PUBLIC RELEASE DATE:

30-Jan-2014

Contact: Bill Hathaway william.hathaway@yale.edu 203-432-1322 Yale University

A fundamental axiom of biology used to be that cell fate is a one-way street once a cell commits to becoming muscle, skin, or blood it always remains muscle, skin, or blood cell. That belief was upended in the past decade when a Japanese scientist introduced four simple factors into skin cells and returned them to an embryonic-like state, capable of becoming almost any cell type in the body.

Hopeful of revolutionary medical therapies using a patient's own cells, scientists rushed to capitalize on the discovery by 2012 Nobel Laureate Shinya Yamanaka. However, the process has remained slow and inefficient, and scientists have had a difficult time discovering a genetic explanation of why this should be.

In the Jan. 30 issue of the journal Cell, Yale School of Medicine researchers identified a major obstacle to converting cells back to their youthful state the speed of the cell cycle, or the time required for a cell to divide.

When the cell cycle accelerates to a certain speed, the barriers that keep a cell's fate on one path diminish. In such a state, cells are easily persuaded to change their identity and become pluripotent, or capable of becoming multiple cell types

"One analogy may be that when temperature increases to sufficient degrees, even a very hard piece of steel can be malleable so that you can give it a new shape easily," said Shangqin Guo, assistant professor of cell biology at the Yale Stem Cell Center and lead author of the paper. "Once cells are cycling extremely fast, they do not seem to face the same barriers to becoming pluripotent."

Guo's team studied blood-forming cells, which when dividing undergo specific changes in their cell cycle to produce new blood cells. Blood-forming progenitor cells normally produce only new blood cells. However, the introduction of Yamanaka factors sometimes but not always help these blood-forming cells become other types of cells. The new report finds that after this treatment blood-forming cells tend to become pluripotent when the cell cycle is completed in eight hours or less, an unusual speed for adult cells. Cells that cycle more slowly remain blood cells.

"This discovery changes the way people think about how to change cell fate and reveals that a basic 'house-keeping' function of a cell, such as its cell cycle length, can actually have a major impact on switching the fate of a cell," said Haifan Lin, director of the Yale Stem Cell Center.

Excerpt from:
Cell cycle speed is key to making aging cells young again

(CNN) We run too hard, we fall down, we're sick - all of this puts stress on the cells in our bodies. But in what's being called a breakthrough in regenerative medicine, researchers have found a way to make stem cells by purposely putting mature cells under stress.

Two new studies published Wednesday in the journal Nature describe a method of taking mature cells from mice and turning them into embryonic-like stem cells, which can be coaxed into becoming any other kind of cell possible. One method effectively boils down to this: Put the cells in an acidic environment.

"I think the process we've described mimics Mother Nature," said Dr. Charles Vacanti, director of the laboratory for Tissue Engineering and Regenerative Medicine at Brigham & Women's Hospital in Boston and senior author on one of the studies. "It's a natural process that cells normally respond to."

Both studies represent a new step in the thriving science of stem cell research, which seeks to develop therapies to repair bodily damage and cure disease by being able to insert cells that can grow into whatever tissues or organs are needed. If you take an organ that's functioning at 10 percent of normal and bring it up to 25 percent functionality, that could greatly reduce the likelihood of fatality in that particular disease, Vacanti said.

This method by Vacanti and his colleagues "is truly the simplest, cheapest, fastest method ever achieved for reprogramming [cells]," said Jeff Karp, associate professor of medicine at the Brigham & Women's Hospital and principal faculty member at the Harvard Stem Cell Institute. He was not involved in the study.

Before the technique described in Nature, the leading candidates for creating stem cells artificially were those derived from embryos and stem cells from adult cells that require the insertion of DNA to become reprogrammable.

Stem cells are created the natural way every time an egg that is fertilized begins to divide. During the first four to five days of cell division, so-called pluripotent stem cells develop. They have the ability to turn into any cell in the body. Removing stem cells from the embryo destroys it, which is why this type of research is controversial.

Researchers have also developed a method of producing embryonic-like stem cells by taking a skin cell from a patient, for example, and adding a few bits of foreign DNA to reprogram the skin cell to become like an embryo and produce pluripotent cells, too. However, these cells are usually used for research because researchers do not want to give patients cells with extra DNA.

The new method does not involve the destruction of embryos or inserting new genetic material into cells, Vacanti said. It also avoids the problem of rejection: The body may reject stem cells that came from other people, but this method uses an individual's own mature cells.

"It was really surprising to see that such a remarkable transformation could be triggered simply by stimuli from outside of the cell," said Haruko Obokata of the Riken Center for Developmental Biology in Japan in a news conference this week.

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New breakthrough in stem cell research

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A new study published in the journal Cell Stem Cell, describes how scientists have developed a way of producing highly sought populations of a pure tissue-specific cell from human pluripotent stem cells.

Human pluripotent stem cells (hPSCs) are precursor cells than can produce over 200 distinct cell types in the human body. They hold great promise for regenerative medicine and drug screening. The idea is to be able to generate a range of pure tissue types by manipulating these precursor cells.

However, it is proving very challenging to obtain large numbers of pure, untainted, tissue-specific cells from hPSCs. Part of the problem is how to ensure they receive highly specific signals, that do not coax them down paths that lead to a range of other tissue types.

Now, a team led by the Genome Institute of Singapore (GIS) in the Agency for Science, Technology and Research (A*STAR) has developed a new way of coaxing hPSCs to produce highly pure populations of endoderm, a valuable cell type that gives rise to organs like the liver and pancreas, bringing closer the day when stem cells can be used in clinical settings.

One of the study leaders is Dr. Bing Lim, senior group leader and associate director of Cancer Stem Cell Biology at the GIS. He and his colleagues developed a highly systematic and novel screening method.

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Scientists make pure precursor liver and pancreas cells from stem cells