间充质干细胞治疗2型糖尿病大鼠晚期并发症的作用及机制的研究

In this study, we use low-dose streptozotocin combined with long-term high-fat diet to build late-stage complications of type 2 diabetic rats model. By investigating the effects of multiple infusions of mesenchymal stem cells on the insulin resistance, the recovery and regeneration of pancreatic β-cell function, and the repair of various target organs such as liver, kidney, lung, heart and lens from the aspects of function and morphology effect, we comprehensive evaluated the therapeutic effect and biosafety of long-term infusion of mesenchymal stem cells. Through analyze the macrophage infiltration of various target organs and its subtypes to clarify the role of mesenchymal stem cells in inhibiting inflammation and the key role of macrophage transformation in the late stage of type 2 diabetes. The topic through the cellular and molecular aspects explores mesenchymal stem cells and macrophage cytokine-mediated interaction and further explores the mechanism of M2 macrophages in the treatment of advanced diabetic nephropathy, especially glomerular fibrosis. Based on the previous theories and research results, we hypothesis the idea of diabetic-microenvironment-pretreated meschymal stem cells to treat the development stage of type 2 diabetic rats for the first time. While maintaining the biological activity of mesenchymal stem cells, inducing them to exert their immunomodulatory effect efficiently, which may provide a new idea of clinical treatment of advanced type 2 diabetes.

本研究利用小剂量链脲佐菌素联合长期高脂饮食构建2型糖尿病晚期并发症大鼠模型。通过探讨多次输注间充质干细胞对晚期2型糖尿病胰岛素抵抗、胰岛β细胞功能恢复与再生以及从功能和形态学两方面对肝脏、肾脏、肺、心脏、晶状体等多种靶器官的修复作用，综合评估了长期输注间充质干细胞的治疗效果及生物安全性。通过对各靶器官的巨噬细胞浸润情况及亚型的分析，以阐明间充质干细胞抑制炎症的作用及巨噬细胞的转化在晚期2型糖尿病中的关键作用。课题从细胞分子水平揭示间充质干细胞与巨噬细胞间细胞因子介导的相互作用，并进一步探究了M2型巨噬细胞在缓解晚期糖尿病肾病肾小球纤维化的具体机制。并基于前期理论和研究结果，针对晚期2型糖尿病模型，首次提出了输注糖尿病样微环境预处理间充质干细胞的设想，在维持间充质干细胞生物学活性的同时，诱导其高效发挥其免疫调节效应，为临床治疗晚期2型糖尿病提供一个新的思路。

提高间充质干细胞治疗2型糖尿病晚期并发症的作用效果已成为当前研究热点，依据国内外对间充质干细胞的作用机制的最新研究进展，结合前期研究基础，首次提出了利用糖尿病微环境预处理间充质干细胞治疗晚期2型糖尿病的研究设想。通过探讨多次输注间充质干细胞对晚期2型糖尿病胰岛素抵抗、胰岛β细胞功能恢复与再生以及从功能和形态学两方面对肝脏、肾脏、肺、心脏、晶状体等多种靶器官的修复作用，综合评估了长期输注间充质干细胞的治疗效果及生物安全性。本研究结果证实，糖尿病微环境预处理后间充质干细胞可发挥更好且持久的降糖效果，且可改善糖尿病长期并发症。同时，通过对各靶器官的巨噬细胞浸润情况及亚型的分析，阐明间充质干细胞抑制炎症的作用及巨噬细胞的转化在晚期2型糖尿病中的关键作用。糖尿病微环境预处理间充质干细胞通过释放外泌体促进巨噬细胞向M2表型极化，以及M1型巨噬细胞可诱导肾小球内皮细胞中活性氧水平升高，从而激活p38 MAPK信号通路，进一步激活了p53-p21信号通路及p16信号通路，发挥促进肾小球内皮细胞衰老的作用。从细胞分子水平揭示间充质干细胞与巨噬细胞间细胞因子介导的相互作用。本研究为间充质干细胞治疗2型糖尿病的临床前转化提供关键的理论基础。