The human brain has been known to be one of the most complex organs in the human body and for years, in order to better study it's nearly inaccessible tissue, researchers have used animal models to help us further understand the brain and all it’s complexities. Yet, there is a bit of a disconnect between animal and human research. Although we can dive into molecular and cellular effects in animal brain models, it’s hard to study structural changes in humans, especially in fetal brains.
Recently, however, researchers have been using human stem cell models (human organoids) to help fill the gap between animal and human studies, especially considering it provides access to tissues that were once extremely difficult to access in vivo. Human brain organoids are 3D structures that are derived from iPSCs and act just as embryonic stem cells do in vivo, having qualities such as unlimited self-renewal and pluripotency. These models are also as sophisticated as a second trimester fetal brain, which opens the door to research for very young, developing brains.
Using brain organoids as a complex model for the fetal brain, Sarah Logan and colleagues wanted to study the apoptotic effects of alcohol on fetal brains, specifically the downstream, toxic effects of alcohol on neural pathways (Logan et al., 2020). They hypothesized that NPAS4 contributes to alcohol-induced developmental brain injury. What they found was that brain organoids can serve as a novel model showing that blood alcohol levels as low as .1 can induce neuroapoptosis in a dose dependent manner, while also affecting the metabolism and ultra structure of these mini brains. They also found that NPAS4 is a key factor in alcohol-induced neuroapoptosis, with it’s down regulation due to alcohol exposure showing severe increase in cell death. This study and it's results would have been extremely difficult to attain had they not had the access to a tissue that is so similar to that of an in vivo human fetal brain.
The use of human brain organoids has been a breakthrough in neurological research as an incredibly powerful tool to study not only normal human embryonic development but also, similarly to Logan and colleagues, any neurodevelopment disorders. A great example of this comes from Jessica Mariani and colleagues, who attempted to understand the early development in those with idiopathic Autism spectrum disorder (ASD), which is normally identified though macrocephaly, an increased head/brain size (Mariani et al., 2015). They understood the brilliance behind a brain organoid's ability to capture species-specific developmental timing found in vivo, where they had previously primarily used mice as a model organism.What they found on these organoids was an increase in expression of FOXG1, a transcription factor, which was caused by an increased production of inhibitory neurons. Thanks to the use of organoids, Mariani and colleagues were able to focus on the role of this gene as not only a molecular stamp for idiopathic ASD, but also as a possible target for any future therapies.
Although more research must be conducted regarding the downfalls of human brain organoids, it's use has allowed for long standing questions regarding early brain development to be researched beyond the use of animal models and to an extent that was once considered unimaginable, allowing for both better and more effective treatments to be developed as a result.
References:
Mariani, Jessica, et al. “FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders.” Cell, 16 July 2015, FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders.
Logan, Sarah, et al. “Dynamic Characterization of Structural, Molecular, and Electrophysiological Phenotypes of Human-Induced Pluripotent Stem Cell-Derived Cerebral Organoids, and Comparison with Fetal and Adult Gene Profiles.” Cells, 23 May 2020, pp. 1-22. MDPI, www.mdpi.com/2073-4409/9/5/1301. doi: 10.3390/cells9051301
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