Stem cells may make new eggs in women.

Scientists may have to come up with a new explanation for how a woman's biological clock works.

A study in mice appears to overturn the long-held assumption that female mammals are born with all the eggs they'll ever have. Researchers have found evidence that the ovaries of even mature rodents retain a population of cells that can spawn new eggs. The finding may force reproductive biologists to rethink the fundamentals of menopause and female infertility and how to treat either condition.

"We're still somewhat in a state of disbelief," says study leader Jonathan L. Tilly of Massachusetts General Hospital in Boston.

Men typically produce sperm throughout their lives, thanks to a small population of germline stem cells. But biologists have for decades assumed that women start life with a fixed supply of eggs, which steadily dwindles until practically no eggs remain and menopause begins.

Studies early in the past century hinted that the ovaries of adult female mammals had their own version of germline stem cells, but an influential paper in 1951 argued against ongoing egg production and effectively ended the debate. "Everyone was taught that it was settled," says Allan Spradling of the Carnegie Institution in Baltimore. "We have to thank Dr. Tilly for doubting this 'proven fact' and looking again."

Tilly and his colleagues began to question the dogma when they performed the first measurements of the death rate of ovarian follicles in mice. In these capsule-like structures, support cells envelop an immature egg, or oocyte.

Scientists knew that the number of oocyte-containing follicles decreases as female mammals age, but Tilly's team found so high a follicle-death rate in young and adult mice that the animals' ovaries should have been depleted of eggs within days or weeks. Since female mice are fertile for more than a year, their ovaries had to be generating new oocytes, the scientists reasoned.

The team subsequently identified cells on the surface of adult-mouse ovaries that look like the germline stem cells seen previously in fetal ovaries. These putative stem cells proliferate and contain a protein used in the making of an oocyte, Tilly's group reports in the March 11 Nature.

The biologists also found that a drug known to kill male germline stem cells appears to kill the female counterparts as well.

Finally, the investigators grafted healthy ovarian tissue from normal adult mice onto the ovaries of other adult mice that had been genetically engineered to have green-glowing cells. About a month later, green-glowing oocytes were found in the transplanted tissue, indicating that germline cells in the engineered mice had spawned new eggs that migrated into the transplanted tissue.

Tilly's team plans to isolate and characterize the mouse germline stem cells, steps useful for determining whether women possess the same cells. If that turns out to be the case, scientists will be confronted with a new question: Why do a woman's germline stem cells stop replenishing her eggs as she nears menopause?

Fertility scientists might try transplanting ovarian germline stem cells to delay menopause, Tilly suggests. The cells could, in theory, also be harvested from women about to undergo sterilizing radiation or chemotherapy for cancer. Says Tilly: "If these cells can be banked and stored, they can be reintroduced back into a patient to restore fertility."--J. TRAVIS