小分子 GSK-3 抑制剂可增加人神经祖细胞的神经发生。

Small molecule GSK-3 inhibitors increase neurogenesis of human neural progenitor cells.

机构信息

Neurobiological Laboratory, Department of Neurology, University of Rostock, Germany.

出版信息

Neurosci Lett. 2011 Jan 13;488(1):36-40. doi: 10.1016/j.neulet.2010.10.076. Epub 2010 Nov 5.

Abstract

Human neural progenitor cells provide a source for cell replacement therapy to treat neurodegenerative diseases. Therefore, there is great interest in mechanisms and tools to direct the fate of multipotent progenitor cells during their differentiation to increase the yield of a desired cell type. We tested small molecule inhibitors of glycogen synthase kinase-3 (GSK-3) for their functionality and their influence on neurogenesis using the human neural progenitor cell line ReNcell VM. Here we report the enhancement of neurogenesis of human neural progenitor cells by treatment with GSK-3 inhibitors. We tested different small molecule inhibitors of GSK-3 i.e. LiCl, sodium-valproate, kenpaullone, indirubin-3-monoxime and SB-216763 for their ability to inhibit GSK-3 in human neural progenitor cells. The highest in situ GSK-3 inhibitory effect of the drugs was found for kenpaullone and SB-216763. Accordingly, kenpaullone and SB-216763 were the only drugs tested in this study to stimulate the Wnt/β-catenin pathway that is antagonized by GSK-3. Analysis of human neural progenitor differentiation revealed an augmentation of neurogenesis by SB-216763 and kenpaullone, without changing cell cycle exit or cell survival. Small molecule inhibitors of GSK-3 enhance neurogenesis of human neural progenitor cells and may be used to direct the differentiation of neural stem and progenitor cells in therapeutic applications.

摘要

人类神经祖细胞为治疗神经退行性疾病的细胞替代疗法提供了来源。因此,人们非常关注能够在多能祖细胞分化过程中指导其命运的机制和工具,以增加所需细胞类型的产量。我们使用人神经祖细胞系 ReNcell VM 测试了糖原合酶激酶-3(GSK-3)小分子抑制剂的功能及其对神经发生的影响。在这里,我们报告了 GSK-3 抑制剂处理增强了人神经祖细胞的神经发生。我们测试了不同的 GSK-3 小分子抑制剂,即 LiCl、Sodium-valproate、Kenpaullone、Indirubin-3-monoxime 和 SB-216763,以确定它们抑制人神经祖细胞中 GSK-3 的能力。发现药物对 GSK-3 的原位抑制作用最高的是 Kenpaullone 和 SB-216763。因此,Kenpaullone 和 SB-216763 是本研究中唯一测试的刺激 Wnt/β-catenin 途径的药物,该途径被 GSK-3 拮抗。人神经祖细胞分化分析显示,SB-216763 和 Kenpaullone 增强了神经发生,而不会改变细胞周期退出或细胞存活。GSK-3 的小分子抑制剂增强了人神经祖细胞的神经发生,可用于指导神经干细胞和祖细胞在治疗应用中的分化。

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