The umbilical cord blood exosome MFG-E8 alleviates hypoxic-ischemic encephalopathy brain injury in neonatal rats by restoring autophagy flux and inhibiting ferroptosis through GSK3β/β-catenin signaling
Background: Recent studies have revealed importance of human umbilical cord blood (HUCB)-derived exosomes (HUCB-Exo) in central nervous system diseases, but the role of HUCB-Exo in hypoxic-ischemic encephalopathy (HIE) remains unclear. This study aims to explore the mechanisms of HUCB-Exo in HIE. Me...
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Elsevier
2025-12-01
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| Series: | Regenerative Therapy |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S235232042500149X |
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| author | Menghua Zhao Yizhong Wu Li Huang Juanmei Wang Aimin Zhang |
| author_facet | Menghua Zhao Yizhong Wu Li Huang Juanmei Wang Aimin Zhang |
| author_sort | Menghua Zhao |
| collection | DOAJ |
| description | Background: Recent studies have revealed importance of human umbilical cord blood (HUCB)-derived exosomes (HUCB-Exo) in central nervous system diseases, but the role of HUCB-Exo in hypoxic-ischemic encephalopathy (HIE) remains unclear. This study aims to explore the mechanisms of HUCB-Exo in HIE. Methods: HIE models were constructed in 7-day-old neonatal rats using classical Rice-Vannucci modeling, and SH-SY5Y cells were induced by oxygen-glucose deprivation/reperfusion (OGD/R) injury, followed by intervention with HUCB and HUBC-Exo, either non-transfected or transfected with si-NC/si-MFG-E8. Results: HUBC-Exo decreased cerebral infarct size and cerebral water content in HIE neonatal rats and improved short-term and long-term neurological function. HUBC-Exo down-regulated Beclin1, ATG7, and LC3 II/I expression, while promoting p62 expression in HIE neonatal rats. After HUBC-Exo treatment, NCOA4 and ACSL4 expression in HIE neonatal rats decreased, while FTH1, SLC7A11, and GPX4 expression were increased. In addition, HUBC-Exo decreased Fe2+, MDA, and ROS levels in HIE neonatal rats. Similarly, these in vivo results were observed in vitro. HUBC-Exo inhibited autophagy and ferroptosis in OGD/R-induced SH-SY5Y cells, and MFG-E8 silencing interrupted HUBC-Exo action. Further results showed that HUBC-Exo-derived MFG-E8 promoted p-GSK3β/GSK3β and Active-β-catenin/β-catenin levels in OGD/R-induced SH-SY5Y cells. Importantly, the GSK3β agonist LiCl revoked the promotion of HUBC-Exosi-MFG-E8 on autophagy and ferroptosis in OGD/R-induced SH-SY5Y cells. HUBC-Exo MFG-E8 inhibited autophagy and ferroptosis, thereby alleviating brain damage in HIE neonatal rats. Conclusion: Our results suggested that HUBC-Exo-transmitted MFG-E8 inhibited autophagy and ferroptosis through GSK3β/β-catenin signaling, thereby alleviating brain injury in HIE neonatal rats, which provided a new idea for treating HIE. |
| format | Article |
| id | doaj-art-6da000cb205145b2bba5677757cc34d2 |
| institution | Kabale University |
| issn | 2352-3204 |
| language | English |
| publishDate | 2025-12-01 |
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| series | Regenerative Therapy |
| spelling | doaj-art-6da000cb205145b2bba5677757cc34d22025-08-20T03:30:13ZengElsevierRegenerative Therapy2352-32042025-12-013032133210.1016/j.reth.2025.06.016The umbilical cord blood exosome MFG-E8 alleviates hypoxic-ischemic encephalopathy brain injury in neonatal rats by restoring autophagy flux and inhibiting ferroptosis through GSK3β/β-catenin signalingMenghua Zhao0Yizhong Wu1Li Huang2Juanmei Wang3Aimin Zhang4Department of Pediatrics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005, China; Corresponding author. Department of Pediatrics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, 61 Jie-Fang West Road, Fu-Rong District, Changsha, 410005, China.Department of Gastroenterology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005, ChinaDepartment of Pediatrics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005, ChinaDepartment of Pediatrics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005, ChinaDepartment of Pediatrics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005, China; Corresponding