RESUMO
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.
RESUMO
Coronavirus Disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to considerable morbidity and mortality worldwide. The clinical manifestation of COVID-19 ranges from asymptomatic or mild infection to severe or critical illness, such as respiratory failure, multi-organ dysfunction or even death. Large-scale genetic association studies have indicated that genetic variations affecting SARS-CoV-2 receptors (angiotensin-converting enzymes, transmembrane serine protease-2) and immune components (Interferons, Interleukins, Toll-like receptors and Human leukocyte antigen) are critical host determinants related to the severity of COVID-19. Genetic background, such as 3p21.31 and 9q34.2 loci were also identified to influence outcomes of COVID-19. In this review, we aimed to summarize the current literature focusing on human genetic factors that may contribute to the observed diversified severity of COVID-19. Enhanced understanding of host genetic factors and viral interactions of SARS-CoV-2 could provide scientific bases for personalized preventive measures and precision medicine strategies.
