Scientists have bred "smarter" brain organs in the lab

• In recent years, small brain organoids have been used in the lab to simulate a variety of diseases, from Alzheimer's to COVID-19
  .
  

• In the absence of a standard process for creating these organoids, some organs mimic the structure of the brain more accurately than others, which can lead to inconsistent scientific findings
  .
  

• A new study provides guidelines and methods for the continued generation of high-quality, well-structured organoids
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By using stem cells in the lab to grow miniature brain-like organs, scientists have opened up a new avenue for research into neurodevelopment, disease, and treatment that can't be done
in living people.
But not all small brain organs are created equal, and getting them to accurately mimic the human brain tissue they model has been a long-term challenge
.

Bennett Novitch, a member of UCLA's Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, said: "Right now, it's like the Western Wilderness because there is no standard way to
generate miniature brain organs.
" He is the senior author
of a new paper on the topic.
"Every neuroscientist wants to make a brain organoid model for their favorite disease, but everyone's organoids don't always look the same
.
"

In fact, because there is no common protocol for their production, and there is a lack of quality control guidelines, organoids may differ between different laboratories – and even between different batches – meaning that a finding made in one organoid may not hold true
in another.

Momoko Watanabe, the lead author of the new paper and an assistant professor of anatomy and neurobiology at UC Irvine, said: "If my lab and another lab at the other end of the hall used a mini-brain organ model of the same disease for drug screening, we might still get different results
.
" We don't know whose findings are correct, because the differences we see may be a different reflection of our model, rather than a reflection
of disease.
”

Their new study suggests guidelines that could help scientists overcome two major barriers that prevent these organoids from reaching their full potential: uniformity and structural differences
.
For studying diseases such as schizophrenia and autism spectrum disorders, it is especially important
to have organoids that accurately and consistently reproduce the structure and cellular composition of specific parts of the brain.
In these diseases, the brains of affected people are usually structurally identical to those of a normal nervous system, but show significant differences
in function.

"If the cell types of our organoids are imbalanced or structurally very irregular, we will never be able to recognize subtle differences in brain structure and function — and this is associated with patients with neurological disorders," said Novitch, who is also director of the UCLA Brain Institute's Comprehensive Center for
Neurorepair.

Creating the best organoids: a matter of maturity

To make miniature brain organoids between 1 and 5 millimeters in diameter, the scientists first reprogrammed human skin or blood cells into induced pluripotent stem cells — a cell
that can differentiate into any cell type in the human body.
They then directed these induced pluripotent stem cells to produce neural stem cells, which can produce most of the cell types
found in the brain.
When neural stem cells form, they can be induced to aggregate into 3D organoids
.
It's simple
.
But why are some organs more like the human brain than others?

To answer this question, the team teamed up
with Kathrin Plath and Amander Clark of pluripotency experts at UCLA's Broad Stem Cell Research Center.
They found that the developmental maturity of stem cells grown by organoids affects their quality, just as
the freshness of an ingredient affects the quality of a dish.

Watanabe said: "During human embryonic development, the nervous system is one of the earliest structures formed, so it makes sense that early developing stem cells are best at producing brain organoids
.
"

The researchers then found that the best way to keep human stem cells in an early developmental state suitable for organoid formation is to grow them in a Petri dish with mouse skin cells, called fibroblast feeders, because these cells provide the necessary chemical signals and structural support to help stem cells swell over time and maintain their immature state
.
Unfortunately, they also found that using mouse cells may make organoids less suitable for developing cell therapies to replace diseased or damaged nerve tissue
.
In addition, these methods of feeding support are more laborious
than stem cell growth methods commonly used in many laboratories.

Next, the team turned to RNA sequencing and computational analysis to try to determine the genetic differences
between stem cells that produce good organoids and stem cells that do not.
This allowed them to identify four molecules — all of which are transformed growth factors β suprafamily molecules — that are responsible for keeping stem cells in a state of
hypoplasia.
These four molecules are added to stem cells growing in a Petri dish, leaving them in an immature state and causing these cells to produce high-quality, well-structured organoids
.

"We found a way to have both fish and bear paws," Novitch said
.
"We have removed mouse cells from the equation, but retained some of their benefits in organoid formation, which brings us closer to our goal
of researching and developing treatments for complex neurological diseases.
"

TGFβ superfamily signaling regulates the state of human stem cell pluripotency and capacity to create well-structured telencephalic organoids