Oligodendrocyte Progenitor Cell Transplantation Reduces White Matter Injury in a Fetal Goat Model

IF 4.8 1区医学 Q1 NEUROSCIENCES CNS Neuroscience & Therapeutics Pub Date : 2024-12-17 DOI:10.1111/cns.70178

Yan Yue, Bixin Deng, Yan Zeng, Wenxing Li, Xia Qiu, Peng Hu, LiuHong Shen, Tiechao Ruan, Ruixi Zhou, Shiping Li, Junjie Ying, Tao Xiong, Yi Qu, Zuo Luan, Dezhi Mu

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Abstract

Background

Preterm white matter injury (PWMI) is the most common type of brain injury in preterm infants, in which, oligodendrocyte progenitor cells (OPCs) are predominantly damaged. In this study, human OPCs (hOPCs) were administered to a fetal goat model of PWMI to examine the differentiation potential and therapeutic effects of the cells on PWMI.

Methods

Preterm goat fetuses were subjected to hypoxic-ischemia (HI) via intermittent umbilical cord occlusion (5 min × 5). Twenty million hOPCs were administered via a nasal catheter 12 h after an HI insult, and brain tissues were collected 14 or 21 days after the HI insult. Myelin basic protein (MBP) and myelin-associated glycoprotein (MAG) were detected by immunofluorescence and western blotting techniques. The percentage of myelinated nerve fibers and g-ratio were examined using transmission electron microscopy. Inflammatory cells were detected by immunohistochemistry. Inflammatory and neurotrophic factors were measured using enzyme-linked immunosorbent assay.

Results

Our results showed that intermittent umbilical cord occlusion induced PWMI in fetal goats. Transplanted hOPCs can survive in periventricular and subcortical white matter. Further, transplanted hOPCs expressed markers of mature oligodendrocytes (MBP and MAG) and few cells expressed markers of preoligodendrocytes (NG2 and A2B5), suggesting that these cells can differentiate into mature oligodendrocytes in the brain. In addition, hOPCs administration increased MBP and MAG levels, percentage of myelinated nerve fibers, and thickness of the myelin sheath, indicating a reduction in PWMI. Furthermore, hOPCs did not increase the inflammatory response after HI. Interestingly, hOPC administration decreased tumor necrosis factor-alpha and increased glial-derived neurotrophic factor and brain-derived neurotrophic factor levels after HI, suggesting that additional mechanisms mediate the inflammatory microenvironment and neuroprotective effects.

Conclusions

Exogenous hOPCs can differentiate into mature oligodendrocytes in fetal goats and alleviate HI-induced PWMI. Transplantation of hOPCs is a promising strategy for treating PWMI.

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少突胶质祖细胞移植减轻胎羊模型的白质损伤

背景：早产儿白质损伤（PWMI）是早产儿中最常见的脑损伤类型，其中少突胶质祖细胞（OPCs）主要受损。本研究将人OPCs （hOPCs）注入胎儿山羊PWMI模型，观察其分化潜能和对PWMI的治疗作用。方法：采用间歇脐带阻断法（5min × 5）对山羊早产儿进行缺氧缺血（HI）治疗。在HI损伤后12小时通过鼻导管给药2000万hopc，并在HI损伤后14或21天收集脑组织。采用免疫荧光和western blotting技术检测髓鞘碱性蛋白（MBP）和髓鞘相关糖蛋白（MAG）。透射电镜观察大鼠有髓神经纤维百分率和g比值。免疫组化法检测炎症细胞。采用酶联免疫吸附法测定炎症因子和神经营养因子。结果：间断性脐带阻断可诱发胎山羊PWMI。移植的hOPCs可在脑室周围和皮层下白质中存活。此外，移植的hOPCs表达成熟少突胶质细胞标记物（MBP和MAG），少数细胞表达前少突胶质细胞标记物（NG2和A2B5），表明这些细胞可以在脑内分化为成熟的少突胶质细胞。此外，hOPCs增加了MBP和MAG水平，髓鞘神经纤维百分比和髓鞘厚度，表明PWMI减少。此外，hopc并未增加HI后的炎症反应。有趣的是，给药hOPC降低了HI后的肿瘤坏死因子- α，增加了胶质源性神经营养因子和脑源性神经营养因子的水平，表明有其他机制介导炎症微环境和神经保护作用。结论：外源性hOPCs可在胎山羊分化为成熟少突胶质细胞，减轻hi诱导的PWMI。hOPCs移植是治疗PWMI的一种很有前途的策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.