miR-663下调TGF-β1对SLE骨髓MSCs功能的影响及机制研究

Our previous study demonstrated that bone marrow derived mesenchymal stem cells (MSCs) in patients with systemic lupus erythematosus (SLE) are defective structurally and functionally, which may be involved in disease onset, allogeneic MSCs transplantation has significant therapeutic effects on lupus mice and humans, but the mechanisms of them are not clear yet. The expression imbalance of microRNAs(miRNAs) can cause cell dysfunction, which participates in a variety of diseases development. Transforming growth factor-beta1 (TGF-β1) is an important negative immune regulatory factors secreted by MSCs, which is also closely related to functions of MSCs. Our previous experiments found that the expressions of miR-663 are markedly up-regulated in MSCs of SLE patients, and the synthesis of TGF-β1 is significantly lower in MSCs of SLE patients compared to normal controls, while TGF-β1 is an important computer predicted target of miR-663. The project is planned to further investigate whether miR-663 can play its role in MSCs by directly down-regulating TGF-β1 mRNA and its specific regulatory mechanism, to determine whether the abnormalities of this process can lead to SLE MSCs dysfunction, to further understand the pathogenesis of SLE, to look for interventional targets, and provide the experimental basis for allogeneic MSCs transplantation in the treatment of SLE patients.

我们前期研究发现系统性红斑狼疮(SLE)患者骨髓间充质干细胞（MSCs）存在异常，可能参与其发病，异基因MSCs移植治疗SLE疗效显著，但其作用机制尚不清楚。MicroRNAs（miRNAs）表达失调可致细胞功能异常，从而参与多种疾病发生发展。转化生长因子（TGF）-β1为MSCs分泌的重要免疫调控因子，与MSCs功能关系密切。我们前期发现SLE患者 MSCs中miR-663表达明显上调，且其合成TGF-β1显著低于正常人，而TGF-β1为miR-663的重要预测靶点。本项目拟深入探讨miR-663能否通过下调TGF-β1发挥其对MSCs的作用及其调控机制，弄清SLE MSCs功能异常是否与这一过程失调相关，深入认识SLE发病机制，寻求更有效的疾病干预靶点，为临床推广异基因MSCs移植治疗SLE提供实验依据。

间充质干细胞（MSC）具有重要的免疫调节作用。尽管已经显示几种微小RNA（miRNA）通过影响淋巴细胞的发育和功能而参与自身免疫性疾病的发生，但miRNA在自身免疫疾病MSC功能障碍中的作用仍不清楚。我们的研究发现，与正常对照相比，系统性红斑狼疮（SLE）患者骨髓衍生MSC（BMSC）中的miRNA有其独特的特征，其中miR-663与SLE疾病活性密切相关。 MiR-663抑制BMSCs的增殖和迁移，通过靶向转化生长因子β1（TGF-β1），损伤BMSC介导的滤泡T辅助细胞（Tfh）下调和调节性T细胞（Treg）上调。 MiR-663过表达减弱了BMSCs的治疗效果，而抑制miR-663促进了MRL / lpr狼疮小鼠疾病的缓解。因此，miR-663是SLE骨髓间充质干细胞调控的关键因子，可能成为治疗狼疮的新靶点。