MSC调控足细胞功能治疗狼疮性肾炎的机制研究

足细胞损伤导致狼疮性肾炎（LN）患者蛋白尿及肾功能进行性丧失，LN足细胞受损机制不明且缺乏有效治疗方法。间充质干细胞（MSC）移植改善LN，但MSC对足细胞损伤的修复机制不明。我们前期研究发现LN患者存在系统和局部免疫细胞亚群和相关细胞因子紊乱，与足细胞损伤相关；MSC移植治疗LN动物模型和患者有效，发挥免疫调控作用，修复足细胞；修饰的MSC（聚集体培养）增强了其旁分泌和免疫调节功能。本项目拟采用单细胞转录子测序等技术筛选介导LN足细胞受损的关键分子，阐明导致足细胞损伤的系统及肾脏局部免疫因素；通过探索促进MSC归巢至肾脏的关键分子，研究MSC对系统及肾脏局部免疫因素的调控，揭示MSC/修饰的MSC改善足细胞功能的机制；进一步通过LN患者的临床研究，明确治疗机制和优化疗效，为提高MSC应用于临床治疗LN患者疗效奠定理论基础。

Podocyte injuries can lead to proteinuria and progressive loss of kidney function in patients with lupus nephritis (LN). The etiology of podocyte injuries in LN is unknown and effective treatment is unavailable. Mesenchymal stem cell (MSC) transplantation has been demonstrated to repair the podocyte injuries in several glomerular diseases. However, the underlying mechanisms of beneficial effects of MSC on podocyte injuries of LN remain to be elucidated. Our previous studies have suggested that systemic and local immune abnormalities were existed in patients with LN and were related to podocyte injuries. MSC transplantation was effective in treating experimental and clinic LN, regulated immune system, and repaired podocytes. Moreover, the paracrine and immune regulation was improved in modified MSC (MSC aggregates). In the current study, we will screen the key molecules through single-cell genome sequencing and determine the specified systemic and local immune factors contributing to podocyte injuries of LN. The strategies to improve homing to kidney of MSC were explored. The regulating effects of MSC on systemic and local immune system were investigated. The mechanisms of MSC/gene-modified MSC on improving podocyte function were explored. The preclinical studies were carried out to verify the mechanisms and improve the effects of MSC transplantation.The findings of the present studies will provide solid evidences for clinical application of MSC transplantation in LN.