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通过人类神经干细胞及其在中年帕金森病小鼠中的移植探索帕金森病的多因素性

Multifactoriality of Parkinson's Disease as Explored Through Human Neural Stem Cells and Their Transplantation in Middle-Aged Parkinsonian Mice.

作者信息

Nelke Anna, García-López Silvia, Martínez-Serrano Alberto, Pereira Marta P

机构信息

Tissue and Organ Homeostasis Program, Centro de Biología Molecular Severo Ochoa UAM-CSIC, Madrid, Spain.

Department of Molecular Biology, Faculty of Science, Universidad Autónoma de Madrid, Madrid, Spain.

出版信息

Front Pharmacol. 2022 Jan 19;12:773925. doi: 10.3389/fphar.2021.773925. eCollection 2021.

Abstract

Parkinson's disease (PD) is an age-associated neurodegenerative disorder for which there is currently no cure. Cell replacement therapy is a potential treatment for PD; however, this therapy has more clinically beneficial outcomes in younger patients with less advanced PD. In this study, hVM1 clone 32 cells, a line of human neural stem cells, were characterized and subsequently transplanted in middle-aged Parkinsonian mice in order to examine cell replacement therapy as a treatment for PD. analyses revealed that these cells express standard dopamine-centered markers as well as others associated with mitochondrial and peroxisome function, as well as glucose and lipid metabolism. Four months after the transplantation of the hVM1 clone 32 cells, striatal expression of tyrosine hydroxylase was minimally reduced in all Parkinsonian mice but that of dopamine transporter was decreased to a greater extent in buffer compared to cell-treated mice. Behavioral tests showed marked differences between experimental groups, and cell transplant improved hyperactivity and gait alterations, while in the striatum, astroglial populations were increased in all groups due to age and a higher amount of microglia were found in Parkinsonian mice. In the motor cortex, nonphosphorylated neurofilament heavy was increased in all Parkinsonian mice. Overall, these findings demonstrate that hVM1 clone 32 cell transplant prevented motor and non-motor impairments and that PD is a complex disorder with many influencing factors, thus reinforcing the idea of novel targets for PD treatment that tend to be focused on dopamine and nigrostriatal damage.

摘要

帕金森病(PD)是一种与年龄相关的神经退行性疾病,目前尚无治愈方法。细胞替代疗法是治疗PD的一种潜在方法;然而,这种疗法在病情较轻的年轻PD患者中具有更显著的临床治疗效果。在本研究中,对人神经干细胞系hVM1克隆32细胞进行了特性鉴定,随后将其移植到中年帕金森病小鼠体内,以研究细胞替代疗法对PD的治疗作用。分析表明,这些细胞表达以多巴胺为中心的标准标志物以及与线粒体和过氧化物酶体功能以及葡萄糖和脂质代谢相关的其他标志物。hVM1克隆32细胞移植四个月后,所有帕金森病小鼠纹状体中酪氨酸羟化酶的表达略有降低,但与细胞治疗组小鼠相比,缓冲液处理组小鼠中多巴胺转运体的表达下降幅度更大。行为测试显示各实验组之间存在显著差异,细胞移植改善了多动和步态改变,而在纹状体中,由于年龄因素,所有组的星形胶质细胞数量均增加,且帕金森病小鼠中发现了更多的小胶质细胞。在运动皮层,所有帕金森病小鼠中未磷酸化的神经丝重链均增加。总体而言,这些发现表明hVM1克隆32细胞移植可预防运动和非运动功能障碍,且PD是一种受多种因素影响的复杂疾病,从而强化了PD治疗新靶点往往聚焦于多巴胺和黑质纹状体损伤这一观点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9740/8807563/846823034b97/fphar-12-773925-g001.jpg

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