Nature: Stem cells that violate the laws of development?

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Nature: Stem cells that violate the laws of development?

Removing a gene from developing heart cells suddenly turns them into precursors to brain cells.

Imagine you’re baking a cake, but you’ve run out of salt. Even without these ingredients, the batter still looks like cake batter, so you pop it in the oven and pray that you end up with something like a regular cake.

However, you come back an hour later to find a perfectly cooked steak.

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

Nature: Stem cells that violate the laws of development?

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

The scientists’ serendipitous discovery upends their previous understanding of how stem cells become adult cells and retain their properties as they mature.

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

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. But it takes many steps for stem cells to grow into adult cells.

Embryonic stem cells, for example, first differentiate into the mesoderm, one of the three primitive tissues found in the earliest embryos, in the process of becoming heart cells.

Further down, mesoderm cells branch off to form bone, muscle, blood vessels, and beating heart cells.

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.

While this didn’t give the cells the ability to hop between valleys, it did act like a ski lift back to the top of the differentiated landscape.

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. But in none of these examples was a single cell able to spontaneously jump between distinct differentiation paths. In particular, mesoderm cells cannot be precursors to distant types like brain cells or gut cells.

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 because 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).

They noticed that these cells no longer differentiated into normal heart cell precursors.

“After 10 days of differentiation, normal cells are beating rhythmically — they are clearly heart cells,” says Swetansu Hota, Ph.D., first author of the study and a scientist in Bruno’s lab.

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. Heart precursor cells are now brain precursor cells.

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

Instead, these cells made a much larger leap between stem cell pathways than had previously been observed.

“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.

While the environment of cells in a lab dish is quite different from that in an entire embryo, the researchers’ observations have implications for cellular health and disease.

Mutations in the gene Brm have been linked to congenital heart disease and syndromes involving brain function. The gene is also associated with several cancers.

“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.”

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.

“Our study also tells us that differentiation pathways are far more complex and fragile than we thought,” Bruneau said. “A better understanding of the pathways of differentiation could also help us understand congenital heart and other defects that are caused in part by defective differentiation.”

Reference:
“Brahma safeguards canalization of cardiac mesoderm differentiation”

Nature: Stem cells that violate the laws of development?

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