Modern clinical approaches in neurological diseases mostly consist of imaging, biomarkers, and cognitive assessment, which often offers poor resolution and are only applicable after the disease has progressed significantly (Logan et al., 2020, p. 1301). Significant development in the exploration of many human congenital or neurodegenerative diseases have been limited by the complexity and ethical restraints of research on the diseased human brain or the usage of embryonic stem cells. In the last decade, neuroscientists have developed cerebral organoids derived from induced pluripotent stem cells (as opposed to embryonic stem cells), providing an effective in vitro 3D model of human brain development and/or disease progression.
Lancaster & Knoblich published their protocol titled “Generation of cerebral organoids from human pluripotent stem cells,” (2014) which was the first to detail the formation of 3D cerebral organoids; it emphasized the clinical advantages of the 3D spatial organization of organoids in investigating the “mechanisms of human neurological conditions that have been difficult or impossible to examine in mice and model organisms” (p. 2330). They also noted that its potential was limited, as in all in vitro systems, “the method lacks surrounding embryonic tissues that are important for the interplay of neural and non-neural tissue cross-talk… specifically, [due to] the lack of meninges and the vasculature” (p. 2330). This highlighted the cerebral organoid model’s applicability particularly to congenital brain conditions or diseases that develop over time, such as Zika-derived microcephaly, lissencephaly, brain cancers, fetal alcohol syndrome, Alzheimer’s disease, and Parkinson’s disease.
In 2018, cerebral organoids were used to model the amyloid beta and tau pathology in Alzheimer’s disease by Gonzalez and colleagues. Unlike 2D cultures, the 3D system was able to mimic in vivo neuropathology of genetic Alzheimer’s disease and Down Syndrome with endogenous levels of protein expression, despite lacking accurate cellular heterogeneity and extracellular matrix organizations, and lack of mature synapse connections and vascularization (Gonzalez et al., 2018, p. 2373). In 2019, Linkous et al. utilized cerebral organoids to model patient-derived glioblastoma, which has a bleak median survival of approximately 15 months from diagnosis (p. 3203). The organoids successfully exhibited stage-specific neural development and demonstrated myelinated axons, dendrodendritic synapses, neurons, and glia (Linkous et al., 2019, p. 3207), the formation and proliferation of infiltrative tumors (Linkous et al., 2019, p. 3208, and the recapitulation of the human pathology overall, including the network of tumor microtubes that facilitate glioblastoma progression (Linkous et al., 2019, p. 3209). In the 2020 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,” Logan and colleagues discussed their advancements in “dynamic development, cellular heterogeneity and electrophysiological activity,” (p. 1301) demonstrating, for the first time, in vitro recapitulation of electrophysiological drug response in cerebral organoids. This study also showcases the rapid development of cerebral organoids, as they displayed the system’s ability to exhibit “(1) a heterogeneous gene and protein markers of various brain cells, such as neuron, astrocytes, and vascular cells including endothelial cells and smooth muscle cells, (2) and increased gene expression of brain cell-specific markers over time, and (3) functional electrophysiological properties as evidenced by the neurons with action potential and synapse-like structure, functional response of ion channels to the drug stimulation” (p. 1317).
As described above, the challenges faced by Gonzalez et al. in their 2017 study had been largely resolved in close future studies, demonstrating cerebral organoids’ rapid growth potential and high utility in the investigation of a broader range of neurological conditions. Conclusively, cerebral organoids will play a critical role in the future of neuroscientific and neuro-medical research. It is, however, imperative to expand on the discourse of ethics around cerebral organoids and their further development to responsibly proceed in this field of research.
Bibliography
Gonzalez, C., Armijo, E., Bravo-Alegria, J., Becerra-Calixto, A., Mays, C. E., & Soto, C. (2018, August 31). Modeling amyloid beta and tau pathology in human cerebral organoids. Molecular Psychiatry, 23(12), 2363-2374. https://doi.org/10.1038/s41380-018-0229-8
Lancaster, M. A., & Knoblich, J. A. (2014, September 4). Generation of cerebral organoids from human pluripotent stem cells. Nature Protocols, 9(10), 2329-2340. https://doi.org/10.1038/nprot.2014.158
Linkous, A., Balamatsias, D., Snuderi, M., Edwards, L., Miyaguchi, K., Milner, T., Reich, B., Cohen-Gould, L., Storaska, A., Nakayama, Y., Schenkein, E., Singhania, R., Cirigliano, S., Magdeldin, T., Lin, Y., Nanjangud, G., Chadalavada, K., Pisapia, D., Liston, C., & Fine, H. A. (2019, March 19). Modeling Patient-Derived Glioblastoma with Cerebral Organoids. Cell Reports, 26(12), 2303-2311. https://doi.org/10.1016/j.celrep.2019.02.063
Logan, S., Arzua, T., Yan, Y., Jiang, C., Liu, X., Yu, L.-K., Liu, Q.-S., & Bai, X. (2020, May 23). 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, 9(5), 1301-1323. MDPI. http://dx.doi.org/10.3390/cells9051301
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