The power of human stem cell-based systems in the study of neurodevelopmental disorders

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.