Knockdown of MicroRNA Let-7a Improves the Functionality of Bone Marrow-Derived Mesenchymal Stem Cells in Immunotherapy
Knockdown of MicroRNA Let-7a Improves the Functionality of Bone Marrow-Derived Mesenchymal Stem Cells in Immunotherapy
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MicroRNA Let-7a 的敲低可改善骨髓间充质干细胞在免疫治疗中的功能
DOI：
10.1016/j.ymthe.2016.11.015
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发表时间：
2017
影响因子：
12.4
通讯作者：
Jin Yan
中科院分区：
文献类型：
--
作者：
Yu Yang;Liao Li;Shao Bingyi;Su Xiaoxia;Shuai Yi;Wang Han;Shang Fengqing;Zhou Zhifei;Yang Deqin;Jin Yan
骨髓间充质干细胞（MSCs）近年来已被用于临床治疗炎症性疾病。MSC免疫治疗迫切需要改善MSC免疫抑制特性的实用策略。在这项研究中，我们的目的是开发一种基于microRNA的策略来改善MSC免疫治疗。生物信息学分析表明let-7a靶向于Fas和FasL mRNA的3′ UTR，这两个基因是MSCs诱导T细胞凋亡所必需的。通过特异性抑制剂敲低let-7a使MSC中的Fas和Fas配体（FasL）蛋白水平加倍。由于Fas吸引T细胞迁移和FasL诱导T细胞凋亡，let-7a的敲低显著促进MSC诱导的T细胞迁移和凋亡在体外和体内。重要的是，敲低let-7a的MSC更有效地降低实验性结肠炎和移植物抗宿主病（GVHD）小鼠模型的死亡率，防止体重减轻，抑制炎症反应，并减轻组织病变。总之，let-7a的敲低显著提高了MSC细胞疗法对炎症性肠病和GVHD的治疗效果。let-7a基因敲除具有安全性高、操作简便等优点，有望为临床MSC治疗炎症性疾病提供新的思路。
Bone marrow-derived mesenchymal stem cells (MSCs) have been recently used in clinical treatment of inflammatory diseases. Practical strategies improving the immunosuppressive property of MSCs are urgently needed for MSC immunotherapy. In this study, we aimed to develop a microRNA-based strategy to improve MSC immunotherapy. Bioinformatic analysis revealed that let-7a targeted the 3′ UTR of mRNA ofFasandFasL, both of which are essential for MSCs to induce T cell apoptosis. Knockdown of let-7a by specific inhibitor doubled Fas and Fas ligand (FasL) protein levels in MSCs. Because Fas attracts T cell migration and FasL induces T cell apoptosis, knockdown of let-7a significantly promoted MSC-induced T cell migration and apoptosis in vitro and in vivo. Importantly, MSCs knocked down of let-7a were more efficient to reduce the mortality, prevent the weight loss, suppress the inflammation reaction, and alleviate the tissue lesion of experimental colitis and graft-versus-host disease (GVHD) mouse models. In conclusion, knockdown of let-7a significantly improved the therapeutic effect of MSC cytotherapy on inflammatory bowel diseases and GVHD. With high safety and convenience, knockdown of let-7a is a potential strategy to improve MSC therapy for inflammatory diseases in clinic.