PMID- 37735415 OWN - NLM STAT- MEDLINE DCOM- 20230925 LR - 20231121 IS - 1757-6512 (Electronic) IS - 1757-6512 (Linking) VI - 14 IP - 1 DP - 2023 Sep 21 TI - Human umbilical cord-derived mesenchymal stem cells ameliorate perioperative neurocognitive disorder by inhibiting inflammatory responses and activating BDNF/TrkB/CREB signaling pathway in aged mice. PG - 263 LID - 10.1186/s13287-023-03499-x [doi] LID - 263 AB - BACKGROUND: Perioperative neurocognitive disorder (PND) is a key complication affecting older individuals after anesthesia and surgery. Failure to translate multiple pharmacological therapies for PND from preclinical studies to clinical settings has necessitated the exploration of novel therapeutic strategies. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) treatment has emerged as a promising therapeutic strategy for treating neurodegenerative diseases and has the potential to translate basic science into clinical practice. In this study, we investigated the effects and underlying mechanism of hUC-MSCs on PND in aged mice. METHODS: hUC-MSCs were isolated from an infant umbilical cord and identified using flow cytometry and differentiation assays. We established PND model by undergoing aseptic laparotomy under isoflurane anesthesia maintaining spontaneous ventilation in eighteen-month-old male C57BL/6 mice. hUC-MSCs were slowly injected into mice by coccygeal vein before anesthesia. Cognitive function, systemic and neuroinflammatory responses, neuroplasticity, endogenous neurogenesis, and brain-derived neurotrophic factor (BDNF) were assessed. To determine the brain mechanisms underlying by which hUC-MSCs mediate their neuroprotective effects in PND, K252a, an antagonist of BDNF receptor, was administered intraperitoneally before surgery. Hippocampal BDNF/TrkB/CREB signaling pathway and metabolomic signatures were evaluated. RESULTS: hUC-MSC treatment ameliorated the learning and memory impairment in aged mice with PND. The downstream effects were the suppression of systemic and hippocampal inflammation and restoration of neurogenesis and neuroplasticity dysregulation. Interestingly, the level of mature BDNF, but not that of proBDNF, was increased in the hippocampus after hUC-MSC treatment. Further analysis revealed that the improved cognitive recovery and the restoration of neurogenesis and neuroplasticity dysregulation elicited by exposure to hUC-MSCs were, at least partially, mediated by the activation of the BDNF/TrkB/CREB signaling pathway. Untargeted metabolomic further identified lipid metabolism dysfunction as potential downstream of the BDNF/TrkB/CREB signaling pathway in hUC-MSC-mediated neuroprotection for PND. CONCLUSIONS: Our study highlights the beneficial effects of hUC-MSC treatment on PND and provides a justification to consider the potential use of hUC-MSCs in the perioperative period. CI - (c) 2023. BioMed Central Ltd., part of Springer Nature. FAU - Wei, Penghui AU - Wei P AD - Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, No. 1 East Jianshe Road, Zhengzhou, 450052, People's Republic of China. AD - Department of Anesthesiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, People's Republic of China. AD - Neuroscience Research Institute, Zhengzhou University Academy of Medical Sciences, Zhengzhou, People's Republic of China. AD - Henan Province International Joint Laboratory of Pain, Cognition and Emotion, Zhengzhou, People's Republic of China. FAU - Jia, Min AU - Jia M AD - Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, No. 1 East Jianshe Road, Zhengzhou, 450052, People's Republic of China. AD - Neuroscience Research Institute, Zhengzhou University Academy of Medical Sciences, Zhengzhou, People's Republic of China. AD - Henan Province International Joint Laboratory of Pain, Cognition and Emotion, Zhengzhou, People's Republic of China. FAU - Kong, Xiangyi AU - Kong X AD - Department of Anesthesiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, People's Republic of China. FAU - Lyu, Wenyuan AU - Lyu W AD - Department of Anesthesiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, People's Republic of China. FAU - Feng, Hao AU - Feng H AD - Department of Anesthesiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, People's Republic of China. FAU - Sun, Xinyi AU - Sun X AD - Department of Anesthesiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, People's Republic of China. FAU - Li, Jianjun AU - Li J AD - Department of Anesthesiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, People's Republic of China. AD - Department of Anesthesiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China. FAU - Yang, Jian-Jun AU - Yang JJ AD - Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, No. 1 East Jianshe Road, Zhengzhou, 450052, People's Republic of China. yjyangjj@zzu.edu.cn. AD - Neuroscience Research Institute, Zhengzhou University Academy of Medical Sciences, Zhengzhou, People's Republic of China. yjyangjj@zzu.edu.cn. AD - Henan Province International Joint Laboratory of Pain, Cognition and Emotion, Zhengzhou, People's Republic of China. yjyangjj@zzu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230921 PL - England TA - Stem Cell Res Ther JT - Stem cell research & therapy JID - 101527581 RN - 0 (Brain-Derived Neurotrophic Factor) SB - IM MH - Infant MH - Humans MH - Male MH - Animals MH - Mice MH - Mice, Inbred C57BL MH - *Brain-Derived Neurotrophic Factor/genetics MH - Neurocognitive Disorders MH - Brain MH - Inflammation/therapy MH - *Mesenchymal Stem Cells PMC - PMC10512658 OTO - NOTNLM OT - Aging brain OT - BDNF/TrkB OT - Cognitive impairment OT - Human umbilical cord-derived mesenchymal stem cells OT - Inflammation OT - Lipid metabolism OT - Perioperative neurocognitive disorder COIS- The authors declare that they have no conflicts of interest. EDAT- 2023/09/22 06:42 MHDA- 2023/09/25 06:43 PMCR- 2023/09/21 CRDT- 2023/09/22 00:41 PHST- 2023/04/12 00:00 [received] PHST- 2023/09/14 00:00 [accepted] PHST- 2023/09/25 06:43 [medline] PHST- 2023/09/22 06:42 [pubmed] PHST- 2023/09/22 00:41 [entrez] PHST- 2023/09/21 00:00 [pmc-release] AID - 10.1186/s13287-023-03499-x [pii] AID - 3499 [pii] AID - 10.1186/s13287-023-03499-x [doi] PST - epublish SO - Stem Cell Res Ther. 2023 Sep 21;14(1):263. doi: 10.1186/s13287-023-03499-x.