美国加州大学旧金山分校Daniel H. Geschwind、斯坦福大学Sergiu P. Pasca等研究人员合作发现，人类皮质类器官的长期成熟能够与关键的早期产后过渡相似。这一研究成果于2021年2月22日在线发表在《自然—神经科学》上。

研究人员利用定向分化方案来全面评估了脑类器官的体外成熟度。基于表观遗传时钟和转录组学的全基因组分析，以及RNA编辑，研究人员观察到三维人类皮质类器官可达到出生后250至300天之间的阶段，这是与体内发育平行的时间线。研究人员验证了几个已知的发育里程碑，包括组蛋白去乙酰基酶复合体和NMDA受体亚基的转换，研究人员在蛋白质和生理水平上证实了这一点。

这些结果表明，体内固有发育程序的重要组成部分可在体外持续存在。研究人员进一步将神经发育和神经退行性疾病风险基因映射到体外基因表达轨迹上，从而提供了资源和网络工具（皮质类器官的基因表达，GECO）来指导疾病建模。

据悉，人类干细胞衍生的模型有望加深人们对脑部疾病的了解，但不知道它们是否具有能够在胎儿中期到晚期发育的能力，这可能会限制其实用性。

附：英文原文

Title: Long-term maturation of human cortical organoids matches key early postnatal transitions

Author: Aaron Gordon, Se-Jin Yoon, Stephen S. Tran, Christopher D. Makinson, Jin Young Park, Jimena Andersen, Alfredo M. Valencia, Steve Horvath, Xinshu Xiao, John R. Huguenard, Sergiu P. Paca, Daniel H. Geschwind

Issue&Volume: 2021-02-22

Abstract: Human stem-cell-derived models provide the promise of accelerating our understanding of brain disorders, but not knowing whether they possess the ability to mature beyond mid- to late-fetal stages potentially limits their utility. We leveraged a directed differentiation protocol to comprehensively assess maturation in vitro. Based on genome-wide analysis of the epigenetic clock and transcriptomics, as well as RNA editing, we observe that three-dimensional human cortical organoids reach postnatal stages between 250 and 300days, a timeline paralleling in vivo development. We demonstrate the presence of several known developmental milestones, including switches in the histone deacetylase complex and NMDA receptor subunits, which we confirm at the protein and physiological levels. These results suggest that important components of an intrinsic in vivo developmental program persist in vitro. We further map neurodevelopmental and neurodegenerative disease risk genes onto in vitro gene expression trajectories to provide a resource and webtool (Gene Expression in Cortical Organoids, GECO) to guide disease modeling.

DOI: 10.1038/s41593-021-00802-y

Source: https://www.nature.com/articles/s41593-021-00802-y