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Gene Rejuvenates Mouse Embryonic Stem Cell Immortality

Researchers have discovered a key to mouse embryonic stem (ES) cell rejuvenation in a gene called Zscan4. If a similar mechanism also operates in human cells, the finding could have major implications for aging research, stem cell biology, regenerative medicine and cancer biology.

ES cells are unique not only because of their ability to develop into nearly any type of cell in the body. They are also what scientists call immortal—they can divide indefinitely in the laboratory to produce new generations of fully functional "daughter" ES cells. Other cells can only produce a certain number of generations of daughter cells before they no longer function properly. This is partially because the telomere, the protective end of the chromosome, shortens each time a cell divides. When a telomere becomes too short, the cell dies, turns itself off or produces abnormal cells.

Until now, the mechanism for ES cell immortality had been a mystery. A research team led by Dr. Minoru S. H. Ko at NIH’s National Institute on Aging (NIA) previously found that Zscan4 is highly expressed in 2-cell embryos and ES cells. In the new study, they more closely examined to discover its role in mouse ES cell immortality.

As reported in the March 24, 2010, online edition of Nature, only about 5% of ES cells have Zscan4 activated at any given time. However, nearly all ES cells undergo a period of Zscan4 activation. When the researchers interfered with Zscan4 expression, cell population growth slowed and eventually reached a crisis, with massive cell death.

The researchers examined telomeres and found that Zscan4 activation led to telomere lengthening. However, telomerase—a protein known to elongate telomeres in other situations—didn't seem to be involved. Rather, Zscan4 activation turned on genes involved with recombination—the process by which DNA strands are broken and joined to other strands. ZSCAN4 protein, along with these recombination proteins, could all be found on telomeres during this telomere "rejuvenation" phase.

The researchers conclude that instead of going through a self-renewal process when they divide, as some researchers thought, ES cells go through a periodic rejuvenation. This rejuvenation is triggered by the intermittent activation of Zscan4, which causes telomeres to lengthen through recombination.

"We were fascinated by the elaborate mechanism that ES cells employ to maintain their immortality," Dr. Ko says. “The work poses many interesting questions, including ones about the very definition of stem cells. We are excited by the many possibilities opened by this discovery."

The researchers are now investigating whether a similar mechanism also operates in human cells. Manipulation of Zscan4 expression could prove useful for future therapies—for example, in creating stem cells or controlling cancer cells.