Retracing How Our Brains Develop After Birth

The Problem: Brain organoids, 3D models of brain tissue created from stem cells, have recently become very useful for studying brain development and disease. While they mimic prenatal brain development very well, it has been unclear how much more of our lifelong brain development organoids can capture. 

The Study: The team of NYSCF–Robertson Stem Cell Investigator Sergiu Pasca, MD, of Stanford University, along with neurogeneticist Daniel Geschwind, MD, PhD, and colleagues at UCLA, set out to measure exactly how well long-term organoid development matched actual brain development. The researchers used human stem cells to create organoids containing neurons and other types of cells located in the outer regions of the brain. After growing for 20 months in the lab, the organoids hit key developmental milestones similar to a developing postnatal brain. The paper appeared in Nature Neuroscience.

Why it Matters: These findings show that organoids can mature in a way just like our own brains do after birth, expanding their applicability for modeling adult-onset diseases like schizophrenia, autism, epilepsy, and other neurodevelopmental disorders. 

Although entertaining to imagine, a concoction of stem cells and nutrients in a lab dish will not emulate “magic grow” capsules and morph into a fully-formed brain. However, they will form an organoid, a powerful tool for brain development and disease. Brain organoid pioneers like Dr. Pasca had  found that organoids reflect the brain’s prenatal development well, but their reflection of postnatal development was less certain. This study, published in Nature Neuroscience, determined that over time, organoid cells can adopt some of the genetic signatures that human brain cells display after birth, enhancing their value as a model. 

Dr. Pasca has been developing brain organoids for roughly a decade, and his team has discovered that organoids can survive in a dish for years. For this study, his team wanted to observe and analyze just how these organoids changed throughout their life in a dish. 

The team of researchers exposed human stem cells to growth-promoting nutrients so that they would synthesize spherical brain organoids containing neurons and other types of cells located in the brain’s outer regions. In examining the gene expression in brain organoids and comparing it to gene expression in the postnatal brain, they found striking similarities. Fascinatingly, when the organoids had aged nine months, their gene expression transformed to more closely resemble that of human brain cells soon following birth. Moreover, methylation patterns in the cells – ways to “turn off” or silence parts of DNA – also corresponded to the mature human brain cells as the organoids continued to age. 

“This is novel – until now, nobody has grown and characterized these organoids for this amount of time, nor shown they will recapitulate human brain development in a laboratory environment for the most part,” said Dr. Geschwind, MacDonald Distinguished Professor in Human Genetics at the David Geffen School of Medicine at UCLA, member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, and the senior associate dean and associate vice chancellor and director of the Institute for Precision Health at UCLA.

Throughout the study, the team detected other signals of maturity in the organoids. For example, some brain cells, around the time of birth, will shift to produce a surplus of one protein and less of another. In general, these same patterns were observed in the brain organoids.

Although these findings are significant, they don’t necessarily indicate that the organoids themselves are fully equivalent to the postnatal brain. Brain organoids lack key features such as blood vessels, sensory inputs, and immune cells. However, the fact that the organoid cells “just know how to progress [in a lab dish],” as Dr. Pasca says, is remarkable in itself.

“This will be an important boost for the field, “ said Dr. Geschwind. “We’ve shown that these organoids can mature and replicate many aspects of normal human development – making them a good model for studying human disease in a dish.”

Journal Article:

Long-term maturation of human cortical organoids matches key early postnatal transitions
Aaron Gordon, Se-Jin Yoon, Stephen S. Tran, Christopher D. Makinson, Jin Young Park, Jimena Andersen, Alfredo M. Valencia, Steve Horvath, Xinshu Xiao, John R. Huguenard, Sergiu P. Pașca & Daniel H. Geschwind. Nature Neuroscience. 2021. DOI: https://doi.org/10.1038/s41593-021-00802-y

Cover image: organoids in a dish. Photo credit: Sergiu Pasca