author. Department of Pediatrics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, 61 Jie-Fang West Road, Fu-Rong District, Changsha, 410005, China.Background: Recent studies have revealed importance of human umbilical cord blood (HUCB)-derived exosomes (HUCB-Exo) in central nervous system diseases, but the role of HUCB-Exo in hypoxic-ischemic encephalopathy (HIE) remains unclear. This study aims to explore the mechanisms of HUCB-Exo in HIE. Methods: HIE models were constructed in 7-day-old neonatal rats using classical Rice-Vannucci modeling, and SH-SY5Y cells were induced by oxygen-glucose deprivation/reperfusion (OGD/R) injury, followed by intervention with HUCB and HUBC-Exo, either non-transfected or transfected with si-NC/si-MFG-E8. Results: HUBC-Exo decreased cerebral infarct size and cerebral water content in HIE neonatal rats and improved short-term and long-term neurological function. HUBC-Exo down-regulated Beclin1, ATG7, and LC3 II/I expression, while promoting p62 expression in HIE neonatal rats. After HUBC-Exo treatment, NCOA4 and ACSL4 expression in HIE neonatal rats decreased, while FTH1, SLC7A11, and GPX4 expression were increased. In addition, HUBC-Exo decreased Fe2+, MDA, and ROS levels in HIE neonatal rats. Similarly, these in vivo results were observed in vitro. HUBC-Exo inhibited autophagy and ferroptosis in OGD/R-induced SH-SY5Y cells, and MFG-E8 silencing interrupted HUBC-Exo action. Further results showed that HUBC-Exo-derived MFG-E8 promoted p-GSK3β/GSK3β and Active-β-catenin/β-catenin levels in OGD/R-induced SH-SY5Y cells. Importantly, the GSK3β agonist LiCl revoked the promotion of HUBC-Exosi-MFG-E8 on autophagy and ferroptosis in OGD/R-induced SH-SY5Y cells. HUBC-Exo MFG-E8 inhibited autophagy and ferroptosis, thereby alleviating brain damage in HIE neonatal rats. Conclusion: Our results suggested that HUBC-Exo-transmitted MFG-E8 inhibited autophagy and ferroptosis through GSK3β/β-catenin signaling, thereby alleviating brain injury in HIE neonatal rats, which provided a new idea for treating HIE.http://www.sciencedirect.com/science/article/pii/S235232042500149XHypoxic-ischemic encephalopathyHUCB-ExoMFG-E8GSK3β/β-catenin pathwayAutophagyFerroptosis |
| spellingShingle | Menghua Zhao Yizhong Wu Li Huang Juanmei Wang Aimin Zhang The umbilical cord blood exosome MFG-E8 alleviates hypoxic-ischemic encephalopathy brain injury in neonatal rats by restoring autophagy flux and inhibiting ferroptosis through GSK3β/β-catenin signaling Regenerative Therapy Hypoxic-ischemic encephalopathy HUCB-Exo MFG-E8 GSK3β/β-catenin pathway Autophagy Ferroptosis |
| title | The umbilical cord blood exosome MFG-E8 alleviates hypoxic-ischemic encephalopathy brain injury in neonatal rats by restoring autophagy flux and inhibiting ferroptosis through GSK3β/β-catenin signaling |
| title_full | The umbilical cord blood exosome MFG-E8 alleviates hypoxic-ischemic encephalopathy brain injury in neonatal rats by restoring autophagy flux and inhibiting ferroptosis through GSK3β/β-catenin signaling |
| title_fullStr | The umbilical cord blood exosome MFG-E8 alleviates hypoxic-ischemic encephalopathy brain injury in neonatal rats by restoring autophagy flux and inhibiting ferroptosis through GSK3β/β-catenin signaling |
| title_full_unstemmed | The umbilical cord blood exosome MFG-E8 alleviates hypoxic-ischemic encephalopathy brain injury in neonatal rats by restoring autophagy flux and inhibiting ferroptosis through GSK3β/β-catenin signaling |
| title_short | The umbilical cord blood exosome MFG-E8 alleviates hypoxic-ischemic encephalopathy brain injury in neonatal rats by restoring autophagy flux and inhibiting ferroptosis through GSK3β/β-catenin signaling |
| title_sort | umbilical cord blood exosome mfg e8 alleviates hypoxic ischemic encephalopathy brain injury in neonatal rats by restoring autophagy flux and inhibiting ferroptosis through gsk3β β catenin signaling |
| topic | Hypoxic-ischemic encephalopathy HUCB-Exo MFG-E8 GSK3β/β-catenin pathway Autophagy Ferroptosis |
| url | http://www.sciencedirect.com/science/article/pii/S235232042500149X |
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