Abstract

The human brain exhibits a number of unique characteristics, such as dramatic size expansion and variation in relative abundance of specific neuron populations. In an effort to better understand human brain development, we developed an in vitro human model system, called cerebral organoids. These 3D tissues are generated from human pluripotent stem cells through directed differentiation and a supportive 3D microenvironment to generate organoids with the stereotypic organization of the early human fetal brain. We have now extended these methods to model later events in neurodevelopment, including neuronal migration and positioning, axon guidance, and neuronal maturation. We have also developed a new choroid plexus organoid system as a model of the human blood-CSF barrier for testing CNS penetrance. These methods are now allowing us to tackle questions previously impossible with more traditional approaches. Indeed, our recent findings provide insight into regulation of brain size and neuron number across species. Furthermore, because organoids are particularly amenable to studies of the effects of external factors, we have recently used this system to examine neurological tropism of the virus responsible for COVID-19. Finally, we have begun examining male – female differences in brain development, focusing on the roles of sex steroid hormones in early neurogenesis. Overall, our findings are pointing to key, human-specific aspects of brain development and function, that have important implications for neurological disease.