Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence RI 02906, USA; Center for Translational Neuroscience, Carney Brain Institute, Brown University, Providence RI 02906, USA.
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence RI 02906, USA; Center for Translational Neuroscience, Carney Brain Institute, Brown University, Providence RI 02906, USA.
Curr Opin Neurobiol. 2024 Dec;89:102916. doi: 10.1016/j.conb.2024.102916. Epub 2024 Sep 17.
Neurodevelopmental disorders (NDDs) affect 15% of children and are usually associated with intellectual disability, seizures, and autistic behaviors, among other neurological presentations. Mutations in a wide spectrum of gene families alter key stages of human brain development, leading to defects in neural circuits or brain architecture. Studies in animal systems have provided important insights into the pathobiology of several NDDs. Human stem cell technologies provide a complementary system that allows functional manipulation of human brain cells during developmental stages that would otherwise be inaccessible during human fetal brain development. Therefore, stem cell-based models advance our understanding of human brain development by revealing human-specific mechanisms contributing to the broad pathogenesis of NDDs. We provide a comprehensive overview of the latest research on two and three-dimensional human stem cell-based models. First, we discuss convergent cellular and molecular phenotypes across different NDDs that have been revealed by human iPSC systems. Next, we examine the contribution of in vitro human neural systems to the development of promising therapeutic strategies. Finally, we explore the potential of stem cell systems to draw mechanistic insight for the study of sex dimorphism within NDDs.
神经发育障碍（NDDs）影响 15%的儿童，通常与智力残疾、癫痫发作和自闭症行为等神经系统表现有关。广泛的基因家族的突变改变了人类大脑发育的关键阶段，导致神经回路或大脑结构的缺陷。动物系统的研究为几种 NDD 的病理生物学提供了重要的见解。人类干细胞技术提供了一个互补的系统，允许在人类胎儿大脑发育过程中无法获得的发育阶段对人类脑细胞进行功能操作。因此，基于干细胞的模型通过揭示导致 NDD 广泛发病机制的人类特异性机制，增进了我们对人类大脑发育的理解。我们全面概述了关于二维和三维人类干细胞模型的最新研究。首先，我们讨论了人类 iPSC 系统揭示的不同 NDD 之间趋同的细胞和分子表型。接下来，我们研究了体外人类神经系统对有前途的治疗策略的发展的贡献。最后，我们探讨了干细胞系统在研究 NDD 内的性别二态性方面的机制见解的潜力。
