The significance of this research
UCLA and Stanford University researchers have grown human iPS cell-derived cultured brains for up to 20 months and found that the artificially cultured brains can mature in a manner that is remarkably similar to human brain development. Growing artificially cultured brains for long periods of time is difficult, so nobody has grown and characterized them for this amount of time until now. This study is the first time that human brain development has been recapitulated in vitro for the most part, which is an important achievement that will enable us to conduct research on the causes of brain diseases and drug discovery in vitro.
Studies about brain organoids
By exposing iPS cells to special chemicals and the right conditions, a three-dimensional artificially cultured brain, which faithfully replicate several aspects of human brain development, can be created.
Artificially cultured three-dimensional brains are called “brain organoids,” and they are valuable experimental materials for accelerating our understanding of brain disorders. For several years, human brain organoids have been developed to study neurological and neurodevelopmental disorders, such as epilepsy, autism, and schizophrenia. However, the challenge was that brain organoids remain stuck in a developmental state analogous to the cells seen in fetal development. If brain organoids can be matured, they should be useful in the study of adult-onset diseases such as schizophrenia and dementia.
Results of this study
The research team generated dorsal forebrain organoids from human iPS cells and cultured them for up to 20 months. They collected samples over time and conducted genetic analysis of the organoids. Since DNA methylation levels can be used to estimate the biological age of cells, they examined the DNA methylation status of genes in the organoids. As a result, a correlation was observed between the length of incubation of the organoids and their predicted methylation age, which indicates that brain organoids mature over time.
Next, they compared changes in gene expression during the maturation of the organoids to changes observed in brain development in vivo in humans. Before 250days in culture, a prenatal signature was observed. Between day 250 and day 300, the organoids displayed both prenatal and postnatal signature, whereas after day 300 they showed a postnatal signature. These results indicate that the transition of organoids from the fetal brain to the infant brain occurs around 250-300 days (8-10 months) in culture.
Moreover, switches in the histone deacetylase complex and NMDA receptor subunits, which characterize the transition from prenatal to postnatal stages of brain development, were also observed in brain organoids during the predicted transition from the fetal brain to the infant brain (250-300 days in culture).
This study has shown that brain organoids can mature following an internal clock that is synchronized with the timeline of human development. Although dorsal forebrain organoids were created in this study, cells not born in the dorsal forebrain (such as ventral forebrain-derived GABAergic neurons) may affect the maturation of dorsal forebrain organoids. Therefore, additional investigation is needed. With further research, brain organoids may be used in transplant medicine in the future.
Additional information for researchers
The research team mapped genes associated with autism spectrum disorder, schizophrenia, Alzheimer’s disease, and Parkinson’s disease onto the gene expression data obtained in this study to see if there were specific expression patterns associated with risk genes. They found that the expression patterns of each gene differed depending on the time of differentiation of the organoids. This result can be used as an indicator to select appropriate in vitro timepoints for creating specific disease models from brain organoids. In addition, they provide a webtool (Gene Expression in Cortical Organoids, GECO) that allows researchers to browse their genes of interest and compare between in vivo and organoid gene trajectories (https://labs.dgsom.ucla.edu/geschwind/files/view/html/GECO.html).
Title: Long-term maturation of human cortical organoids matches key early postnatal transitions