Modeling congenital brain malformations with brain organoids: a narrative review

BACKGROUND AND OBJECTIVE: 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. METHODS: 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. KEY CONTENT AND FINDINGS: 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. CONCLUSIONS: 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.