Ji Xiao-Shan, Ji Xiao-Li, Xiong Man, Zhou Wen-Hao
Department of Neonatology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
Key Laboratory of Birth Defects, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
Transl Pediatr. 2023 Jan 31;12(1):68-78. doi: 10.21037/tp-22-239. Epub 2022 Dec 8.
During embryonic development, the dysregulation of the proliferation and differentiation of neuronal progenitors triggers congenital brain malformations. These malformations are common causes of morbidity and mortality in patients younger than 2 years old. Animal models have provided considerable insights into the etiology of diseases that cause congenital brain malformations. However, the interspecies differences in brain structure limit the ability to transfer these insights directly to studies of humans. In recent years, brain organoids generated from human embryonic stem cells (hESCs) or human induced pluripotent stem cells (hiPSCs) using a 3-dimensional (3D) culture system have been used to resemble the structure and function of a developing human brain. Therefore, we aimed to summarize the different congenital brain malformations that have been modeled by organoids and discuss the ability of this model to reveal the cellular and molecular mechanisms of congenital brain malformations.
A comprehensive search was performed using PubMed and Web of Science's Core Collection for literature published from July 1, 2000 to July 1, 2022. Keywords included terms related to brain organoids and congenital brain malformations, as well as names of individual malformations.
The self-assembled 3D aggregates have been used to recapitulate structural malformations of human brains, such as microcephaly, macrocephaly, lissencephaly (LIS), and periventricular nodular heterotopia (PH). The use of disease-specific brain organoids has revealed unprecedented details of mechanisms that cause congenital brain malformations.
This review summarizes the establishment and development of brain organoid technologies and provides an overview of their applications in modeling congenital brain malformations. Although several hurdles still need to be overcome, using brain organoids has greatly expanded our ability to reveal the pathogenesis of congenital brain malformations. Compared with existing methods, the combination with cutting-edge technologies enables a more accurate diagnosis and development of increasingly personalized targeted therapy for patients with congenital brain diseases.
在胚胎发育过程中，神经祖细胞增殖和分化的失调会引发先天性脑畸形。这些畸形是2岁以下患者发病和死亡的常见原因。动物模型为导致先天性脑畸形的疾病病因提供了相当多的见解。然而，脑结构的种间差异限制了将这些见解直接应用于人类研究的能力。近年来，利用三维（3D）培养系统从人类胚胎干细胞（hESCs）或人类诱导多能干细胞（hiPSCs）生成的脑类器官已被用于模拟发育中的人类大脑的结构和功能。因此，我们旨在总结已通过类器官建模的不同先天性脑畸形，并讨论该模型揭示先天性脑畸形细胞和分子机制的能力。
使用PubMed和Web of Science核心合集对2000年7月1日至2022年7月1日发表的文献进行全面检索。关键词包括与脑类器官和先天性脑畸形相关的术语，以及个别畸形的名称。
自组装的3D聚集体已被用于重现人类大脑的结构畸形，如小头畸形、巨头畸形、无脑回畸形（LIS）和室管膜下结节性异位（PH）。使用疾病特异性脑类器官揭示了导致先天性脑畸形机制的前所未有的细节。
本综述总结了脑类器官技术的建立和发展，并概述了其在先天性脑畸形建模中的应用。尽管仍需克服一些障碍，但使用脑类器官极大地扩展了我们揭示先天性脑畸形发病机制的能力。与现有方法相比，与前沿技术相结合能够为先天性脑疾病患者进行更准确的诊断并开发越来越个性化的靶向治疗。
