In the article, "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" by Logan et. al, the researcher Sarah Logan and her lab studied cerebral organoids made from human induced pluripotent stem cells (iPSCs). These cells are stem cells that are bioengineered from somatic cells through reversing differentiation. iPSCs are used with minimal ethical concerns since they do not originate from embryonic cells or even adult stem cells. Over two months, the researchers grew the cerebral organoids and then compared their activity to fetuses and adult brains. Manual activation of specific transcription factors that regulate gene expression affected the rate and location of differentiation in the organoid similar to real brain tissue. Microarray assay accurately monitored the level of gene expression in different areas. The researchers found that the longer the organoid grew, the lower it expressed OCT4. OCT4 is a pluripotency marker, so the decrease in its levels indicates successful differentiation. This means that cerebral organoid is growing very similarly to a normal brain. Another crucial part of this study is the electrophysiological testing of the organoid. The researchers tested GABA agonists with the organoid and saw the expected behavior. Synaptic activity like this is an essential component for the brain modeling organoid because many neural questions revolve around changes in synaptic activity that eventually manipulate neuron structure. Loss of neuron structure is a common pathway of neurodegeneration. The study also compiled various measures of brain activity to determine that the organoid was much closer to approximating a fetal brain than an adult brain. The researchers concluded the study by adding that targeted manipulation of transcription factors can accelerate the maturation of organoid. They hope that the organoids will eventually be able to grow longer to allow researchers to model adult brains. This study shows that iPSCs are and the organoids from their growth have promising applications to the future of 3D brain modeling.
In the article, “Modeling and Targeting Alzheimer’s Disease With Organoids” by Papaspyropoulous et. al, the researcher Angelos Papaspyropoulous and his lab studied the current efficacy of hPSC derived cerebral organoids in modeling Alzheimer’s Disease. Past systems like mice fail to depict early AD, while neuronal cultures from AD patients are too limited to be used to assess AD growth. One process that helps organize the brain more recognizably is called guided brain formation. This process requires the use of extrinsic factors to emulate the ECM (extracellular matrix) to control the differentiation of organoid tissue into regions which is more similar to the brain. The greatest obstacle that the new cerebral organoids have are not able to survive the long times needed to study the growth of AD from onset to severe symptoms. The in vivo process of AD takes much longer to occur than the iPSC derived organoids can withstand. In addition to this, the complex ligand-receptor activation that causes signal cascades is also difficult to emulate in the cerebral organoids due to low maturation. Although the organoids cannot currently support the long periods needed to depict AD maturation, simpler processes like inducing various mutations and testing the immediate phenotypic result can help better understand the genetic risk factors of AD. In addition, the organoid models showed promise in understanding how current pharmacological agents affect AD patients. The researchers discussed how a study β- and γ-secretase inhibitors decreased the presence of β-amyloid plaques that are known to be an indicator of AD. Another limitation that the researchers discussed was the lack of vascularization in the organoid models. To accurately mimic the human brain, the organoid models need to depict the blood-brain barrier. The blood-brain barrier is critical to studies of neuropharmacology. The researchers concluded that the current scope of organoid models in AD research is restricted due to the technology being very new, however, organoid models have already started to contribute to discovering genetic markers and potential drugs for AD.
Both studies looked at the potential of cerebral organoids in discovering neuropathology. Dr. Logan grew iPSC derived organoids to better understand and compare them to the brain, while Dr. Papaspyropoulous weighed the current benefits and limitations of organoid modeling in researching AD. Organoid modeling from primary tissue-derived stem cells is becoming a popular way to model various organs. The brain is the most complex organ of them all, and that is why neurodegeneration can be frightening and unexplainable. Cerebral organoids offer a bridge to discover, to experiment, and to explain not only neurodegeneration but also other secrets of the brain.
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