人脑发育是一个复杂的过程,涉及精确定时的细胞增殖协调,命运规范,神经元分化,迁移,和不同细胞类型的整合。了解这些基本过程,然而,在很大程度上受到胎儿脑组织的限制,以及无法前瞻性地研究人类神经发育的分子,细胞和系统水平。尽管非人类模型生物对大脑发育的潜在机制提供了重要的见解,这些系统并没有完全概括许多通常与疾病相关的人类特异性特征。为了应对这些挑战,人脑类器官,自组装的三维神经聚集体,已经从人类多能干细胞工程,以模拟发育中的人类大脑的结构和细胞多样性。使用小分子和生长因子的神经诱导和区域模式的最新进展已经产生了用于生成脑类器官的方案,该方案概括了不同脑区域的结构和神经元组成。这里,我们首先提供哺乳动物早期大脑发育的概述,重点是指导区域规范的分子线索。然后,我们专注于最近在生成人脑类器官方面的努力,这些器官模拟了特定大脑区域的发育,并强调了增强细胞复杂性以更好地模仿体内发育中的人脑的努力。我们还提供了类器官模型如何增强我们对人类神经系统疾病的理解的示例,并通过讨论大脑类器官的局限性以及我们对未来进步的看法来得出结论,以最大限度地发挥其潜力。
Human brain development is an intricate process that involves precisely timed coordination of cell proliferation, fate specification, neuronal differentiation, migration, and integration of diverse cell types. Understanding of these fundamental processes, however, has been largely constrained by limited access to fetal brain tissue and the inability to prospectively
study neurodevelopment in humans at the molecular, cellular and system levels. Although non-human model organisms have provided important insights into mechanisms underlying brain development, these systems do not fully recapitulate many human-specific features that often relate to disease. To address these challenges, human brain organoids, self-assembled three-dimensional neural aggregates, have been engineered from human pluripotent stem cells to model the architecture and cellular diversity of the developing human brain. Recent advancements in neural induction and regional
patterning using small molecules and growth factors have yielded protocols for generating brain organoids that recapitulate the structure and neuronal composition of distinct brain regions. Here, we first provide an overview of early mammalian brain development with an emphasis on molecular cues that guide region specification. We then focus on recent efforts in generating human brain organoids that model the development of specific brain regions and highlight endeavors to enhance the cellular complexity to better mimic the in vivo developing human brain. We also provide examples of how organoid models have enhanced our understanding of human neurological diseases and conclude by discussing limitations of brain organoids with our perspectives on future advancements to maximize their potential.