Gene delivery with IFN-γ-expression plasmids enhances the therapeutic effects of MSCs on DSS-induced mouse colitis
Gene delivery with IFN-γ-expression plasmids enhances the therapeutic effects of MSCs on DSS-induced mouse colitis
复制标题
DOI：
10.1007/s00011-015-0845-6
复制
发表时间：
2015-09-01
影响因子：
6.7
通讯作者：
Hou, Yayi
中科院分区：
文献类型：
--
作者：
Chen, Yueqiu;Song, Yuxian;Hou, Yayi
干扰素-γ可增强间充质干细胞(MSCs)的免疫抑制特性。为探讨干扰素-γ表达载体的基因修饰是否能提高骨髓间充质干细胞对DSS诱导的结肠炎的治疗效果，本研究首先构建了pcDNA3.1-干扰素-γ真核表达载体，并将其导入人脐血来源的骨髓间充质干细胞，检测其免疫表型、细胞活力、增殖、凋亡及细胞周期进程等基本特征。随后，我们分析了干扰素-γ-MSCs对T细胞体外增殖的抑制作用。最后，用3%DSS诱导C57BL/6雌性小鼠结肠炎模型，评价干扰素-γ-MSCs对结肠炎的治疗效果。有趣的是，与正常MSCs相比，干扰素-γ-MSCs对T细胞增殖的免疫抑制作用更强。此外，全身注射干扰素-γ-MSCs能更有效地改善DSS诱导的小鼠结肠炎，包括结肠炎相关性体重减轻、结肠长度增加、疾病活动性指数降低和小肠组织结构改善。此外，干扰素-γ-MSCs还能增加肠系膜淋巴结和脾组织中Foxp3(+)Tregs和Th2细胞的数量，上调吲哚胺2，3-双加氧酶的表达，抑制小鼠结肠炎性细胞因子的产生。本研究为MSCs治疗炎症性疾病提供了一种有效的治疗策略。
Interferon-gamma (IFN-gamma) is known to enhance the immunosuppressive properties of mesenchymal stem cells (MSCs). The aim of this study was to determine whether gene modification with IFN-gamma-expression plasmids could boost the therapeutic effects of MSCs on DSS-induced colitis.We first reconstructed pcDNA3.1-IFN gamma plasmids, transfected them to human umbilical cord derived MSCs, and detected the basic characters of MSCs including immune phenotype, cell vitality, proliferation, apoptosis and cell cycle progression after transfection. Subsequently, we analyzed the inhibition effect of IFN-gamma-MSCs on T cell proliferation in vitro. Finally, we induced colitis in female C57BL/6 mice by 3 % DSS treatment and evaluated the therapeutic efficacy of IFN-gamma-MSCs on colitis.Transfection with pcDNA3.1-IFN gamma did not change the basic characters of MSCs. Interestingly, IFN-gamma-MSCs showed more potent immunosuppressive effects on the proliferation of T cells compared to normal MSCs. Furthermore, systemic infusion with IFN-gamma-MSCs more efficiently ameliorated DSS-induced mouse colitis including colitis-related ease of body weight, increase of colon length, decrease of disease activity index, and improvement of small intestine tissues structure. In addition, IFN-gamma-MSCs increased the populations of Foxp3(+) Tregs and Th2 cells both in mesenteric lymph node and spleen, upregulated indoleamine 2, 3-dioxygenase expression, and suppressed inflammatory cytokine production in mouse colon.Gene delivery with IFN-gamma-expression plasmids enhanced the therapeutic effects of MSCs on DSS-induced mouse colitis. This study provides an effective therapeutic strategy of MSCs for inflammatory diseases.