获得sRAGE-MSCs。炎症条件下骨髓间充质干细胞表达血管内皮生长因子、IL-1β、IL-6和hMGB-1。然而，SRAGE-MSCs显示这些促炎分子的产生明显减少。免疫调节分子IL-10、转化生长因子-β和吲哚-2，3-双加氧酶在sRAGE-MSCs中的表达高于对照组。SRAGE-MSCs显示出更强的迁移潜能。将sRAGE-MSCs移植到关节炎IL-1ra基因敲除小鼠可显著抑制炎性关节炎，减少Th17细胞，并反过来增加调节性T细胞。与对照组相比，sRAGE-MSCs对干扰素-γ+和IL-17+CD4+细胞的分化均有抑制作用。这些发现表明，在Ad-hMSCs中过表达sRAGE可以优化其免疫调节特性，这可能是一种治疗类风湿关节炎的新细胞疗法。
Mesenchymal stem cells (MSCs) are attractive agents for cellular therapy in rheumatoid arthritis (RA). The receptor for advanced glycation end products (RAGE) serves as a pattern recognition receptor for endogenous inflammatory ligands. Soluble RAGE (sRAGE) is a truncated form of RAGE that functions as a decoy and acts as an anti-inflammatory molecule. The aim of this study was to determine whether sRAGE has therapeutic effects and the mechanisms active in sRAGE-overexpressing MSCs (sRAGE-MSCs) in an experimental model of RA. sRAGE-MSCs were generated by DNA transfection of human adipose tissue-derived MSCs (Ad-hMSCs). MSCs showed increased expression of VEGF, IL-1β, IL-6, and HMGB-1 under inflammatory conditions. However, sRAGE-MSCs showed significantly lower production of these proinflammatory molecules. Expression of immunomodulatory molecules such as IL-10, TGF-β, and indoleamine 2, 3-dioxygenase was higher in sRAGE-MSCs than in mock-MSCs. sRAGE-MSCs showed enhanced migration potential. Transplantation of sRAGE-MSCs into arthritic IL-1Ra-knockout mice markedly suppressed inflammatory arthritis, decreased Th17 cells, and reciprocally increased regulatory T cells. The differentiation of IFN-γ+CD4+ and IL-17+CD4+ cells was inhibited by incubation with sRAGE-MSCs compared with mock-MSCs. These findings suggest that sRAGE overexpression in Ad-hMSCs optimizes their immunoregulatory properties, which may be useful as a novel cellular therapy for RA.
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DOI：
10.1155/2011/765624
发表时间：
2011
期刊：
Arthritis
影响因子：
--
作者：
Hashizume M;Mihara M
通讯作者：
Mihara M
影响因子：
--
作者：
Gonzalez, Manuel A.;Gonzalez-Rey, Elena;Delgado, Mario
通讯作者：
Delgado, Mario
影响因子：
14.8
作者：
Fantini, Massimo C.;Dominitzki, Sabine;Becker, Christoph
通讯作者：
Becker, Christoph
影响因子：
7.3
作者：
Chatterjee, Debanjana;Marquardt, Nicole;Jacobs, Roland
通讯作者：
Jacobs, Roland
调节性T细胞在类风湿关节炎和抗TNFALPHA治疗中的逆转功能受损。
影响因子：
15.3
作者：
Ehrenstein, MR;Evans, JG;Singh, A;Moore, S;Warnes, G;Isenberg, DA;Mauri, C
通讯作者：
Mauri, C