MAR 24, 2016 4:30 AM PDT

Eraser drug makes stem cells embryonic again

If you want to harness the full power of stem cells, all you might need is an eraser.

More than half of mouse epiblast stem cells treated with the drug reversed course within three days, and regained an embryonic "be anything" state, also called pluripotency. And mice bred using the cells grew up healthy.

Not an ordinary eraser, of course. More of a drug, really. But if you use it right, it can erase the tiny labels that tell cells where to start reading important chapters in DNA, their inner instruction manual.

And if they can’t read that manual, the cells regain their full stem cell power—the power to become any kind of cell in the body.

Now scientists have proven that a drug can do this—at least in mice.

It’s the first time scientists have shown they can get stem cells to revert to their original state by erasing specific labels called epigenetic markers. The drug specifically targets markers on histones, the protein “spools” that DNA coils around to create structures called chromatin.

Writing in the journal Cell Stem Cell, the team from the University of Michigan Medical School reports that more than half of mouse epiblast stem cells treated with the drug reversed course within three days, and regained an embryonic “be anything” state, also called pluripotency.

In addition to generating pluripotent stem cells, the team showed that mice bred using the cells grew up healthy.

“We’ve demonstrated that we don’t have to manipulate the pluripotent genes to get to the ground state, but rather that we can block all other options of where the cell ‘wants’ to go. Then the only option is going back to the ground, or naïve, pluripotent state,” says Yali Dou, senior author of the new paper and an associate professor of pathology and biological chemistry.
 

Will it work with people?


The researchers used a relatively new compound called MM-401, which University of Michigan scientists originally designed for use in treating leukemia. Now, they’re working to see if the MM-401 eraser technique works with human stem cells that bear some resemblance to mouse epiblast stem cells.

They will share the drug with any other researchers who want to try the technique.

However, it’s far too early to see the approach as a way to avoid the use of human embryos for research or potential treatments. Currently, embryos left over from infertility treatments are the only source of human embryonic stem cells.

Other techniques can reprogram “adult” cells in the human body taken from skin, for example—but the cells still carry baggage from their previous state.

Still, the new achievement shows the power of altering the epigenetic labels that dot the chromatin packaging, without altering the DNA itself. Past attempts by other teams to restore pluripotency to mouse cells from the epiblast stem cell state have yielded far lower amounts, or non-viable cells. And, they’ve required cocktails of multiple drugs, given over the long term, to achieve it.

The team shows that using MM-401 for just a few days, and then stopping its use, is enough.
 

Leaves no trace behind


Epigenetic labels signal to the cell’s DNA-reading machinery where they should start uncoiling a chromosome in order to read it. The drug targets the labels that come from the activity of a gene called MLL1.

MLL1 plays a key role in the uncontrolled explosion of white blood cells that’s the hallmark of leukemia. But it also plays a much more mundane role in regular cell development, and the formation of blood cells and the cells that form the spinal cord in later-stage embryos.

It does this by placing tiny tags—called methyl groups—on histones. Without those labels, the cell’s DNA-reading machinery doesn’t know where to start reading. It’s as if the invitation to open the instruction manual had vanished.

Stem cells don’t harness the power of MLL1 until they’re older. So using MM-401 to block MLL1’s normal activity in cells that had started down the path to adulthood meant that histone marks were missing before the cell needed them. The cells couldn’t continue on their journey to becoming different types of cells. But they could still function as healthy pluripotent stem cells.

“People have been focused on other epigenetic changes that are more dramatic, but ignored methylation by the MLL family,” says Dou. “Deleting MLL1 entirely causes failure later in differentiation. But inhibiting it with a drug temporarily leaves no trace behind.”

The National Institutes of Health and the Leukemia and Lymphoma Society funded the study.

Source: University of Michigan

This article was originally published on futurity.org.
About the Author
  • Futurity features the latest discoveries by scientists at top research universities in the US, UK, Canada, Europe, Asia, and Australia. The nonprofit site, which launched in 2009, is supported solely by its university partners (listed below) in an effort to share research news directly with the public.
You May Also Like
DEC 16, 2020
Cell & Molecular Biology
A Close Connection Between Two Organelles is ID'ed
DEC 16, 2020
A Close Connection Between Two Organelles is ID'ed
The cell has many specialized components that perform specific functions, like an organelle called the endoplasmic retic ...
DEC 21, 2020
Cell & Molecular Biology
Mutagens May Be Having a Bigger Effect Than We Knew
DEC 21, 2020
Mutagens May Be Having a Bigger Effect Than We Knew
New research has suggested that our DNA is more susceptible to mutagenic influences than we've appreciated. While organi ...
JAN 05, 2021
Microbiology
Finding ways to Culture Bacteria From Extreme Environments
JAN 05, 2021
Finding ways to Culture Bacteria From Extreme Environments
In order to study bacteria, it has to be grown in the lab. That’s no problem for many common strains of bacteria t ...
FEB 07, 2021
Cell & Molecular Biology
Watching the Body Plan Emerge
FEB 07, 2021
Watching the Body Plan Emerge
Animals grow from what looks like a clump of cells, but those cells organize into specific patterns, laying the right fo ...
FEB 09, 2021
Cell & Molecular Biology
Brain Cells Called Astrocytes Linked to Depression
FEB 09, 2021
Brain Cells Called Astrocytes Linked to Depression
Depression is thought to affect at least 264 million people of all ages worldwide, and the available treatment options d ...
FEB 09, 2021
Plants & Animals
Venus Flytraps Generate Magnetic Fields
FEB 09, 2021
Venus Flytraps Generate Magnetic Fields
The Venus flytrap (Dionaea muscipula) might be the most famous carnivorous plant; it can entice prey to land on its leaf ...
Loading Comments...