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
Abstract 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 ther...
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| Format: | Article |
| Language: | English |
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BMC
2023-09-01
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| Series: | Stem Cell Research & Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13287-023-03499-x |
| _version_ | 1797577730921857024 |
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| author | Penghui Wei Min Jia Xiangyi Kong Wenyuan Lyu Hao Feng Xinyi Sun Jianjun Li Jian-jun Yang |
| author_facet | Penghui Wei Min Jia Xiangyi Kong Wenyuan Lyu Hao Feng Xinyi Sun Jianjun Li Jian-jun Yang |
| author_sort | Penghui Wei |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-10T22:12:07Z |
| format | Article |
| id | doaj.art-2ab01416f0f24cccac0362ae7fad989f |
| institution | Directory Open Access Journal |
| issn | 1757-6512 |
| language | English |
| last_indexed | 2024-03-10T22:12:07Z |
| publishDate | 2023-09-01 |
| publisher | BMC |
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| series | Stem Cell Research & Therapy |
| spelling | doaj.art-2ab01416f0f24cccac0362ae7fad989f2023-11-19T12:33:56ZengBMCStem Cell Research & Therapy1757-65122023-09-0114112210.1186/s13287-023-03499-xHuman umbilical cord-derived mesenchymal stem cells ameliorate perioperative neurocognitive disorder by inhibiting inflammatory responses and activating BDNF/TrkB/CREB signaling pathway in aged micePenghui Wei0Min Jia1Xiangyi Kong2Wenyuan Lyu3Hao Feng4Xinyi Sun5Jianjun Li6Jian-jun Yang7Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Anesthesiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong UniversityDepartment of Anesthesiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong UniversityDepartment of Anesthesiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong UniversityDepartment of Anesthesiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong UniversityDepartment of Anesthesiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong UniversityDepartment of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou UniversityAbstract 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.https://doi.org/10.1186/s13287-023-03499-xHuman umbilical cord-derived mesenchymal stem cellsCognitive impairmentAging brainPerioperative neurocognitive disorderBDNF/TrkBLipid metabolism |
| spellingShingle | Penghui Wei Min Jia Xiangyi Kong Wenyuan Lyu Hao Feng Xinyi Sun Jianjun Li Jian-jun Yang 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 Stem Cell Research & Therapy Human umbilical cord-derived mesenchymal stem cells Cognitive impairment Aging brain Perioperative neurocognitive disorder BDNF/TrkB Lipid metabolism |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Human umbilical cord-derived mesenchymal stem cells Cognitive impairment Aging brain Perioperative neurocognitive disorder BDNF/TrkB Lipid metabolism |
| url | https://doi.org/10.1186/s13287-023-03499-x |
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