The study of the human brain now has one more powerful and innovative tool. It is a new 3D brain organoid model, which will give scientists a deeper insight into human-specific brain development and disorders, particularly those rooted in early developmental stages such as autism.
The new model is illustrated in the study ‘A polarised FGF8 source specifies frontotemporal signatures in spatially oriented cell populations of cortical assembloids’ just published in Nature Methods, and is the result of the collaborative work of an international team of researchers, led by Dr. Veronica Krenn, holder of the Human Technopole Early Career Grant at Milano-Bicocca, in collaboration with the team led by Professor Jürgen Knoblich of the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) in Vienna and the team led by Professor Giuseppe Testa of Human Technopole in Milan.
Organoid technologies, originally developed by Prof. Knoblich's team at IMBA, are three-dimensional models derived from pluripotent stem cells and have been widely used worldwide to study the development of the human brain, to answer fundamental questions about how the human cortex achieve its large size, and to learn about the origin of brain diseases.
The cortical organoids used to date are spherical, like miniature footballs, and relatively homogeneous. This structure is very different from the elongated human cortex, which is structured in a map of distinct areas from front to back. The researchers have therefore developed a new protocol to generate elongated organoids organised into distinct domains along the longitudinal axis, similar to the polarity of the cortex.
The map of the developing brain is shaped by different signalling molecules, called morphogens, making it difficult to understand how each component contributes to development individually. In the new method developed, the researchers first created elongated organoids using moulds specially designed by collaborators at the University of Paris and the Institut Curie, and then added a source of a morphogen called FGF8. 'This single source of morphogen, placed asymmetrically, is sufficient to generate cells with different identities along the longitudinal axis of a single elongated organoid, forming a map similar to that of the human cortex at very early stages of development,' explains Dr Veronica Krenn, one of the study's lead authors.'Using the new model, the researchers were able to identify one of the crucial factors in the creation of this cortical map, the FGFR3 gene, mutations in which cause skeletal dysplasia - called achondroplasia'.
These polarised cortical organoids," concludes Krenn, "are an important step forward in reproducing the early stages of cortical development in the laboratory. We look forward to using this new technology to gain insight into the mechanisms of disease genes and how risk factors that contribute to the onset of mental illness may alter these crucial processes.