Modeling Human Brain Development in Cerebral Organoids

Human brain development exhibits a number of unique characteristics, such as dramatic size expansion and variation in relative abundance of specific neuron populations. Until very recently, model organisms were the only experimental tools available to functionally examine brain developmental mechanisms on the whole organ scale. This has obvious limitations when it comes to human-specific features.

In an effort to better understand human brain development, we developed a human model system, called cerebral organoids. Cerebral organoids, or “mini-brains”, are 3D tissues generated from human pluripotent stem cells that allow modelling of brain development in vitro. Through a process of directed differentiation and a supportive 3D microenvironment, neural precursor tissue can spontaneously self-organize to form the stereotypic organization of the early human embryonic brain. We were able to show that cerebral organoids can also model a neurodevelopmental disorder, microcephaly, characterised by a significantly reduced brain size. This makes brain organoids particularly powerful for not only examining human specific mechanisms, but also pathogenesis of neurological disease.

We have now performed extensive characterization of brain organoids and their potential uses, as well as improvements to better control their differentiation. Current findings reveal the timed generation of excitatory neurons and inhibitory interneurons as well as their proper migration and positioning. This method provides a tractable system for studying human brain development, evolution and neurodevelopmental disorders.