This article is from WeChat official account:Academic Jingwei (ID: Global_Academia)< span class="text-remarks">, edited by WuXi AppTec’s content team, original title: “The Milestone of the “Mini Human Brain”: 300 days of growth in a petri dish, how similar is it to a real newborn brain? “, the head picture comes from: Visual China

Putting human stem cells in a laboratory dish and applying specific growth-promoting nutrients can encourage them to spontaneously form a “mini human brain” with a 3D structure. Although it looks like a globular cluster of cells to the naked eye, it contains neurons with synaptic connections and other cell types that make up the cerebral cortex. Scientists therefore call it “human brain organoids.” In fact, organoids are becoming a powerful tool for studying brain development and diseases.

It is generally believed that these mini-human brains differentiated from stem cells reflect the development of the prenatal stage, which is the earliest and simplest stage of the human brain. However, a recent study published in the sub-Journal of “Nature” Nature Neuroscience revealed that when grown in a petri dish for a long enough time-after 250 to 300 days, the cells in the mini-human brain are genetically In terms of characteristics, appeared some key characteristics the same as neonatal brain cells.

One of the co-corresponding authors of this study is Professor Sergiu Pasca, a neurobiologist at Stanford University. His research team has been committed to using organoids to study brain development and diseases for nearly a decade. This time, they collaborated with Professor Daniel Geschwind of the University of California, Los Angeles (UCLA) to analyze these in vitro cultures.The changes in the raised mini human brain during long-term growth. “So far, no one has been cultivating and characterizing these organoids for such a long time.” Professor Geschwind said.

Professor Sergiu Pasca and Professor Daniel Geschwind, who co-led this research (Image source: Stanford University and UCLA official website)

Researchers regularly take out cells in human brain organoids and use RNA sequencing to check gene expression, that is, which genes are actively making proteins. When they compared the results with RNA databases from human brain cells of different ages, they found that When human brain organoids grow to about 9 months-the same as the length of time that human embryos develop in the body, their gene expression patterns There has been a shift, close to the brain cells of the newborn fetus. The methylation patterns of these cells, that is, the chemical tags attached to DNA and affecting gene activity, also correspond to the increasingly mature human brain cells.

Researchers also recorded other signals that indicate maturity in organoids and discovered more critical developmental changes. For example, before and after birth, the NMDA receptors of some brain cells gradually change, and one subunit of the receptor complex becomes more and the other subunit becomes less, which is very important for transmitting signals between neurons. The cells in organoids also showed changes in the composition of NMDA receptor subunits.

However, the researchers caution that these findings do not mean that the mini-human brain itself is equivalent to the brain after birth. For example, they do not have key features such as blood vessels and immune cells, and the electrical activity of the cells is also inconsistent with the fully developed human brain. In addition, these organoids will not receive sensory input like the real human brain. However, “Even under the unnatural conditions of a laboratory dish, it is surprising that the cells themselves know how to progress.”Professor Pasca said.

Researchers pointed out that the new discovery will expand the classifierThe scope of application of this tool helps us to better study brain diseases.

The huge application potential has attracted the attention of many scientists. For example, in the opinion of Dr. Madeline Lancaster, a developmental geneticist, she thought that using organoids to study schizophrenia might be difficult, because this type of disease is generally believed to occur in the brain after birth, when neural communication has become complicated. However, if the cells from the patient can be “reprogrammed” to return to the original stem cell state and mature in the brain organoids, it may reveal important cellular differences behind schizophrenia.

In fact, scientists also observed a series of genes related to brain diseases in this study, involving autism, schizophrenia, epilepsy and Alzheimer’s disease. The research team determined that these genes are in When the expression activity in brain organoids rises and when it falls, and the correlation with the normal development time point of humans, it further guides how to use brain organoids to establish human disease models.

“Our research shows which aspects of human brain development can be modeled with high fidelity, which specific genes perform well in vitro, what is the best time to simulate disease, etc. This is an important milestone.” Professor Geschwind said.

Reference materials:

[1] Gordon, A., et al. Long-term maturation of human cortical organoids matches key early postnatal transitions. Nat Neurosci (2021). https://doi.org/10.1038/s41593-021-00802-y

[2] Brain cell clusters, grown in lab for more than a year, mirror changes in a newborn’s brain. Retrieved Feb. 24, 2021 from https://www.sc