目的 探讨人脐带间充质干细胞（human umbilical cord mesenchymal stem cell, HUC-MSC）通过核转录因子红系2相关因子2（nuclear factor-erythroid 2-related factor 2, Nrf2）/Kelch样环氧氯丙烷相关蛋白1（Kelch-like epichlorohydrin-associated protein 1, Keap1）/血红素加氧酶1（heme oxygenase-1, HO-1）信号通路对新生大鼠脑白质损伤（white matter injury, WMI）的保护作用。 方法 将3日龄Sprague-Dawley大鼠通过单侧颈总动脉结扎联合低氧法构建新生大鼠WMI模型。实验分为两部分：（1）将新生大鼠随机分为假手术组、缺氧缺血（hypoxia-ischemia, HI）组、HUC-MSC组（各组n=36），于建模后7、14、21 d收集脑组织样本进行检测；（2）将新生大鼠随机分为假手术组、HI组、HUC-MSC组、HUC-MSC+ML385（Nrf2特异性抑制剂）组（各组n=12），于建模后14 d收集脑组织样本进行检测。采用苏木精-伊红染色观察脑组织病理改变，劳克坚牢蓝染色观察脑组织髓鞘化情况，免疫组织化学染色检测Nrf2、髓磷脂碱性蛋白质（myelin basic protein, MBP）及髓鞘蛋白脂质蛋白质（proteolipid protein, PLP）的定位表达，免疫荧光染色观察突触素（synaptophysin, SYP）、突触后致密区95（postsynaptic density-95, PSD-95）的定位表达，免疫印迹法检测Nrf2、Keap1、HO-1、SYP、PSD-95、MBP、PLP蛋白表达，Morris水迷宫实验评估大鼠空间认知能力改变。 结果 建模后7、14、21 d，假手术组脑白质结构完整，细胞形态正常，神经纤维排列整齐；HI组脑白质结构破裂、细胞空泡化、神经纤维排列紊乱；HUC-MSC组脑白质病理改变较HI组减轻；与HI组相比，HUC-MSC组Nrf2阳性表达和蛋白表达、HO-1蛋白表达增加（P<0.05），Keap1蛋白表达减少（P<0.05）。与HI组相比，HUC-MSC组SYP、PSD-95平均荧光强度和蛋白表达及MBP、PLP阳性表达和蛋白表达、髓鞘平均光密度值、平台穿越次数、目标象限停留时间增加（P<0.05）；与HUC-MSC组相比，HUC-MSC+ML385组上述指标降低（P<0.05）。 结论 HUC-MSC可能通过激活Nrf2/Keap1/HO-1信号通路促进新生大鼠WMI后少突胶质细胞的成熟和突触形成，改善其空间认知能力。

Objective To investigate whether human umbilical cord mesenchymal stem cells (HUC-MSCs) play protective effects against white matter injury (WMI) in neonatal rats via activation of the nuclear factor-erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)/heme oxygenase-1 (HO-1) signaling pathway. Methods A neonatal WMI model was established in 3-day-old Sprague-Dawley rats by unilateral common carotid artery ligation combined with hypoxia. The study comprised two parts. (1) Rats were randomized into sham, hypoxia-ischemia (HI), and HUC-MSC groups (n=36 per group); brain tissues were collected at 7, 14, and 21 days after modeling. (2) Rats were randomized into sham, HI, HUC-MSC, and HUC-MSC+ML385 (Nrf2 inhibitor) groups (n=12 per group); tissues were collected 14 days after modeling. Hematoxylin-eosin staining assessed histopathology, and Luxol fast blue staining evaluated myelination. Immunohistochemistry examined the localization and expression of Nrf2, myelin basic protein (MBP), and proteolipid protein (PLP). Immunofluorescence assessed synaptophysin (SYP) and postsynaptic density-95 (PSD-95). Western blotting quantified Nrf2, Keap1, HO-1, SYP, PSD-95, MBP, and PLP. Spatial learning and memory were evaluated by the Morris water maze. Results At 7, 14, and 21 days after modeling, the sham group showed intact white matter, whereas the HI group exhibited white matter disruption, cellular vacuolation, and disorganized nerve fibers. These pathological changes were attenuated in the HUC-MSC group. Compared with the HI group, the HUC-MSC group showed increased Nrf2 immunopositivity and protein levels, increased HO-1 protein levels, and decreased Keap1 protein levels (P<0.05). Compared with the HI group, the HUC-MSC group had higher SYP and PSD-95 immunofluorescence intensities and protein levels, higher MBP and PLP positivity and protein levels, increased mean optical density of myelin, more platform crossings, and longer time in the target quadrant (all P<0.05). These improvements were reduced in the HUC-MSC+ML385 group compared with the HUC-MSC group (P<0.05). Conclusions HUC-MSCs may promote oligodendrocyte maturation and synaptogenesis after neonatal WMI by activating the Nrf2/Keap1/HO-1 pathway, thereby improving spatial cognitive function.