Transplantation of human umbilical cord mesenchymal stem cells to repair myelination disorders in neonatal rats with white matter injury

Abstract

BACKGROUND: Myelination deficits are a core feature of white matter injury in preterm infants. In recent years, human umbilical cord mesenchymal stem cells have been applied in various animal models of brain injury, demonstrating the capacity to promote myelin repair. Elucidating the regulatory mechanisms by which human umbilical cord mesenchymal stem cells enhance neural myelination will contribute to optimizing therapeutic strategies and facilitating clinical translation. OBJECTIVE: To clarify the reparative effect of human umbilical cord mesenchymal stem cells on myelination disorders caused by maturation arrest of the oligodendrocyte lineage in neonatal rats with white matter injury. METHODS: Seventy-two 2-day-old Sprague-Dawley rats were randomly divided into sham operation group, white matter injury group, and human umbilical cord mesenchymal stem cell transplantation group (n=24 per group). A neonatal rat model of white matter injury was established by combining low-dose lipopolysaccharide with hypoxia-ischemia. On day 14 after modeling, pathological changes in white matter were observed by hematoxylin-eosin staining; the positive expression, protein and mRNA levels of oligodendrocyte lineage transcription factor 2, neural/glial antigen 2, and myelin basic protein were detected by immunohistochemistry, western blot, and real-time quantitative PCR. On day 28 after modeling, myelin formation was observed by Luxol fast blue staining, and spatial learning and memory ability were tested by Morris water maze. RESULTS AND CONCLUSION: On day 14 after modeling, hematoxylin-eosin staining showed that in the white matter injury group, a large number of cells degenerated and necrosed, and nerve fibers were arranged disorderly; in the human umbilical cord mesenchymal stem cell transplantation group, cell morphology was close to normal and nerve fibers were arranged relatively neatly. On day 14 after modeling, there was no statistically significant difference in the positive expression, protein and mRNA levels of oligodendrocyte lineage transcription factor 2 among groups (P > 0.05). Compared with the sham operation group, the positive expression, protein and mRNA levels of neural/glial antigen 2 were upregulated (P < 0.05), while those of myelin basic protein were downregulated (P < 0.05) in the white matter injury group. Compared with the white matter injury group, the positive expression, protein and mRNA levels of neural/glial antigen 2 were downregulated (P < 0.05), while those of myelin basic protein were upregulated (P < 0.05) in the human umbilical cord mesenchymal stem cell transplantation group. On day 28 after modeling, Luxol fast blue staining showed that compared with the sham operation group, myelin expression was decreased in the white matter injury group (P < 0.05); compared with the white matter injury group, myelin expression was increased in the human umbilical cord mesenchymal stem cell transplantation group (P < 0.05). On day 28 after modeling, Morris water maze results showed that compared with the sham operation group, the escape latency was prolonged and the number of platform crossings was decreased in the white matter injury group (P < 0.05); compared with the white matter injury group, the escape latency was shortened and the number of platform crossings was increased in the human umbilical cord mesenchymal stem cell transplantation group (P < 0.05); there was no statistically significant difference in average swimming distance among groups (P > 0.05). These findings indicate that human umbilical cord mesenchymal stem cells can promote the maturation of the oligodendrocyte lineage, repair myelination disorders, and improve cognitive function in neonatal rats with white matter injury.

1. Introduction

Preterm white matter injury mainly occurs in premature infants born at 24-32 weeks of gestation [1], and can lead to typical neurodevelopmental deficits such as motor impairment, intellectual disability, learning difficulties, and long-term psychiatric abnormalities. Currently, clinical treatment for preterm white matter injury remains primarily symptomatic and supportive, including infection prevention, respiratory and circulatory management, and nutritional support, but lacks effective targeted therapy. Therefore, there is an urgent need to explore new early intervention strategies to improve prognosis.

Oligodendrocytes are the key cells responsible for myelination in the central nervous system. They originate from oligodendrocyte precursor cells derived from neural stem cells, and gradually differentiate into mature oligodendrocytes through the pre-myelinating oligodendrocyte stage, and begin to produce myelin [2]. The critical period of oligodendrocyte differentiation and maturation coincides with the vulnerable peak of preterm white matter injury, and oligodendrocytes are extremely sensitive to inflammation and hypoxia-ischemia, making them the main target cells of white matter injury [3]. Studies have shown that myelination disorder caused by oligodendrocyte maturation arrest is the core pathological feature of preterm white matter injury [4]. By regulating the disordered development of the oligodendrocyte lineage to promote white matter repair, it is possible to improve the prognosis of preterm white matter injury.