Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292, USA; University of Louisville Alcohol Research Center, Louisville, KY 40292, USA; Department of Medicine, University of Louisville, Louisville, KY 40292, USA.
Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292, USA; University of Louisville Alcohol Research Center, Louisville, KY 40292, USA.
Exp Neurol. 2023 Apr;362:114325. doi: 10.1016/j.expneurol.2023.114325. Epub 2023 Jan 18.
Radial glial cells (RGCs) play a pivotal role in cerebral cortical development by functioning as a source of new neurons and by supporting the migration of newborn neurons. These functions are primarily dependent on the apical-basolateral structures of radial glial processes. This study aims to investigate the effects of ethanol exposure on the development of radial glial processes and the generation, migration, and transformation of outer radial glial cells (oRGCs). For this purpose, forebrain organoids were developed from human embryonic stem cells. These forebrain organoids contain abundant neural progenitor cells (SOX2), express high levels of neural epithelial markers β-catenin and PKCλ, and dorsal forebrain marker PAX6, and display well-organized cortical architectures containing abundant apical and basal RGCs, intermediate progenitors (IPCs), and neurons. Exposure of forebrain organoids to ethanol resulted in a significant increase in apoptosis in Nestin-positive radial glial cells. Ethanol exposure also remarkably decreased the levels of radial glial process-associated proteins, including Nestin, GFAP, and Vimentin, in radial glial cells and distinctly impaired the integrity and morphologies of radial glial processes. In addition, the ethanol-induced impairment of the radial glial processes is associated with decreased migration and proliferation of radial glial cells, reduction in the generation of HOPX oRGCs, and the accelerated transformation of oRGCs into astrocytes. These results demonstrate that ethanol exposure can disrupt cerebral cortex development by impairing the formation of radial glial processes and the generation, migration, and transformation of oRGCs.
放射状胶质细胞（RGCs）在大脑皮层发育中起着至关重要的作用，它既是新神经元的来源，又能支持新生神经元的迁移。这些功能主要依赖于放射状胶质突起的顶-底结构。本研究旨在探讨乙醇暴露对放射状胶质突起发育以及外放射状胶质细胞（oRGC）的发生、迁移和转化的影响。为此，从人胚胎干细胞中开发出了前脑类器官。这些前脑类器官含有丰富的神经祖细胞（SOX2），表达高水平的神经上皮标志物β-连环蛋白和 PKCλ，以及背侧前脑标志物 PAX6，并呈现出具有丰富顶和基底 RGCs、中间祖细胞（IPCs）和神经元的组织良好的皮质结构。将前脑类器官暴露于乙醇中会导致巢蛋白阳性放射状胶质细胞的凋亡显著增加。乙醇暴露还明显降低了放射状胶质细胞中与放射状胶质突起相关的蛋白质的水平，包括巢蛋白、GFAP 和波形蛋白，并明显损害了放射状胶质突起的完整性和形态。此外，乙醇诱导的放射状胶质突起损伤与放射状胶质细胞的迁移和增殖减少、HOPX oRGCs 的生成减少以及 oRGCs 向星形胶质细胞的加速转化有关。这些结果表明，乙醇暴露可通过损害放射状胶质突起的形成以及 oRGC 的发生、迁移和转化来破坏大脑皮层的发育。
