Studying Age-related Neurological Disease with induced Pluripotent Stem Cells | Part 3 | Brain Organoids

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Last week I published Part 2 of this article series, which looked at how we derived induced pluripotent stem cells (iPSCs), and why they are so useful when it comes to helping us study disease.

However, despite iPSCs being an invaluable resource for the study of the mechanisms of neurological diseases, they are not without limitation. Accurately modelling diseases with cell cultures usually requires the derivation of the cell population and tissue architecture of which the disease affects. As neurological disease primarily impacts the brain and cerebral tissue, this is what must be replicated.

The main flaw of iPSCs is their two dimensional structure when grown on a cell culture plate, which, is obviously vastly different, from the 3D structure of a human brain. This failure to replicate the three dimensions of a real life brain reduces the model’s capacity to accurately mimic real life [1].

Recent biotechnological innovations in biomaterials and stem cell cultures have allowed the generation of complex three dimensional models, known as brain organoids. Brain organoids showcase a significant step forward with respect to 2D models, allowing the formation of far more representative tissue architecture and complex neural networks to that of a real brain [2].

To get from having a population of iPSCs on a plate, to a brain organoid, requires roughly two months of directional differentiation of these stem cells into brain cells. This is done via the use of specific proteins, known as patterning factors, which were found to drive the process of brain development in the growing embryo. As the organoids develop and grow, it forms the grooves and troughs characteristic of the human brain. These ‘artificial brains’ can then be maintained for up to a year [3].

Full brain organoids mimic the entire human brain, whereas regionally specific organoids are designed to replicate different regions of the brain. Combining one or more of these regionally-specific organoids, can help to model the interactions between two distinct regions in detail, which would not be possible for a full brain organoid.

There is a continued strive to improve these 3D models, one aspect of which is to achieve organoid vascularisation. An established vascular system enables the organoid to sustain growth over a longer duration and to improve the accuracy of the in vivo environment it attempts to recapitulate [2].

Another aspect is to introduce an immune system to the organoid. The immune system of the brain differs from the rest of the body, as it comprises of cells called microglia. Microglia are a specialised population of macrophages, found in the central nervous system, which boast a range of functions that helps to maintain the cerebral environment in its optimal conditions.

In conclusion, the development and continued improvement of 3D brain organoids has provided an environment that more closely resembles that of a real brain. This provides a more intricate and elaborate neural network in which to recreate and model neurological disease.

Keep an eye out for Part 4, where we will be looking at real-life cases in which the use of brain organoids has facilitated some ground-breaking discoveries in regards to age-related neurological disease!

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References

[1] Barral, S. and Kurian, M. A. (2016) ‘Utility of induced pluripotent stem cells for the study and treatment of genetic diseases: Focus on childhood neurological disorders’, Frontiers in Molecular Neuroscience, 9(SEP2016), pp. 1–11. doi: 10.3389/fnmol.2016.00078.

[2] Baldassari, S. et al. (2020) ‘Brain Organoids as Model Systems for Genetic Neurodevelopmental Disorders’, Frontiers in Cell and Developmental Biology, 8(October), pp. 1–9. doi: 10.3389/fcell.2020.590119.

[3] Lancaster, M., Renner, M., Martin, CA. et al. Cerebral organoids model human brain development and microcephaly. Nature 501, 373–379 (2013). https://doi.org/10.1038/nature12517