Human cerebral organoids as a model system for neural development and disease

项目摘要/摘要 耐人寻味的是，一个受精卵是如何分裂并产生一个包含不同种类的 细胞、组织和器官以精确的方式具有美丽的三维(3D)架构。这个 新皮质特别令人感兴趣，因为它是高度专业化的结构，其特征明显 不同物种之间的差异。例如，灵长类动物的新大脑皮层的大小和 复杂性，这可能赋予人类非凡的感觉活动和智力能力，如 抽象思维和创造力。了解人类的皮质醇生成不仅对获得一些 进化洞察力，也是为了发现人类特有疾病的根本原因，如 神经发育、神经退行性和神经精神障碍。我们理想上需要一个人脑 考虑到啮齿动物模型有时无法模拟人类症状和预测临床结果，研究人员提出了一种新的模型。 然而，由于对人脑组织的接触有限，以及伦理方面的考虑，直接 研究人的发展。因此，体外培养细胞的产生受到了极大的关注。 使用人类多能干细胞(HPSCs)概括人类发育和 疾病。大脑器质是来源于hPSCs的三维皮质组织，可概括为板层。 体内发育中的大脑新皮质的组织。这种有机化合物技术的出现开启了 这是研究人类特定发育特征的大门，为疾病建模铺平了道路。 然而，许多有机物鉴别方案效率低下且不一致，并且表现出明显的可变性 他们有能力重述发育中的人脑中神经发生的3D结构和过程。 这项建议的目标是了解1)可以预测高效和成功的hPSC的状态 类有机物分化，2)使用这个强大的类有机物系统来发现具有 对人类大脑活动及其故障的潜在重要性很可能与神经精神障碍有关， 例如自闭症，以及3)研究脆性X综合征，这是认知障碍最常见的可遗传形式， 使用人类皮质有机体，可以提供一些人类特有的洞察机制和治疗方法 疾病。

Project Summary/Abstract It is intriguing how a single fertilized egg divides and gives rise to an organism containing a diverse array of cells, tissues, and organs with beautiful three-dimensional (3D) architecture in a precise manner. The neocortex is of particular interest because it is highly-specialized structure with features that are markedly different between species. For example, the neocortex in primates is enormously increased in size and complexity, which probably endow humans with remarkable sensory activities and intellectual ability such as abstract thinking and creativity. Understanding human corticogenesis is important for not only to gain some evolutionary insights but also to discover the underlying causes of human-specific diseases such as neurodevelopmental, neurodegenerative, and neuropsychiatric disorders. We ideally need a human brain model, given that rodent models sometimes fail to mimic human symptoms and predict clinical outcomes. However, due to limited access to human brain tissue and ethical concerns, it has been challenging to directly study human development. Consequently, considerable attention has been placed on the generation of in vitro models using human pluripotent stem cells (hPSCs) to recapitulate aspects of human development and disease. The cerebral organoid is a 3D cortical tissue derived from hPSCs and recapitulates laminar organization of the developing cerebral neocortex in vivo. The advent of such organoid techniques has opened the door for studies of human specific developmental features and paves the way for disease modeling. However, many organoid differentiation protocols are inefficient and inconsistent and display marked variability in their ability to recapitulate the 3D architecture and course of neurogenesis in the developing human brain. The goal of this proposal is to understand 1) the state of hPSCs that can predict efficient and successful organoid differentiation, 2) to use this robust organoid system to uncover microcircuit formation that has the underlying importance for human brain activities and its malfunction is likely link to neuropsychiatric disorders, such as autism, and 3) to study Fragile X Syndrome, the most common heritable form of cognitive impairment, using human cortical organoids that can give some human-specific insights into mechanisms and cures of this disease.