Bershteyn Marina, Nowakowski Tomasz J, Pollen Alex A, Di Lullo Elizabeth, Nene Aishwarya, Wynshaw-Boris Anthony, Kriegstein Arnold R
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA.
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA.
Cell Stem Cell. 2017 Apr 6;20(4):435-449.e4. doi: 10.1016/j.stem.2016.12.007. Epub 2017 Jan 19.
Classical lissencephaly is a genetic neurological disorder associated with mental retardation and intractable epilepsy, and Miller-Dieker syndrome (MDS) is the most severe form of the disease. In this study, to investigate the effects of MDS on human progenitor subtypes that control neuronal output and influence brain topology, we analyzed cerebral organoids derived from control and MDS-induced pluripotent stem cells (iPSCs) using time-lapse imaging, immunostaining, and single-cell RNA sequencing. We saw a cell migration defect that was rescued when we corrected the MDS causative chromosomal deletion and severe apoptosis of the founder neuroepithelial stem cells, accompanied by increased horizontal cell divisions. We also identified a mitotic defect in outer radial glia, a progenitor subtype that is largely absent from lissencephalic rodents but critical for human neocortical expansion. Our study, therefore, deepens our understanding of MDS cellular pathogenesis and highlights the broad utility of cerebral organoids for modeling human neurodevelopmental disorders.
经典型无脑回畸形是一种与智力迟钝和难治性癫痫相关的遗传性神经障碍，而米勒-迪克尔综合征（MDS）是该疾病最严重的形式。在本研究中，为了探究MDS对控制神经元输出并影响脑拓扑结构的人类祖细胞亚型的影响，我们使用延时成像、免疫染色和单细胞RNA测序分析了源自对照和MDS诱导多能干细胞（iPSC）的脑类器官。我们观察到一种细胞迁移缺陷，当我们纠正MDS致病染色体缺失时该缺陷得到挽救，同时发现奠基神经上皮干细胞发生严重凋亡，并伴有水平细胞分裂增加。我们还在外侧放射状胶质细胞中发现了一种有丝分裂缺陷，外侧放射状胶质细胞是一种祖细胞亚型，在无脑回畸形啮齿动物中基本不存在，但对人类新皮层扩张至关重要。因此，我们的研究加深了我们对MDS细胞发病机制的理解，并突出了脑类器官在模拟人类神经发育障碍方面的广泛用途。
