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Sliced Human Cortical Organoids for Modeling Distinct Cortical Layer Formation.
Cell Stem Cell ( IF 23.9 ) Pub Date : 2020-03-05 , DOI: 10.1016/j.stem.2020.02.002
Xuyu Qian 1 , Yijing Su 2 , Christopher D Adam 3 , Andre U Deutschmann 4 , Sarshan R Pather 5 , Ethan M Goldberg 6 , Kenong Su 7 , Shiying Li 8 , Lu Lu 2 , Fadi Jacob 9 , Phuong T T Nguyen 3 , Sooyoung Huh 2 , Ahmet Hoke 10 , Sarah E Swinford-Jackson 11 , Zhexing Wen 12 , Xiaosong Gu 13 , R Christopher Pierce 14 , Hao Wu 15 , Lisa A Briand 4 , H Isaac Chen 16 , John A Wolf 17 , Hongjun Song 18 , Guo-Li Ming 19
Affiliation  

Human brain organoids provide unique platforms for modeling development and diseases by recapitulating the architecture of the embryonic brain. However, current organoid methods are limited by interior hypoxia and cell death due to insufficient surface diffusion, preventing generation of architecture resembling late developmental stages. Here, we report the sliced neocortical organoid (SNO) system, which bypasses the diffusion limit to prevent cell death over long-term cultures. This method leads to sustained neurogenesis and formation of an expanded cortical plate that establishes distinct upper and deep cortical layers for neurons and astrocytes, resembling the third trimester embryonic human neocortex. Using the SNO system, we further identify a critical role of WNT/β-catenin signaling in regulating human cortical neuron subtype fate specification, which is disrupted by a psychiatric-disorder-associated genetic mutation in patient induced pluripotent stem cell (iPSC)-derived SNOs. These results demonstrate the utility of SNOs for investigating previously inaccessible human-specific, late-stage cortical development and disease-relevant mechanisms.

中文翻译:

切片人类皮质类固醇用于建模不同的皮质层形成。

人脑类器官动物通过概述胚胎脑的结构,为建模发育和疾病提供了独特的平台。然而,当前的类器官方法受到内部缺氧和由于表面扩散不足而导致细胞死亡的限制,从而阻止了类似于晚期发育阶段的结构的产生。在这里,我们报道了切片的新皮层类器官(SNO)系统,该系统绕过了扩散限制,以防止长期培养后细胞死亡。这种方法导致持续的神经发生并形成膨胀的皮质板,该皮质板为神经元和星形胶质细胞建立了明显的上层皮质层和深层皮质层,类似于孕晚期胚胎人类新皮层。使用SNO系统 我们进一步确定了WNT /β-catenin信号在调节人类皮质神经元亚型命运规范中的关键作用,后者在患者诱导的多能干细胞(iPSC)衍生的SNO中被精神疾病相关的基因突变所破坏。这些结果表明,SNOs可用于研究以前无法接近的人特异性晚期皮质发育和与疾病相关的机制。
更新日期:2020-03-05
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