Scientists at the John van Geest Centre for Brain Repair at the University of Cambridge used stem cells derived from patients suffering from amyotrophic lateral sclerosis that overlaps with frontotemporal dementia (ALS/FTD) to grow brain organoids. The “mini brains” resemble parts of the human cerebral cortex in terms of their embryonic and fetal developmental milestones, 3D architecture, cell-type diversity and cell-cell interactions.
Although this is not the first time that scientists have grown mini brains from patients with neurodegenerative diseases, most efforts have only been able to grow them for a relatively short time frame, representing a limited spectrum of dementia-related disorders. In a paper published today in Nature Neuroscience, the team reports growing these models for 240 days from stem cells harboring the commonest genetic mutation in ALS/FTD.
“To come close to capturing this complexity, we need models that are more long-lived and replicate the composition of those human brain cell populations in which disturbances typically occur, and this is what our approach offers,” explained senior author András Lakatos. “Not only can we see what may happen early on in the disease, long before a patient might experience any symptoms, but we can also begin to see how the disturbances change over time in each cell.”
While organoids are usually grown as balls of cells, first author Kornélia Szebényi generated patient cell-derived organoid slice cultures. This technique ensured that most cells within the model could receive the nutrients required to keep them alive. “When the cells are clustered in larger spheres, those cells at the core may not receive sufficient nutrition, which may explain why previous attempts to grow organoids long term from patients’ cells have been difficult.”
Using this approach, Dr Szebényi and colleagues observed changes occurring in the cells of the organoids at a very early stage, including cell stress, damage to DNA, and changes in how the DNA is transcribed into proteins. These changes affected those nerve cells and astroglia.
“Although these initial disturbances were subtle, we were surprised at just how early changes occurred in our human model of ALS/FTD,” added Dr Lakatos. “This and other recent studies suggest that the damage may begin to accrue as soon as we are born. We will need more research to understand if this is in fact the case, or whether this process is brought forward in organoids by the artificial conditions in the dish.”