Neuronal connectivity and functional output in brain 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 extended these methods to generate tissues that are capable of modelling even later events in neurodevelopment, including neuronal migration and positioning, axon guidance, and neuronal maturation. These newer approaches can model CNS tract formation with the generation of neural circuits, and even functional output through a motor circuit to modulate and activate muscle contractions. This opens the door to ever more faithful in vitro models for interrogating complex neuronal circuitry.
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Dr Madeline Lancaster is a Group Leader in the Cell Biology Division of the Medical Research Council (MRC) Laboratory of Molecular Biology, part of the Cambridge Biomedical Campus in Cambridge, UK. Madeline studied biochemistry at Occidental College, Los Angeles, USA, before completing a PhD in 2010 in biomedical sciences at the University of California, San Diego, USA. She then joined the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) in Vienna, Austria as a postdoctoral researcher, before joining the LMB in 2015.
Research in the Lancaster lab focuses on human brain development using a new model system, called cerebral organoids. These ‘mini-brains’ are 3D tissues generated from stem cells that allow modelling of human brain development in vitro. The laboratory uses mini-brains to study the most fundamental differences between human brain development and that of other mammalian species – what makes us human. We are also studying neurodevelopmental disorders such as autism and intellectual disability, and the cellular mechanisms underlying neurodevelopmental disease progression and potential therapeutic avenues.
