Public release date: 23-Jan-2013 [ | E-mail | Share ]

Contact: Jim Fessenden james.fessenden@umassmed.edu 508-856-2600 University of Massachusetts Medical School

WORCESTER, MA A retrovirus called HERV-H, which inserted itself into the human genome millions of years ago, may play an important role in pluripotent stem cells, according to a new study published in the journal Retrovirology by scientists at UMass Medical School. Pluripotent stem cells are capable of generating all tissue types, including blood cells, brain cells and heart cells. The discovery, which may help explain how these cells maintain a state of pluripotency and are able to differentiate into many types of cells, could have profound implications for therapies that would use pluripotent stem cells to treat a range of human diseases.

"What we've observed is that a group of endogenous retroviruses called HERV-H is extremely busy in human embryonic stem cells," said Jeremy Luban, MD, the David L. Freelander Memorial Professor in HIV/AIDS Research, professor of molecular medicine and lead author of the study. "In fact, HERV-H is one of the most abundantly expressed genes in pluripotent stem cells and it isn't found in any other cell types."

In the study, Dr. Luban and colleagues describe how RNA from the HERV-H sequence makes up as much as 2 percent of the total RNA found in pluripotent stem cells. The HERV-H sequence is controlled by the same factors that are used to reprogram skin cells into induced pluripotent stem (iPS) cells, a discovery that garnered the 2012 Nobel Prize in Physiology or Medicine. "In other words, HERV-H is a new marker for pluripotency in humans that has the potential to aid in the development of iPS cells and transform current stem cell technology," said Luban.

When a retrovirus infects a cell, it inserts its own genes into the chromosomal DNA of the host cell. As a result, the host cell treats the viral genome as part of its own DNA sequence and begins making the proteins required to assemble new copies of the virus. And because the retrovirus is now part of the host cell's genome, when the cell divides, the virus is inherited by all daughter cells.

In rare cases, it's believed that retroviruses can infect human sperm or egg cells. If this happens, and if the resulting embryo survives, the retrovirus can become a permanent part of the human genome, and be passed down from generation to generation. Scientists estimate that as much as 8 percent of the human genome may be comprised of extinct retroviruses left over from infections that occurred millions of years ago. Yet these sequences of fossilized retrovirus were thought to have no discernible functional value.

"The human genome is filled with retrovirus DNA thought to be no more than fossilized junk," said Luban. "Increasingly, there are indications that these sequences might not be junk. They might play a role in gene expression after all."

An expert in HIV and other retroviruses, Luban and his colleagues were seeking to understand if there was a rationale behind where, in the expansive human genome, retroviruses inserted themselves. Knowing where along the chromosomal DNA retroviruses might attack could potentially lead to the development of drugs that protect against infection; better gene therapy treatments; or novel biomarkers that would predict where a retrovirus would insert itself in the genome, said Luban.

Turning these same techniques on the retrovirus sequences already in the human genome, they discovered a sequence, HERV-H, that appeared to be active. "The sequences weren't making proteins because they had been so disrupted over millions of years, but they were making these long, noncoding RNAs," said Luban.

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Retrovirus in the human genome is active in pluripotent stem cells

Researchers in Japan said Wednesday they have succeeded in growing human kidney tissue from stem cells for the first time in a potential breakthrough for millions with damaged organs who are dependent on dialysis.

Kidneys have a complex structure that is not easily repaired once damaged, but the latest findings put scientists on the road to helping a diseased or distressed organ fix itself.

Kenji Osafune of Kyoto University said his team had managed to take stem cells -- the "blank slates" capable of being programmed to become any kind of cell in the body -- and nudge them specifically in the direction of kidney tissue.

"It was a very significant step," he told AFP.

Osafune said they had succeeded in generating intermediate mesoderm tissue from the stem cells, a middle point between the blank slate and the finished kidney tissue.

"There are about 200 types of cells in the human body, but this tissue grows into only three types of cells," namely adrenal cells, reproductive gland cells and kidney cells, he said, adding that as much as 90 percent of cultures in their research developed into viable mesoderm tissue.

This embryonic intermediary can be grown either in test tubes or in a living host into specific kidney cells.

Osafune and his team created part of a urinary tubule, a small tube in the kidney that is used in the production of urine.

While the research is not aimed at growing an entire working kidney, he said the method his team had developed would help scientists learn more about intermediate mesoderm development and may provide a source of cells for regenerative therapy.

"I would say that we have arrived at the preliminary step on the road to the clinical level," he said.

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Japan researchers grow kidney tissue from stem cells

In this week's issue of Science Signaling (22 January, 2013), Danen and colleagues of the Division of Toxicology of LACDR report novel insights into the question how stem cells decide to commit suicide when their DNA is damaged.

It is known that damaged DNA, especially in stem cells can lead to accumulation of potentially dangerous mutations that may be a source for cancer. To prevent this, evolution has provided our cells with the ability to recognize damaged DNA and to rapidly respond to it. This so-called "DNA damage response" activates repair mechanisms, and, if damage is too severe to repair, turns on a cascade of events leading to cell death.

All cells in our body are constantly experiencing small injuries in their DNA, for instance due to UV light or chemicals. It is important that cells first try to repair damaged DNA and only decide to commit suicide if damage is beyond repair. If suicide signals would be turned on too fast, stem cells in our tissues might be depleted causing premature aging. The discovery published in this week's Science Signaling is a new mechanism that acts as a break on the suicide signals.

In collaboration with colleagues from the Department of Toxicogenetics of the LUMC and from the University of Copenhagen, Danen et al. have been able to integrate several large-scale analyses to unravel the events that make up the DNA damage response. Genome-wide changes in gene activity and protein modifications, as well as genome-wide "gene silencing" screens were integrated with bioinformatics tools to create signaling networks. This was possible through extensive collaboration within the NGI-funded, "Netherlands Toxicogenomics Center".

The signaling networks point to novel methods to recognize chemicals or drugs that activate a DNA damage response and hence, might be dangerous for human exposure. At the same time, the networks provide new clues for why cancer cells are often able to avoid activation of suicide signals when exposed to radiotherapy or chemotherapy. The publication in Science Signaling is one of the outcomes of this project; additional publications will come out this year.

Journal reference: Science Signaling

Provided by Leiden University

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Stem cells: Tuning the death sentence