"Nature" cake becomes steak?

It might sound like a hoax, but this shocking transformation did happen on mouse stem cells in a petri dish

Scientists at the Gladstone Institute took out just one genetic stem cell destined to become a heart cell, but suddenly it became a precursor to a brain cell

Dr Benoit Bruneau, director of the Gladstone Institute of Cardiovascular Disease and senior author of the new study, published in Nature, said: "This really challenges how cells maintain the process of becoming heart or brain cells once they start.

can't go back

Embryonic stem cells are pluripotent - they can differentiate or transform into any type of cell in a fully mature adult body

A widely accepted view is that once a cell begins to differentiate along one of these paths, it cannot turn around and choose a different fate

"Almost every scientist who talks about cell fate has used a picture of the Waddington landform, which looks a lot like a ski resort, with different ski slopes descending into steep, separated valleys, and if a cell is in a deep valley, it doesn't way to jump into a completely different valley

A decade ago, Gladstone Senior Research Fellow Shinya Yamanaka, PhD, discovered how to reprogram fully differentiated adult cells into induced pluripotent stem cells

Since then, other researchers have found that, with the right chemical cues, some cells can be transformed into closely related types through a process called "direct reprogramming," like in the woods between adjacent ski runs open up a shortcut

In the new study, however, Bruneau and his colleagues found, to their surprise, that the precursors of heart cells can indeed be converted directly into precursors of brain cells—if a protein called Brahma is missing

a surprising observation

Researchers are studying the protein Brahma's role in heart cell differentiation, as they discovered in 2019, that it works with other molecules involved in heart formation

In a dish of mouse embryonic stem cells, they used CRISPR genome editing to turn off the gene Brm (the gene that makes the protein Brahma)

"After 10 days of differentiation, normal cells were beating rhythmically -- they were clearly heart cells," said Swetansu Hota, Ph.

After further analysis, Bruneau's team realized that the reason the cells weren't beating was because removing Brahma not only turned off genes needed in heart cells, but also activated genes needed in brain cells

The researchers then followed each step of the cells' differentiation and unexpectedly found that the cells never returned to their pluripotent state

"What we're seeing is that in one valley in the Waddington landscape, under the right conditions, a cell can jump into another valley without first taking the elevator back to the top of the mountain," Bruneau said
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"If removing Brahma can turn mesoderm cells (like heart cell precursors) into ectodermal cells (like brain cell precursors) in a petri dish, then perhaps mutations in the Brm gene enable some cancer cells to grow massively," Bruneau said.
alter its genetic program
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The findings are also important at the basic research level, he added, because they could shed light on how cells change their properties in disease settings, such as heart failure, and develop regenerative therapies by inducing new heart cells
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"Our study also tells us that differentiation pathways are far more complex and fragile than we thought," Bruneau said
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"A better understanding of the pathways of differentiation could also help us understand the congenital heart and other defects that are caused in part by defective differentiation
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Reference article: "Brahma safeguards canalization of cardiac mesoderm differentiation"