Small extracellular vesicles secreted by induced pluripotent stem cell-derived mesenchymal stem cells improve postoperative cognitive dysfunction in mice with diabetes.
Small extracellular vesicles secreted by induced pluripotent stem cell-derived mesenchymal stem cells improve postoperative cognitive dysfunction in mice with diabetes.
复制标题
DOI：
10.4103/1673-5374.350205
复制
发表时间：
2023-03
影响因子：
6.1
通讯作者：
Xu GH
中科院分区：
文献类型：
--
作者：
Lang HL;Zhao YZ;Xiao RJ;Sun J;Chen Y;Hu GW;Xu GH
术后认知功能障碍（POCD）是常见的手术并发症。糖尿病(DM)会增加术后发生POCD的风险。糖尿病合并POCD严重威胁患者的生活质量，但其内在机制尚不清楚，缺乏有效的治疗方法。先前的研究表明，小鼠POCD模型海马中神经元丢失和神经发生减少。本研究通过腹腔注射链脲佐菌素构建DM小鼠模型，并通过短暂性双侧颈总动脉闭塞诱导术后认知功能障碍。我们发现DM-POCD小鼠模型表现出最严重的认知障碍，以及最严重的海马神经干细胞（H-NSCs）丢失和神经发生下降。随后，我们假设由诱导多能干细胞衍生间充质干细胞（imsc - sev）分泌的小细胞外囊泡可能促进DM-POCD患者的神经发生并恢复认知功能。imsc - sev于术后第2天开始通过尾静脉给药，此后每3天一次，持续1个月。我们的研究结果表明，imsc - sev治疗显著恢复了H-NSCs受损的增殖和神经元分化能力，并逆转了DM-POCD小鼠模型的认知障碍。此外，miRNA测序和qPCR显示miR-21-5p和miR-486-5p在imsc - sev中表达最高。我们发现imsc - sev主要通过转移miR-21-5p和miR-486-5p促进H-NSCs的增殖和神经发生。因为miR-21-5p被证明直接靶向Epha4和CDKN2C，而miR-486-5p可以抑制NSCs中的FoxO1。然后，我们证明了imsc - sev可以转移miR-21-5p和miR-486-5p来抑制H-NSCs中EphA4、CDKN2C和FoxO1的表达。综上所述，这些结果表明显著的H-NSC缺失和神经发生减少导致DM-POCD， imsc - sev的应用可能为糖尿病术后认知功能障碍患者提供一种新的无细胞治疗工具。
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.
登录
查看更多内容
影响因子：
46.9
作者：
Alvarez-Erviti, Lydia;Seow, Yiqi;Wood, Matthew J. A.
通讯作者：
Wood, Matthew J. A.
影响因子：
6.1
作者：
Gualerzi A;Lombardi M;Verderio C
通讯作者：
Verderio C
影响因子：
5.2
作者：
Moheet A;Mangia S;Seaquist ER
通讯作者：
Seaquist ER
白介素-1β在术后认知功能障碍中的作用。
影响因子：
11.2
作者：
Cibelli M;Fidalgo AR;Terrando N;Ma D;Monaco C;Feldmann M;Takata M;Lever IJ;Nanchahal J;Fanselow MS;Maze M
通讯作者：
Maze M
影响因子：
12.4
作者：
Kim, D-Y;Hwang, I.;Paik, J-H
通讯作者：
Paik, J-H