NMDAR inhibitor preconditioned mesenchymal stromal cell-derived extracellular vesicles enhance post-stroke recovery by targeting excitotoxicity and neuronal regeneration
BackgroundStroke is a leading global cause of disability and mortality, with ischemic stroke triggering NMDAR overactivation and excitotoxic neuronal injury. Extracellular vesicles (EVs) derived from stem cells under specific microenvironmental conditions show therapeutic potential for stroke recove...
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Frontiers Media S.A.
2025-08-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fncel.2025.1608615/full |
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| author | XiaoLu Zhang XiaoLu Zhang HuanNa Tian HuanNa Tian HaiMei Bo Li Zhong |
| author_facet | XiaoLu Zhang XiaoLu Zhang HuanNa Tian HuanNa Tian HaiMei Bo Li Zhong |
| author_sort | XiaoLu Zhang |
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| description | BackgroundStroke is a leading global cause of disability and mortality, with ischemic stroke triggering NMDAR overactivation and excitotoxic neuronal injury. Extracellular vesicles (EVs) derived from stem cells under specific microenvironmental conditions show therapeutic potential for stroke recovery.Materials and MethodsPhotothrombotic stroke was induced in male ICR mice, followed by intravenous administration of EVs from memantine-preconditioned human umbilical cord mesenchymal stem cells (HUC-MSCs; M-EV). Behavioral outcomes were assessed using modified neurological severity scores (mNSS) and Morris water maze tests. Tissue damage was evaluated via TTC staining, Evans blue extravasation, and immunofluorescence. PCR-array analysis identified neuronal regeneration pathways. In vitro, oxygen-glucose deprivation (OGD)-challenged HT22 hippocampal neurons were co-cultured with M-EV to assess viability, migration, and apoptosis.ResultsM-EV outperformed conventional EVs in functional recovery, with miR-139-5p and miR-133b identified as key miRNAs enriched in M-EV, mediating neuroprotective effects. M-EV treatment activated neuronal regeneration pathways and reduced infarct volume. In OGD models, M-EV enhanced HT22 neuron viability, promoted migration, and suppressed apoptosis.ConclusionMemantine-preconditioned EVs (M-EVs) exhibit superior neurorestorative capacity via miRNA-mediated mechanisms, offering a promising translational approach for stroke therapy. The study highlights the potential of microenvironment-tailored EVs in neural repair. |
| format | Article |
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| institution | DOAJ |
| issn | 1662-5102 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Cellular Neuroscience |
| spelling | doaj-art-d9cb6af56e3e47f18bd9bbe979cbfbb92025-08-20T03:03:50ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022025-08-011910.3389/fncel.2025.16086151608615NMDAR inhibitor preconditioned mesenchymal stromal cell-derived extracellular vesicles enhance post-stroke recovery by targeting excitotoxicity and neuronal regenerationXiaoLu Zhang0XiaoLu Zhang1HuanNa Tian2HuanNa Tian3HaiMei Bo4Li Zhong5College of Life Sciences, Institute of Life Science and Green Development, Hebei University, Baoding, Hebei, ChinaDepartment of Neurosurgery, The First Affiliated Hospital of Baotou Medical College, Baotou, ChinaCollege of Life Sciences, Institute of Life Science and Green Development, Hebei University, Baoding, Hebei, ChinaHebei Key Laboratory of Nerve Injury and Repair, Institute of Basic Medicine, Chengde Medical University, Chengde, Hebei, ChinaCollege of Life Sciences, Institute of Life Science and Green Development, Hebei University, Baoding, Hebei, ChinaCollege of Life Sciences, Institute of Life Science and Green Development, Hebei University, Baoding, Hebei, ChinaBackgroundStroke is a leading global cause of disability and mortality, with ischemic stroke triggering NMDAR overactivation and excitotoxic neuronal injury. Extracellular vesicles (EVs) derived from stem cells under specific microenvironmental conditions show therapeutic potential for stroke recovery.Materials and MethodsPhotothrombotic stroke was induced in male ICR mice, followed by intravenous administration of EVs from memantine-preconditioned human umbilical cord mesenchymal stem cells (HUC-MSCs; M-EV). Behavioral outcomes were assessed using modified neurological severity scores (mNSS) and Morris water maze tests. Tissue damage was evaluated via TTC staining, Evans blue extravasation, and immunofluorescence. PCR-array analysis identified neuronal regeneration pathways. In vitro, oxygen-glucose deprivation (OGD)-challenged HT22 hippocampal neurons were co-cultured with M-EV to assess viability, migration, and apoptosis.ResultsM-EV outperformed conventional EVs in functional recovery, with miR-139-5p and miR-133b identified as key miRNAs enriched in M-EV, mediating neuroprotective effects. M-EV treatment activated neuronal regeneration pathways and reduced infarct volume. In OGD models, M-EV enhanced HT22 neuron viability, promoted migration, and suppressed apoptosis.ConclusionMemantine-preconditioned EVs (M-EVs) exhibit superior neurorestorative capacity via miRNA-mediated mechanisms, offering a promising translational approach for stroke therapy. The study highlights the potential of microenvironment-tailored EVs in neural repair.https://www.frontiersin.org/articles/10.3389/fncel.2025.1608615/fullextracellular vesiclesischemic strokeexcitotoxicityumbilical cord mesenchymal stem cellspreconditioningneuroprotection |
| spellingShingle | XiaoLu Zhang XiaoLu Zhang HuanNa Tian HuanNa Tian HaiMei Bo Li Zhong NMDAR inhibitor preconditioned mesenchymal stromal cell-derived extracellular vesicles enhance post-stroke recovery by targeting excitotoxicity and neuronal regeneration Frontiers in Cellular Neuroscience extracellular vesicles ischemic stroke excitotoxicity umbilical cord mesenchymal stem cells preconditioning neuroprotection |
| title | NMDAR inhibitor preconditioned mesenchymal stromal cell-derived extracellular vesicles enhance post-stroke recovery by targeting excitotoxicity and neuronal regeneration |
| title_full | NMDAR inhibitor preconditioned mesenchymal stromal cell-derived extracellular vesicles enhance post-stroke recovery by targeting excitotoxicity and neuronal regeneration |
| title_fullStr | NMDAR inhibitor preconditioned mesenchymal stromal cell-derived extracellular vesicles enhance post-stroke recovery by targeting excitotoxicity and neuronal regeneration |
| title_full_unstemmed | NMDAR inhibitor preconditioned mesenchymal stromal cell-derived extracellular vesicles enhance post-stroke recovery by targeting excitotoxicity and neuronal regeneration |
| title_short | NMDAR inhibitor preconditioned mesenchymal stromal cell-derived extracellular vesicles enhance post-stroke recovery by targeting excitotoxicity and neuronal regeneration |
| title_sort | nmdar inhibitor preconditioned mesenchymal stromal cell derived extracellular vesicles enhance post stroke recovery by targeting excitotoxicity and neuronal regeneration |
| topic | extracellular vesicles ischemic stroke excitotoxicity umbilical cord mesenchymal stem cells preconditioning neuroprotection |
| url | https://www.frontiersin.org/articles/10.3389/fncel.2025.1608615/full |
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