Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
Curr Top Dev Biol. 2021;142:477-530. doi: 10.1016/bs.ctdb.2020.12.011. Epub 2021 Feb 18.
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.
人类大脑发育是一个复杂的过程，涉及细胞增殖、命运特化、神经元分化、迁移和不同细胞类型的整合的精确时间协调。然而，对这些基本过程的理解在很大程度上受到胎儿脑组织获取有限和无法在分子、细胞和系统水平上前瞻性研究人类神经发育的限制。尽管非人类模式生物为大脑发育的机制提供了重要的见解，但这些系统不能完全再现许多与疾病相关的人类特有的特征。为了解决这些挑战，人类类器官，即由人类多能干细胞自组装成的三维神经聚集体，已被设计用于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进行神经诱导和区域模式化的最新进展已经产生了生成类器官的方案，这些类器官再现了不同脑区的结构和神经元组成。在这里，我们首先概述早期哺乳动物大脑发育，重点介绍指导区域特化的分子线索。然后，我们专注于最近生成类器官的努力，这些类器官可模拟特定脑区的发育，并强调努力提高细胞复杂性以更好地模拟体内发育中的人类大脑。我们还提供了类器官模型如何增强我们对人类神经疾病的理解的示例，并通过讨论类器官的局限性以及我们对未来最大程度发挥其潜力的进展的看法来结束。
