Building a realistic model of the human brain is a crucial part of understanding brain development, as well as neurological disorders such as Alzheimer's or Parkinson's disease. Using human stem cells, researchers have created a 3-D model of the human brain - and new research investigates how similar it is to a real brain.

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A new study assesses the functionality of a 3-D brain model, shown here in a fluorescent cross-section.
Image credit: Madeline Lancaster/Medical Research Council, Laboratory of Molecular Biology, United Kingdom.

Having a good model of the human brain enables scientists to investigate neurological disorders, find out more about brain development and function, and, perhaps in the future, even test experimental drugs before they enter the clinical trial stage.

Currently, scientists typically use 2-D brain models. Latest developments in brain modeling, however, include creating functional 3-D brain-like tissue and entire "mini-brains" from human stem cells.

New research investigates such a 3-D mini-brain model and examines its advantages over a 2-D brain model.

The study was carried out by scientists at the Salk Institute, and the findings were published in the journal Cell Reports.

Developments in brain modeling

The ability to grow a brain entirely out of human cells is not new, but it is quite recent and has been hailed by the authors of this new study as "a real breakthrough."

Salk Institute researchers cite the 2013 European study, in which scientists grew a cerebral organoid (CO) model in vitro from embryonic and adult stem cells. Researchers then placed the cells in a 3-D gel, where they developed into realistic layers that reflected an actual human brain.

Before that, embryonic stem cells had been transformed into single-layered brain cells inside a petri dish, but this had the obvious limitation of being 2-D instead of the 3-D real brain.

Limited 2-D brain models are widely used today, but Salk Institute researchers point to the advantages of 3-D CO models.

"Being able to grow human brain cells as miniature three-dimensional organs was a real breakthrough," says Joseph Ecker, the senior author of the new study, a Howard Hughes Medical Institute Investigator, and professor and director of Salk's Genomic Analysis Laboratory. "Now that we have a structurally realistic model, we can start to ask whether it is also functionally realistic, by looking at its genetic and epigenetic features."

Assessing genetic and epigenetic features of mini-brains

Researchers led by Ecker compared early development COs with real brain tissue at the same early developmental stage.

The team created COs for their analysis using a human embryonic cell line called H9. They chemically induced the cells into a neurodevelopmental pathway for 60 days.

Then, researchers analyzed the mini-brains' epigenetics, looking at the patterns of chemical markers that are responsible for activating or silencing genes.

The researchers' interest in epigenetics comes from the mounting evidence that environmental factors, including diet or stress, play a role in brain diseases such as schizophrenia.

Ecker and team compared their results to age-matched real tissue from the National Institutes of Health (NIH) NeuroBioBank and other 2-D brain model data.

3-D models very similar to real brains

Although COs have been grown in laboratories for three years now, it was previously unknown how similarly they behaved to real brains until Ecker and team analyzed them in their new study.

The researchers found that COs were a lot more similar to real brain tissue than 2-D models in terms of cell differentiation and gene expression. In the early developmental stage, mini-brains develop at a very similar pace to real brains.

Epigenetically, the study has shown that both 3-D and 2-D models had similarly aberrant patterns, which is common to all cells grown in vitro as opposed to in vivo. The meaning of this difference is not yet clear, Ecker points out, but it is highly significant in terms of how similar a model can be to a real brain.

"Our findings show that cerebral organoids as a 3-D model of brain function are getting closer to a real brain than 2-D models, so perhaps by using the epigenetic pattern as a gauge we can get even closer," says Ecker.

The first author of the paper, Chongyuan Luo, also emphasizes the contribution their study brings to neurology.

"No one has done epigenome sequencing for cerebral organoids before. This kind of assessment is so important for understanding brain development, especially if we are eventually going to use these tissues for neurological therapies."

Chongyuan Luo

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