Using Brain Organoids To Model Neurodevelopmental Disorders
Post by Lila Metko
The takeaway
Neurodevelopmental Disorders (NDDs) are characterized by improper brain development and deficits in cognition and behavior. Organoids are three-dimensional cellular structures, grown from human stem cells that may provide a solution for modeling NDDs for potential human therapeutics.
What's the science?
Research using human-induced pluripotent stem cells (iPSC) is becoming increasingly sophisticated, as it is possible to differentiate these cells into many specialized cell types. Previously, most research with iPSCs has used two-dimensional culture systems, which cannot model complex cell processes such as cell migration and high-complexity cell-cell interactions. This week in Brain, Dionne and colleagues review the ability for three-dimensional, human iPSC derived brain organoids to model many of the NDDs that are difficult to translate from animal models to humans. They discuss how organoids are not without drawbacks: genomes may be altered in the process of cell reprogramming, and there are no standardized procedures to validate the quality of new iPSC lines. Organoids are, however, becoming increasingly more advanced and are a powerful tool for studying NDDs as an alternative to animal models or clinical research in humans.
How did they do it?
The authors investigated the role of organoids in finding treatments for several common NDDs and summarized many of the advanced experiments that have been done with organoids in recent years. Many of these NDDs have pathology that makes them difficult to model in animals. For example, microlissencephaly, a disorder characterized by lower levels of brain gyrification, is difficult to model in animals because rodent brains are normally lissencephalic. Other disorders, such as Fragile X syndrome, may necessitate organoid models because treatments that have shown high success rates in animals have proven to be untranslatable to humans. Organoids have also proved useful for disorders that are believed to develop pathology in a particular stage of cellular differentiation. Further, there are limitations to studying rodent organs because they develop differently than human organs and the developmental timeline is different. Therefore, organoids give researchers the opportunity to more accurately mimic the developmental pathways of the human brain and apply interventions at particular stages.
What did they find?
Among the organoid models used for disorders discussed, many produced new data that could not be found in animal models. For example, in research of Fragile X Syndrome, a NDD caused by abnormal translation regulation, animal models showed that mGluR5 inhibition (excitatory) or enhancement of GABAergic signaling (inhibitory) reversed cellular and behavioral deficits. However, these therapies did not show promising results in clinical trials. Organoid models of Fragile X syndrome showed that within targets of the primary protein that is absent in the disorder, FMRP, 66% were human specific. This means that the majority of the targets that the missing protein in Fragile X Syndrome acts on are found only in humans.
Additionally, there are promising results for using organoid models to map out a more human-like developmental timescale. Angelman Syndrome (AS), is an NDD in which a mutation causes a loss of function in a specific protein, UBE3A, leading to intellectual disabilities and seizures. Organoid models developed from patients with AS, have shown that in these specific organoids, UBE3A localizes to the cytoplasm at a different developmental stage than in a typically developing human. Another instance of organoids better mimicking the development of humans is in Tuberous Sclerosis Complex (TSC). In this disorder, cortical tubers, malformed regions within the cortex, are a major part of the disease pathology but do not develop in mouse models. Research with human-based organoids showed that TSC organoids had a different ratio of glial (supporting) cells to neurons than those in a typically developing human.
What's the impact?
This review highlights a technology that has the potential to make huge gains in expanding our translational knowledge of neurodevelopmental disorders. These findings suggest that human iPSC organoids have already made big strides towards developing therapeutics for NDDs and will likely continue to in the future. Based on these findings, there is a high likelihood that future neuroscience research will be increasingly dependent upon organoid models as a route to finding effective therapies.