Abstract
Background: The development of 3D cerebral organoid technology using human-induced pluripotent stem cells (iPSCs) provides a promising platform to study how brain diseases are appropriately modeled and treated. So far, understanding of the characteristics of organoids is still in its infancy. The current study profiled, for the first time, the electrophysiological properties of organoids at molecular and cellular levels and dissected the potential age equivalency of 2-month-old organoids to human ones by a comparison of gene expression profiles among cerebral organoids, human fetal and adult brains. Results: Cerebral organoids exhibit heterogeneous gene and protein markers of various brain cells, such as neurons, astrocytes, and vascular cells (endothelial cells and smooth muscle cells) at 2 months, and increases in neural, glial, vascular, and channel-related gene expression over a 2-month differentiation course. Two-month organoids exhibited action potentials, multiple channel activities, and functional electrophysiological responses to the anesthetic agent propofol. A bioinformatics analysis of 20,723 gene expression profiles showed the similar distance of gene profiles in cerebral organoids to fetal and adult brain tissues. The subsequent Ingenuity Pathway Analysis (IPA) of select canonical pathways related to neural development, network formation, and electrophysiological signaling, revealed that only calcium signaling, cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) signaling in neurons, glutamate receptor signaling, and synaptogenesis signaling were predicted to be downregulated in cerebral organoids relative to fetal samples. Nearly all cerebral organoid and fetal pathway phenotypes were predicted to be downregulated compared with adult tissue. Conclusions: This novel study highlights dynamic development, cellular heterogeneity and electrophysiological activity. In particular, for the first time, electrophysiological drug response recapitulates what occurs in vivo, and neural characteristics are predicted to be highly similar to the human brain, further supporting the promising application of the cerebral organoid system for the modeling of the human brain in health and disease. Additionally, the studies from these characterizations of cerebral organoids in multiple levels and the findings from gene comparisons between cerebral organoids and humans (fetuses and adults) help us better understand this cerebral organoid-based cutting-edge platform and its wide uses in modeling human brain in terms of health and disease, development, and testing drug efficacy and toxicity.
Highlights
A host of diseases affect the human brain, including congenital, traumatic, and neurodegenerative conditions
Of the selected canonical pathways, only calcium signaling, cyclic adenosine monophosphate response element-binding protein (CREB) signaling in neurons, glutamate receptor signaling, and the synaptogenesis signaling were predicted to be downregulated in cerebral organoids relative to fetal samples
We characterized cerebral organoids as models of the human brain in the aspects of development, electrophysiological properties, gene profiles, and their potential to be utilized in physiological studies of human brain structure and function
Summary
A host of diseases affect the human brain, including congenital, traumatic, and neurodegenerative conditions. The purpose of the current study was to expand upon the previous development of the iPSC-derived cerebral organoid model by the characterization of electrophysiological properties at both molecular and cellular levels, and dynamic development throughout the 2-month differentiation process, dissecting the approximate age of cerebral organoids relative to the fetal and adult human brains by a comparison of genome-wide expression profiles among organoids, fetal and human brain tissues This is the first time in the field that the dynamic emergence of spontaneous electrical activity, electrochemical responses, drug action, heterogeneous tissue components, and comparisons of gene profiles among organoids, fetal and human brains have been reported. Pathway analyses of gene expression profiles shed light on the equivalency between cerebral organoids and the fetal brain versus the adult brain
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.