Researchers came up with a new method to make the brain organoid "Brainier"

The brain organoids are only one to five millimeters in diameter.
Ayesha Gulzar
Brain-like organs from stem cells
Slices of mini–brain organoids with neural stem cells (red) and cortical neurons (green)

Put human stem cells in a lab dish with the proper nutrients, and they'll form a mini-brain, also known as an organoid, a semi-organized clump of cells. Now researchers from UCLA have come up with a new method to create tiny brain organoids from stem cells. The well-structured and high-quality organoids are only one to five millimeters in diameter. The study will help scientists to better understand neurological disorders in humans.

Problem with current organoids

The human brain is a delicate organ, and studying it without causing harm is difficult. A solution to this problem is provided by stem cells, which can be used to grow brain organoids in the lab. Because these organoids behave in ways similar to real brains, they can be studied without testing treatments and therapies on live patients.

Researchers have been growing brain organoids for several years, but not all organoids are created the same. It can vary from lab to lab — and even from batch to batch — which means that a finding made in one organoid may not hold true in another.

"Right now, it's like the Wild West because there is no standard method for generating mini–brain organoids," said Bennett Novitch, a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA and the senior author of a new paper on the topic.

Creating the best organoids: A question of maturity

In the current study, researchers proposed new guidelines to make organoids that are consistent in their structure and uniformity.

To produce mini-brains, scientists took human skin or blood cells and reprogrammed them to become induced pluripotent stem cells (iPSC)- cells that can mutate into any cell type in the body.

They then direct this iPSC to create neural stem cells, which can produce most cell types found in the brain. As neural stem cells are forming, they can be coaxed to aggregate into 3D organoids. Simple enough. But why do some organoids better resemble the human brain than others?

Researchers found that the developmental maturity of stem cells influences their quality. The best way to keep the human stem cells in their early developmental state was to put them in a dish with mouse skin cells, also referred to as fibroblast feeders. These feeder layers provide essential chemical signals and structural support that helps stem cells expand and preserve their immaturity over time.

Unfortunately, they discovered that using mouse cells could make organoids less suitable for developing cellular therapies to replace diseased or damaged neural tissues. Furthermore, these feeder-supported methods are more laborious than the stem cell growth methods commonly used in many labs.

Researchers then turned to RNA sequencing and computational analysis to pinpoint the genetic differences between stem cells that produce good organoids and those that don't. Using these techniques, they identified four molecules that were responsible for keeping stem cells in a less-developed state. These molecules belonged to the transforming growth factor beta superfamily, a family of related proteins that regulate many cellular processes.

Adding these four molecules to stem cells growing in a dish kept them in an immature state and enabled these cells to produce high-quality, well-structured organoids.

Having organoids that accurately and consistently recreate the structure and cellular makeup of specific brain sections would allow researchers to study neurological disorders like schizophrenia and autism. In these disorders, the brains of affected people often appear identical to neurotypical brains in structure yet exhibit marked differences in function.

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