Human umbilical cord mesenchymal stem cells protect against neonatal white matter injury by activating the Nrf2/Keap1/HO-1 signaling pathway.
10.7499/j.issn.1008-8830.2504152
- Author:
Chao WANG
1
;
Meng-Xin WANG
1
;
Yan-Ping ZHU
Author Information
1. Department of Neonatology, First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China.
- Publication Type:Journal Article
- Keywords:
Human umbilical cord mesenchymal stem cell;
Neonatal rat;
Nuclear factor-erythroid 2-related factor 2;
Oligodendrocyte;
White matter injury
- MeSH:
NF-E2-Related Factor 2/physiology*;
Animals;
Rats, Sprague-Dawley;
Signal Transduction/physiology*;
Humans;
Rats;
White Matter/pathology*;
Kelch-Like ECH-Associated Protein 1/physiology*;
Umbilical Cord/cytology*;
Heme Oxygenase-1/physiology*;
Animals, Newborn;
Male;
Mesenchymal Stem Cell Transplantation;
Heme Oxygenase (Decyclizing)/physiology*;
Mesenchymal Stem Cells/physiology*;
Female;
Hypoxia-Ischemia, Brain
- From:
Chinese Journal of Contemporary Pediatrics
2025;27(11):1398-1407
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVES: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.
