Yu Yang, Liao Li, Shao Bingyi, Su Xiaoxia, Shuai Yi, Wang Han, Shang Fengqing, Zhou Zhifei, Yang Deqin, Jin Yan
State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China; Stomatological Hospital of Chongqing Medical University, Chongqing 401147, China; Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, China; Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China.
State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China; Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi 710032, China; State Key Laboratory of Military Stomatology, Department of Oral Histology and Pathology, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
Mol Ther. 2017 Feb 1;25(2):480-493. doi: 10.1016/j.ymthe.2016.11.015. Epub 2016 Dec 28.
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 of Fas and FasL, 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.
骨髓间充质干细胞（MSCs）最近已被用于炎症性疾病的临床治疗。MSCs免疫疗法迫切需要提高MSCs免疫抑制特性的实用策略。在本研究中，我们旨在开发一种基于微小RNA的策略来改善MSCs免疫疗法。生物信息学分析表明，let-7a靶向Fas和FasL mRNA的3'UTR，这两者对于MSCs诱导T细胞凋亡至关重要。用特异性抑制剂敲低let-7a可使MSCs中Fas和Fas配体（FasL）蛋白水平加倍。由于Fas吸引T细胞迁移而FasL诱导T细胞凋亡，敲低let-7a在体外和体内均显著促进了MSCs诱导的T细胞迁移和凋亡。重要的是，敲低let-7a的MSCs在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、抑制炎症反应以及减轻组织损伤方面更有效。总之，敲低let-7a显著改善了MSCs细胞疗法对炎症性肠病和GVHD的治疗效果。敲低let-7a具有高安全性和便利性，是临床上改善MSCs治疗炎症性疾病的潜在策略。
