中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (3): 609-617.doi: 10.4103/1673-5374.350205

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

诱导多能干细胞源性间充质干细胞分泌小细胞外囊泡改善糖尿病术后认知功能障碍

  

  • 出版日期:2023-03-15 发布日期:2022-08-28
  • 基金资助:
    中国国家自然科学基金项目（82101463）；江西省科技厅自然科学基金项目（20202BAB216013）；江西省卫健委科技攻关项目（202130370）；南昌大学第二附属医院青年科技创新团队项目（2019YNQN12009）

Small extracellular vesicles secreted by induced pluripotent stem cell-derived mesenchymal stem cells improve postoperative cognitive dysfunction in mice with diabetes

Hai-Li Lang1, Yan-Zhi Zhao2, Ren-Jie Xiao1, Jing Sun1, Yong Chen1, Guo-Wen Hu3, *, Guo-Hai Xu1, *   

  1. 1Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China; 2The First Clinical Medical College of Nanchang University, Nanchang, Jiangxi Province, China; 3Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
  • Online:2023-03-15 Published:2022-08-28
  • Contact: Guo-Hai Xu, MD, xuguohai@sina.com; Guo-Wen Hu, PhD, hugw0625@163.com.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, No. 82101463 (to GWH); Natural Science Foundation of Jiangxi Provincial Science and Technology Department, No. 20202BAB216013 (to HLL); Jiangxi Provincial Health Commission General Science and Technology Project, No. 202130370 (to HLL); and The Second Affiliated Hospital of Nanchang University’s Youth Innovation Team of Science and Technology Program, No. 2019YNQN12009 (to HLL).

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摘要：

既往多项研究发现术后认知功能障碍小鼠模型海马中存在神经元丢失，海马神经发生减少的现象，因此，实验假设诱导多能干细胞源性间充质干细胞分泌小细胞外囊泡可能促进神经发生，而恢复糖尿病术后认知功能障碍的认知功能。首先构建了腹腔注射链脲佐菌素诱导的小鼠糖尿病模型，而后以瞬时双侧颈总动脉闭塞建立糖尿病术后认知功能障碍小鼠模型。从术后第2天开始尾静脉注射诱导多能干细胞源性间充质干细胞分泌的小细胞外囊泡，连续1个月。糖尿病小鼠在短暂性全脑缺血后出现严重的海马神经干细胞耗竭、神经发生减少以及认知功能障碍；接受诱导多能干细胞源性间充质干细胞分泌的小细胞外囊泡可转移miR-21-5p和miR-486-5p以抑制海马神经干细胞中EphA4、CDKN2C和FoxO1的表达，促进了海马神经发生和认知功能的恢复。提示这种方法值得进一步以一种新型无细胞治疗工具去深入研究和开发。

https://orcid.org/0000-0002-5591-6038 (Guo-Hai Xu); https://orcid.org/0000-0003-0345-5505 (Guo-Wen Hu)

关键词: 糖尿病, 术后认知功能障碍, 诱导多能干细胞, 间充质干细胞, 小细胞外囊泡, 海马, 神经干细胞, 微小RNA, 神经发生, 信号通路

Abstract: Postoperative cognitive dysfunction (POCD) is a common surgical complication. Diabetes mellitus (DM) increases risk of developing POCD after surgery. DM patients with POCD seriously threaten the quality of patients’ life, however, the intrinsic mechanism is unclear, and the effective treatment is deficiency. Previous studies have demonstrated neuronal loss and reduced neurogenesis in the hippocampus in mouse models of POCD. In this study, we constructed a mouse model of DM by intraperitoneal injection of streptozotocin, and then induced postoperative cognitive dysfunction by transient bilateral common carotid artery occlusion. We found that mouse models of DM-POCD exhibited the most serious cognitive impairment, as well as the most hippocampal neural stem cells (H-NSCs) loss and neurogenesis decline. Subsequently, we hypothesized that small extracellular vesicles secreted by induced pluripotent stem cell-derived mesenchymal stem cells (iMSC-sEVs) might promote neurogenesis and restore cognitive function in patients with DM-POCD. iMSC-sEVs were administered via the tail vein beginning on day 2 after surgery, and then once every 3 days for 1 month thereafter. Our results showed that iMSC-sEVs treatment significantly recovered compromised proliferation and neuronal-differentiation capacity in H-NSCs, and reversed cognitive impairment in mouse models of DM-POCD. Furthermore, miRNA sequencing and qPCR showed miR-21-5p and miR-486-5p were the highest expression in iMSC-sEVs. We found iMSC-sEVs mainly transferred miR-21-5p and miR-486-5p to promote H-NSCs proliferation and neurogenesis. As miR-21-5p was demonstrated to directly targete Epha4 and CDKN2C, while miR-486-5p can inhibit FoxO1 in NSCs. We then demonstrated iMSC-sEVs can transfer miR-21-5p and miR-486-5p to inhibit EphA4, CDKN2C, and FoxO1 expression in H-NSCs. Collectively, these results indicate significant H-NSC loss and neurogenesis reduction lead to DM-POCD, the application of iMSC-sEVs may represent a novel cell-free therapeutic tool for diabetic patients with postoperative cognitive dysfunction.

Key words: diabetes mellitus, hippocampus, induced pluripotent stem cell, mesenchymal stem cell, miRNA, neural stem cell, neurogenesis, postoperative cognitive dysfunction, signaling pathway, small extracellular vesicle