Neural Regeneration Research ›› 2023, Vol. 18 ›› Issue (3): 609-617.doi: 10.4103/1673-5374.350205

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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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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