An international team of researchers has used stem cells to create a 3D structure that mimics early human brain development. The group showed that these "cerebral organoids" can be used as a model system to analyse the origins of the human genetic disorder microcephaly, in which brain size is significantly reduced.
The research, led by
To create the brain tissue, the researchers developed a finely-tuned culture system that capitalises on stem cells' innate ability to organise themselves into complex organ structures.
They began with human embryonic and induced pluripotent stem cells, which they used to produce neuroectoderm - the layer of cells in the embryo from which all components of the brain and nervous system develop. Fragments of this tissue were then embedded in gel droplets that provided a scaffold for complex tissue growth and placed into a spinning bioreactor. The circulation of culture media in the bioreactor improves oxygen and nutrient supply allowing the organoids to grow to a larger size.
After a month, the tissue fragments had organised themselves into primitive structures that could be recognised as developing brain regions such as retina, choroid plexus and cerebral cortex. At the microscopic level in the cortex, radial glial stem cells, pivotal in developing the central nervous system, were seen to generate neurons in an identical manner to that known to occur in normal development. At two months, the organoids had reached their maximum size of 4mm, but they lacked the more detailed organisational structure of a fully developed brain.
Using patient induced pluripotent stem cells, the researchers were able to model the development of microcephaly, a disorder that has proved difficult to reproduce in mice. As expected, the organoids created using these cells grew to a smaller size.
On further investigation, they found that genetic mutations in these patients results in an earlier than normal switch in neural stem cells from self-renewal (making copies of themselves) to differentiation into nerve cells, leading to an overall reduction in cell number and size of the organoid.
The research was led by Dr
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