EPO基因修饰MSC来源的微泡治疗慢性肾衰竭的基础研究

In our previous study, more than 276 kinds of miRNA, including miR200 and miR29 families, have been detected in the microvesicles (MV) derived from mesenchymal stem cells (MSC). And we have found that MV released from MSC may account for mitigating injury or favouring repair in the impaired kidney. Additionally several observations have demonstrated that erythropoietin (EPO) could ameliorate renal anemia and renal injury, as well as enhance the vitality of MSC. Therefore, the present project aims to explore the role of MV derived from MSC modified with EPO gene by novel self-complementary AAV (EPO-MSC-MV) in the treatment of chronic renal failure (CRF). The study follows the latest progress in the field of MSC and MV therapy and the international forefront of gene therapy in the area of AAV vectors. This study will focus on: (1) exploring the function of MSC-MV in the renal restoration of chronic kidney injury; (2) determining whether EPO-MSC-MV could repair renal injury better than MSC-MV; (3) investigating the possible renal repair functions and mechanisms associated with miRNA transferred by MSC-MV or EPO-MSC-MV, such as miR-200 and miR-29 families. The administration of MV may provide a promising opportunity for stem cell therapeutic research. MV derived from genetically-modified MSC, the custom-engineered super-micro-vesicles, may become a new class of cell-derived therapeutics. The project is expected to achieve a breakthrough in stem cell therapy for CRF.

我们前期研究在间充质干细胞(MSC)来源的微泡(MV)中检出包括miR-200家族等276种miRNA，并发现MV具有肾损伤修复作用。既往研究显示促红细胞生成素(EPO)可在纠正肾性贫血的同时减轻肾损伤，并增加MSC的活力。本项目将MSC和MV研究新进展，与基因治疗载体的领先技术相结合，探索突变型双链腺相关病毒(scAAV)介导EPO基因修饰MSC来源的MV(EPO-MV)治疗慢性肾衰竭(CRF)的新方法。本研究将：⑴深入探讨MV的肾修复作用；⑵明确EPO-MV是否进一步促进肾损伤修复；⑶探明MV和EPO-MV依赖传递miRNA如miR-200和miR-29家族而发挥肾修复作用及其机制。MV治疗有望成为干细胞治疗的新方向，而基因修饰MSC来源的MV，这一特定设计的"超微泡"可能成为细胞治疗新的方法。本研究预期在CRF的治疗上有所突破，为CRF干细胞治疗提供新途径。

骨髓间充质干细胞（MSC）在细胞和组织损伤的修复中发挥了重要作用。前期研究表明MSC外泌的微囊泡（MV）可以缓解急慢性肾损伤，且适量促红细胞生成素（EPO）可增加 MSC 活力和修复功能。本研究进一步探讨EPO对MSC外泌的MV在抑制肾脏纤维化方面的作用机制。主要研究成果：1. 通过体内外实验探讨EPO对MSC及其外泌MV的变化。2.探讨 EPO对MSC外泌的MV在肾损伤修复作用中的影响及其可能机制。3.观察EPO作用下MSC分泌的MV的miRNA表达谱变化。本研究紧密联系基础研究和临床实际，发现EPO能增强MSC外泌MV的肾损伤修复作用，为慢性肾衰竭新的治疗途径奠定了基础。