骨髓间充质干细胞来源的微囊泡通过miR-34a/Notch信号通路对缺血性肾损伤修复作用的机制研究

Bone marrow mesenchymal stem cells (BMSC) derived micro-vesicles (MV) which diliver a variety of biologically active substances, play a key role in tissue repair of the kidney and other organs. Gene-modified MSC-MV, or particular design of the "Super Micro-Vesicle" may become a new kind of cell therapy. Our study showed that MSC-MV could repair ischemic renal injury, and several micor-RNAs were highly expressed in MV associated with fibrosis, including miRNA-34a, which we found for the first time that is down-regulated in kidney cells under hypoxic conditions, and we confirmed that down-regulated miRNA-34a promotes the epithelial-mesenchymal transition of renal tubular epithelial cells by increasing the expression of the Notch signaling pathway and its downstream target genes. Combined with the new gene carriers of MV and the latest achievements in the field of gene carriers research, we aim: ⑴ to prove that MSC-MV-dependent miRNAs play a key role in the repair of injured kidney; ⑵ to elucidate the repair mechanism of MSC-MV in the ischemic renal injury through the miR-34a/Notch signaling pathway. This study aims to establish the role of MV-miRNA-34a/Notch in renal fibrosis, and promotes a new stem cell therapy for kidney repair.

骨髓间充质干细胞(MSC)来源的微囊泡(MV)传递多种生物活性物质，在肾脏等器官修复中起关键作用。基因修饰的MSC-MV，这一特定设计的“超微囊泡”可能成为细胞治疗新一族。前期研究我们发现MSC-MV对缺血性肾损伤具有修复作用，且MV高表达数种与纤维化相关的micorRNA，其中包括我们首次证实缺氧条件下肾脏细胞低表达的miRNA-34a，并初步证明miRNA-34a的下调促进Notch信号通路及下游靶基因的表达，直接导致肾小管上皮细胞转分化的发展。结合MV这一新型载体物质和基因载体研究领域前沿，本研究将：⑴探明MSC-MV依赖传递miRNA在肾损伤修复中发挥作用；⑵深入探讨MSC-MV经miR-34a/Notch信号通路对缺血性肾损伤修复作用的机制。本研究拟建立MV-miRNA-34a/Notch与肾脏纤维化关系调节器，将MV对肾修复作用的深入到基因调节水平，有望成为干细胞治疗新途径。

骨髓间充质干细胞(MSC)来源的微囊泡(MV)传递多种生物活性物质，在肾脏等器官修复中起关键作用。基因修饰的MSC-MV，这一特定设计的“超微囊泡”可能成为细胞治疗新一族。我们既往已发现MSC-MV对缺血性肾损伤具有修复作用，且MV高表达数种与纤维化相关的micorRNA，其中包括我们首次证实缺氧条件下肾脏细胞低表达的miRNA-34a，并初步证明miRNA-34a的下调促进Notch信号通路及下游靶基因的表达，直接导致肾小管上皮细胞转分化的发展。主要研究成果：1.探明MV中的miR34a在肾损伤修复中发挥作用；2.初步探讨微囊泡经miR-34a/Notch信号通路对缺血性肾损伤发挥修复作用的机制。本项目虽为基础研究，但立足于临床应用，通过建立MV-miRNA-34a/Notch与肾脏纤维化关系调节器，将MV对肾修复作用的深入到基因调节水平，在慢性肾衰竭治疗方面取得了一定的突破，为慢性肾衰竭新的治疗途径奠定了基础。