Human iPSC-Derived Cerebral Organoids Model Cellular Features of Lissencephaly and Reveal Prolonged Mitosis of Outer Radial Glia.
Human iPSC-Derived Cerebral Organoids Model Cellular Features of Lissencephaly and Reveal Prolonged Mitosis of Outer Radial Glia.
复制标题
DOI：
10.1016/j.stem.2016.12.007
复制
发表时间：
2017-04-06
期刊：
影响因子：
23.9
通讯作者：
Kriegstein AR
中科院分区：
文献类型：
--
作者：
Bershteyn M;Nowakowski TJ;Pollen AA;Di Lullo E;Nene A;Wynshaw-Boris A;Kriegstein AR
经典无脑畸形是一种遗传性神经系统疾病，与智力低下和难治性癫痫有关，米勒-迪克尔综合征（MDS）是该疾病最严重的形式。在这项研究中，为了研究MDS对控制神经元输出和影响大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诱导的多能干细胞（iPSC）的脑类器官。当我们纠正MDS致病染色体缺失时，我们看到了细胞迁移缺陷，以及伴随水平细胞分裂增加的创始神经上皮干细胞的严重凋亡。我们还确定了一个有丝分裂缺陷的外部放射状胶质细胞，祖亚型，这是在很大程度上缺乏无脑啮齿动物，但人类新皮层扩张的关键。因此，我们的研究加深了对MDS细胞发病机制的理解，并强调了脑类器官在模拟人类神经发育障碍方面的广泛用途。Bershteyn及其同事表明，使用来自米勒-迪克尔综合征患者的iPSC进行无脑回畸形的脑类器官建模可以表征细胞和神经发育疾病表型，并鉴定外放射状胶质细胞中的有丝分裂缺陷，这是一种对人类皮质发育特别重要的细胞类型。
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 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 timelapse 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 understanding of MDS cellular pathogenesis and highlights the broad utility of cerebral organoids for modeling human neurodevelopmental disorders. Bershteyn and colleagues show that cerebral organoid modeling of lissencephaly using iPSCs derived from Miller Dieker Syndrome patients can characterize cellular and neurodevelopmental disease phenotypes, and identify a mitotic defect in outer radial glia, a cell type that is particularly important for human cortical development.
登录
查看更多内容
影响因子：
9.8
作者：
Cardoso, C;Leventer, RJ;Ledbetter, DH
通讯作者：
Ledbetter, DH
影响因子：
11.2
作者：
CHI, JG;DOOLING, EC;GILLES, FH
通讯作者：
GILLES, FH
影响因子：
64.8
作者：
HATTORI, M;ADACHI, H;INOUE, K
通讯作者：
INOUE, K
影响因子：
5.1
作者：
DOBYNS, WB;STRATTON, RF;LEDBETTER, DH
通讯作者：
LEDBETTER, DH
影响因子：
3.7
作者：
Hevner, Robert F.;Haydar, Tarik F.
通讯作者：
Haydar, Tarik F.