Organoid models provide an opportunity to model the unique features of human brain development in a complex tissue-like environment.
The intrinsic patterning of whole brain organoids in intrinsic organoid protocols promotes the generation of diverse brain regions.
Signalling molecules can be used to mimic in vivo patterning and increase the efficiency of directed differentiation in comparison to the intrinsic patterning of regional brain organoids.
There are a number of advantages of an in vitro system for experimentation purposes, including the relative ease of genomic manipulation and the possibility of using patient-derived cell lines.
Human brain organoids can model human development and shed light on human-specific diseases.
Protocols will benefit from systematic analysis of cell types generated and a robust comparison to in vivo counterparts.
Pre-patterned, region-specific organoids can be fused to model complex brain structures.
Current organoid protocols still face a number of limitations, including low reproducibility, incomplete cell type diversity and slow maturation.
Understanding the development and dysfunction of the human brain is a major goal of neurobiology. Much of our current understanding of human brain development has been derived from the examination of post-mortem and pathological specimens, bolstered by observations of developing non-human primates and experimental studies focused largely on mouse models. However, these tissue specimens and model systems cannot fully capture the unique and dynamic features of human brain development. Recent advances in stem cell technologies that enable the generation of human brain organoids from pluripotent stem cells (PSCs) promise to profoundly change our understanding of the development of the human brain and enable a detailed study of the pathogenesis of inherited and acquired brain diseases.
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The authors thank A. Bhaduri, J. Spatazza, T. Nowakowski, M. Bershteyn, H. Retallack, M. A. Mostajo Radji and A. Pollen for their scientific discussions and thoughtful input. The authors are very grateful to T. Nowakowski for his help with the illustrations. This work was supported by funding from the US National Institutes of Health R35NS097305.
The authors declare no competing financial interests.
The capacity to autonomously generate the architectural complexity of vertebrate organs.
- Inductive signals
Molecular signals that can influence the developmental fate of a cell.
- Outer radial glial cells
A subclass of radial glial cell residing primarily in the outer subventricular zone.
Secreted factors that can induce different cell fates across a sheet of cells in a concentration-dependent manner by forming gradients.
A manufactured or engineered device that supports a biologically active environment.
- Intermediate progenitors
Transient-amplifying cells that can produce neurons or new intermediate progenitor cells.
- RNA sequencing
(RNA-seq). A high-throughput method to sequence whole-genome cDNA in order to obtain quantitative measures of all expressed RNAs in a tissue.
- Principal component analysis
A mathematical algorithm that reduces the dimensionality of data while retaining important variation.
- Single-cell transcriptional profiling
RNA sequencing of single cells.
- Regulatory elements
Sequences of a gene that are involved in regulation of genetic transcription.
A multitude of biochemical modifications to DNA that have key roles in regulating genome structure and function, including the timing, strength, and memory of gene expression.
- Forebrain organizing centres
Groups of cells that send signals that induce distinct fates in neighbouring cells, resulting in spatial patterning in the forebrain.
- Viral tropism
The specificity of a virus for a particular host cell.
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Di Lullo, E., Kriegstein, A. The use of brain organoids to investigate neural development and disease. Nat Rev Neurosci 18, 573–584 (2017). https://doi.org/10.1038/nrn.2017.107
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