Zhao Menghua, Wu Yizhong, Huang Li, Wang Juanmei, Zhang Aimin
Department of Pediatrics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005, China.
Department of Gastroenterology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005, China.
Regen Ther. 2025 Jul 4;30:321-332. doi: 10.1016/j.reth.2025.06.016. eCollection 2025 Dec.
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.
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.
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 Fe, MDA, and ROS levels in HIE neonatal rats. Similarly, these results were observed . 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-Exo 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.
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.
近期研究揭示了人脐带血（HUCB）来源的外泌体（HUCB-Exo）在中枢神经系统疾病中的重要性，但HUCB-Exo在缺氧缺血性脑病（HIE）中的作用仍不清楚。本研究旨在探讨HUCB-Exo在HIE中的作用机制。
采用经典的Rice-Vannucci模型在7日龄新生大鼠中构建HIE模型，并用氧糖剥夺/复灌注（OGD/R）损伤诱导SH-SY5Y细胞，然后分别用未转染或转染了si-NC/si-MFG-E8的HUCB和HUBC-Exo进行干预。
HUBC-Exo减小了HIE新生大鼠的脑梗死面积和脑含水量，并改善了短期和长期神经功能。HUBC-Exo下调了HIE新生大鼠中Beclin1、ATG7和LC3 II/I的表达，同时促进了p62的表达。HUBC-Exo处理后，HIE新生大鼠中NCOA4和ACSL4的表达降低，而FTH1、SLC7A11和GPX-4的表达增加。此外，HUBC-Exo降低了HIE新生大鼠中的铁、丙二醛和活性氧水平。同样，在OGD/R诱导的SH-SY5Y细胞中也观察到了这些结果。HUBC-Exo抑制了OGD/R诱导的SH-SY5Y细胞中的自噬和铁死亡，而MFG-E8沉默则中断了HUBC-Exo的作用效果。进一步的结果表明，HUBC-Exo来源的MFG-E8促进了OGD/R诱导的SH-SY5Y细胞中p-GSK3β/GSK3β和活性-β-连环蛋白/β-连环蛋白的水平。重要的是，GSK3β激动剂氯化锂消除了HUBC-Exo对OGD/R诱导的SH-SY5Y细胞中自噬和铁死亡的促进作用。HUBC-Exo的MFG-E8抑制了自噬和铁死亡，从而减轻了HIE新生大鼠的脑损伤。
我们的结果表明，HUBC-Exo传递的MFG-E8通过GSK3β/β-连环蛋白信号通路抑制自噬和铁死亡，从而减轻HIE新生大鼠的脑损伤，这为治疗HIE提供了新思路。
