干细胞来源的外泌体通过microRNA-146a调控胰岛去分化的机制研究

胰岛功能减退是糖尿病发生及发展的中心环节，传统药物及胰岛素治疗只能对症处理，并不能阻止胰岛β细胞功能的衰竭。研究显示以干细胞及其分泌的外泌体为代表的的再生医学治疗可以有效延缓甚至逆转胰岛β细胞功能衰竭。我们预实验发现，骨髓间充质干细胞来源的外泌体（bmMDEs）可以有效的改善糖尿病大鼠的胰岛功能。在细胞实验中发现，bmMDEs可通过miRNA-146a阻断NUMB基因的转录，从而上调成熟胰岛β细胞标志物PDX1和FOXO1的表达，同时降低胰岛前体细胞标志物NGN3、OCT4水平。因此我们提出“干细胞来源的外泌体可以通过microRNA-146a逆转胰岛去分化改善2型糖尿病小鼠的胰岛功能”的假设。本研究将从分子、细胞、动物多层次观察骨髓间充质干细胞来源的外泌体对T2DM胰岛β细胞去分化的影响，并从miRNA及下游相关信号通路探讨其调控机制，以期临床2型糖尿病干预策略供新思路和和科学依据。

Islet hypofunction is the central link in the development and development of diabetes. Traditional medicine and insulin therapy can only treat symptomatically and cannot prevent the progressive failure of islet β-cell function. Studies have shown that regenerative medicine treatments represented by stem cells and their secreted exosomes can effectively delay or even reverse islet β-cell failure. Our preliminary experiments found that bone marrow mesenchymal stem cell-derived exosomes （bmMDEs）can improve islet function in diabetic rats. It was found in cell experiments that bmMDEs can block the transcription of NUMB gene through microRNA-146a, thereby up-regulating the expression of mature islet β-cell markers PDX1 and FOXO1, and reducing islet precursor cell markers NGN3, OCT4 Level. Therefore, we propose the hypothesis that "stem cell-derived exosomes can reverse islet dedifferentiation and improve islet function in type 2 diabetic mice through micro-RNA 146a." This study will observe the effects of stem cell-derived exosomes on the dedifferentiation of T2DM islet β cells from molecular, cellular, and animal levels, and explore its regulatory mechanism from miRNA and downstream related signaling pathways, with a view to providing clinical strategies for type 2 diabetes intervention ideas and scientific basis.