Neural Organoids and the Quest to Understand and Treat Psychiatric Disease.
Neural Organoids and the Quest to Understand and Treat Psychiatric Disease.
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神经类器官和理解和治疗精神疾病的探索。
DOI：
10.1016/j.biopsych.2023.01.021
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发表时间：
2023
影响因子：
10.6
通讯作者：
Gage,FredH
中科院分区：
文献类型：
--
作者：
Arlotta,Paola;Gage,FredH
由于缺乏能够反映人类认知疾病的遗传状态 8 以及大脑 9 发育和功能的物种特异性差异的模型，理解人类精神疾病 7 疾病分子机制的进展受到阻碍。对于占大多数病例的散发型精神疾病 10 来说尤其如此；这些病例通常与 11 多种常见风险变异的累积贡献有关，每种变异的影响都很小，12 类型的遗传结构很难或不可能在动物模型中复制。 13 源自人类患者的 iPS 细胞为研究更广泛的基因组景观对疾病状态的贡献提供了革命性的进展，15 3D 大脑类器官模型的出现为研究人脑发育和疾病的细胞和 16 分子基础打开了一个新窗口。在本期特刊 17 中，该领域的领导者就使用人体类器官模型 18 了解精神疾病提出了他们的观点。 19在过去的几十年里，该领域逐渐开发出了 20 个正在发育的人类中枢神经系统的更复杂的 3D 模型。基于胚胎用来生成不同大脑区域的模式机制 21 ，该领域已经开发了针对多个单独大脑区域的 22 个类器官模型的协议。这项工作导致人们尝试 23 开发结合不同区域的模型，例如组合体，这使得 24 能够研究依赖于多个区域的大脑发育和功能的各个方面，例如长距离连接和神经迁移。张 26 等人 (1) 总结了区域特定模型的进展及其在研究遗传风险和人类发展的 27 种影响方面的效用。 Urenda 等人 (2) 描述了使用多区域类器官研究长距离连接的 28 机会及其在疾病中的功能障碍。正如两篇文章中所指出的，建立 30 个可稳健重复和标准化的多区域模型仍有工作要做，包括建立通常位于两个特定大脑区域之间的 31 个大脑区域，以及 32 个可能对于指导正确的连接很重要。还存在 33 种建立方法的挑战，这些方法允许来自多个大脑区域的组织（可能有 34 种不同的生长要求）作为单一系统培养 35 时间。此外，虽然多个类器官系统在产生 36 种细胞类型和转录组状态时表现出良好的保真度，但正常大脑结构（例如 37 皮质层或丘脑核）的建模迄今为止仍然难以实现。 38 39
Progress in understanding the molecular mechanisms underlying human psychiatric 7 disease has been hampered by the lack of models that can reflect the genetic states 8 underlying human cognitive disease and species-specific differences in brain 9 development and function. This is particularly true of sporadic forms of psychiatric 10 disease, which account for the majority of cases; these cases are often associated with 11 the cumulative contribution of multiple common risk variants, each with small effects, a 12 type of genetic structure that is difficult or impossible to replicate in animal models. 13 Human patient-derived iPS cells present a revolutionary advance for the study of the 14 contribution of the broader genomic landscape to disease states, and the emergence of 15 3D brain organoid models has opened a new window to investigate the cellular and 16 molecular underpinnings of human brain development and disease. In this special 17 issue, leaders in this field offer their perspectives on the use of human organoid models 18 to understand psychiatric disease. 19In the last decades, the field has developed progressively more complex 3D models of 20 the developing human central nervous system. Building on patterning mechanisms used 21 by the embryo to generate distinct brain regions, the field has developed protocols for 22 organoid models of a multitude of individual brain regions. This work has led to attempts 23 to develop models that combine different regions, such as assembloids, which enable 24 the study of aspects of the development and functionality of the brain that depend on 25 more than one region, such as long-distance connectivity and neural migration. Zhang 26 et al.(1) summarize progress on region-specific models and their utility to investigate the 27 effects of genetic risk and human development. Urenda et al.(2) describe the 28 opportunity to use multi-region organoids to investigate long-distance connectivity and 29 its dysfunction in disease. As pointed out in both pieces, work remains to establish 30 robustly reproducible and standardized multi-region models, including the establishment 31 of brain territories that are normally located between two specific brain regions and that 32 may be important for guiding proper connectivity. There is also the challenge of 33 establishing methods that allow tissue from multiple brain regions, which may have 34 different growth requirements, to be cultured as a single system for extended periods of 35 time. In addition, while multiple organoid systems have shown good fidelity in production 36 of cell types and transcriptomic states, modelling of normal brain architecture such as 37 cortical layers or thalamic nuclei has so far remained elusive. 38 39