Put the human stem cells in a lab dish with the proper nutrients and they will do their best to make a tiny brain. They will fail, but you will get an organoid – a group of semi-organized cells. Organoids have become a powerful tool for studying brain development and disease, but researchers assumed that these microscopic spots only reflect prenatal brain development, its earliest and simplest stages. Today’s study reveals that, given enough time, organoid cells can acquire some of the genetic signatures that brain cells display after birth, potentially expanding the range of disorders and developmental stages they can recreate.
“Things that, before seeing this document, I would have said you can‘What to do with organoids … actually, maybe you can, ”says Madeline Lancaster, development geneticist for the Medical Research Council.‘s Molecular Biology Laboratory. For example, Lancaster was not optimistic about the use of organoids to study schizophrenia, which is suspected to arise in the brain after birth, once neural communication becomes more complex. But now he wonders whether the cells of a person with this disorder, once “reprogrammed” to a primitive state of stem cells and forced to mature within a brain organoid, could reveal important cellular differences underlying the condition.
Stanford University neurobiologist Sergiu Pașca has been making brain organoids for about 10 years, and his team has learned that some of these tissue stains can thrive on a plate for years. In the new study, they teamed up with neurogeneticist Daniel Geschwind and his colleagues at the University of California, Los Angeles (UCLA), to analyze how the spots changed throughout their lives.
The researchers exposed human stem cells to a specific set of growth-promoting nutrients to create spherical organoids that contain neurons and other types of cells found in the outer layers of the brain. They periodically kill cells to sequence their RNA, indicating which genes are active in protein production. They then compared this gene expression to a database of RNA from human brain cells of different ages. They noted that when an organoid reached 250 to 300 days of age, approximately 9 months, its gene expression changed to more closely resemble that of human brain cells shortly after birth. Cell methylation patterns – chemical tags that can adhere to DNA and influence gene activity – also corresponded to increasingly mature human brain cells as organoids aged, the team reports today in Neuroscience of nature.
The researchers documented other signs of maturity in their organoids. Around the time of birth, some brain cells gradually change to produce more of one variant of one protein and less of another. A component of a brain cell receptor called NMDA, key to neuronal communication, is found among proteins that change shape. And organoid cells, like their counterparts in the developing brain, made the NMDA switch.
The findings do not mean that gout itself is comparable to a postnatal brain, Pașca cautions. Its electrical activity does not match that of a mature brain, for example, and the cluster of cells lacks key features, including blood vessels, immune cells, and sensory inputs. However, what is surprising is that, even in the unnatural conditions of a laboratory dish, “cells simply know how to progress, ”says Pașca.
Organoid cells and actual brain cells might not mature in perfect unison, says Aparna Bhaduri, a developmental neurobiologist at UCLA who was not involved in the new work. In an earlier study, she and her colleagues found that organoid cells showed significant genetic differences from fetal brain cells, along with signs of metabolic stress. She says it’s reassuring that in the new study, the key changes seen at birth appear to occur in an organoid just when scientists expected, around 9 months.
Pașca’s team also analyzed the expression of genes associated with brain disorders, such as autism, schizophrenia, epilepsy, and Alzheimer’s disease. The scientists identified groups of these genes whose activity rose and fell at the same time, reaching their maximum expression at the same time. The ridges could indicate when those genes are most relevant to brain development and when an organoid might be most useful in modeling a certain disorder.
Now that it is clear that the cells of an organoid can go through some of the normal developmental routines of the human brain after birth, Pașca‘The s team is exploring ways to “boost [the organoids] back and forth in time to obtain the appropriate period for a disease model, ”he says. That could allow his group and others to study brain diseases in mature organoids without caring for the cells for years.