Image from Clouds Hill Imaging/Corbis
Published February 29, 2012
Women may make new eggs throughout their reproductive years—challenging a longstanding tenet that females are born with finite supplies, a new study says. The discovery may also lead to new avenues for improving women's health and fertility.
A woman has two ovaries, which release eggs during her monthly ovulation. (Learn more about the human body.)
Previous research had suggested that a woman is born with all the egg cells she will ever have in her lifetime.
But in recent experiments, scientists discovered a new type of stem cell in the ovaries that—when grown in the lab—generates immature egg cells. The same immature cells isolated from adult mouse ovaries can turn into fertile eggs.
Stem cells, found in embryos and certain adult body tissues, have the potential to grow into many different types of cells.
The finding reinforces the team's previous experiments in mice, which had identified a new type of ovarian stem cell that renews a female mouse's source of eggs throughout its fertile years.
That study, published in the journal Nature in 2004, was the "first to reach the conclusion that this long-held belief in our field—that young girls are given a bank account at birth that you can no longer deposit eggs to, just withdraw from—was no longer true," said study leader Jonathan Tilly.
By reinforcing these earlier results in people, the new study is a "big step forward" from the mouse work, emphasized Tilly, director of the Vincent Center for Reproductive Biology at Massachusetts General Hospital in Boston.
From a purely biological perspective, the concept that a woman would continually generate new eggs during her reproductive years makes sense—since men constantly replenish their sperm, Tilly added. (Read how men produce 1,500 sperm a second.)
"There's no fathomable reason," he said, why a woman would have evolved to carry stale eggs around for decades before attempting to get pregnant while men evolved to have fresh sperm always available.
Stem Cells From Donated Ovaries
At first, Tilly faced a roadblock in finding healthy human ovarian tissue to use for his research.
To get experimental ovary tissue in the U.S., the only current option is to use tissue that has been surgically removed from a person with a disease. In these cases, not only is the tissue unhealthy but surgeons also take out only small pieces, and it's impossible to know exactly which part of the ovary the tissue came from.
"If we're going to try to change a fundamental belief in this field regarding how human ovaries function, we needed to have ovaries that were indisputable in their abilities to contain these rare cells," he said.
A chance conversation with a Japanese colleague led Tilly to a source of healthy ovary tissue: Japanese women who'd undergone sex-reassignment surgery and had donated some of their reproductive organs to science.
With healthy tissue in hand, Tilly and colleagues repeated the same technique used in the mouse experiments to isolate the human ovaries' stem cells.
The team first identified ovarian stem cells via a gene-encoded protein that's unique to germ cells: eggs, sperm, and their precursor cells. This protein leaves little "ropes" on the surfaces of the egg precursor cells.
The scientists then used another protein called an antibody to "grab that rope" and tag it with a fluorescent marker.
When the entire pool of ovarian cells was marched single file through a special machine that detects the fluorescent tag, the egg stem cells were easily separated from all other cell types, and the human ovarian stem cells emerged "like a charm," Tilly said.
But the team discovered that egg stem cells are very rare in the ovaries—fewer than one percent of the organs' total cell count. That's a possible reason why ovarian stem cells have gone undiscovered for so long: They were "buried in the crowd," Tilly noted.
Decline in Fertility Due to Aging "House"?
Next the team needed a model for testing how ovarian stem cells would grow in the human body.
Since it's prohibited to legally experiment on a living person, the scientists injected the fluorescent-tagged stem cells into small pieces of human ovarian tissue and grafted that tissue onto female mice, which had been engineered to have no immune system and thus not reject the graft.
Within one to two weeks, the fluorescent human stem cells had developed into fluorescent immature egg cells, which were indistinguishable from the egg cells already present in the tissue.
By showing that the stem cells can produce immature egg cells in living human tissue, this experiment "sealed the identity of these newly discovered cells in women," said Tilly, whose study was published online February 26 in the journal Nature Medicine.
"The existence of these egg precursor cells in ovaries of women during their reproductive years does not conflict at all with the fact that fertility and ovarian function decline with advancing age," he added.
"Rather, our discovery of these cells in women indicates what we might need to rethink how the ovaries in women fail with age, by accounting for these cells as an important variable."
For instance, other scientists have found that sperm stem cells are still present in aging mice with atrophying testicles, but the cells have become nonfunctional. However, if the older stem cells are transplanted into a young mouse's testis, the cells "awaken and begin sperm production all over again."
"Hence, in males, failure of the gonads with age is not due to a loss of these rare stem cells but rather deterioration of the 'house' that they live in."
Tilly suspects a similar phenomenon may be going on in ovaries as women age, which means they stop producing new egg cells.
Fluorescent Technology a "Real Advance"
For now, the new study can show only indirectly that women may be constantly producing new egg cells during their reproductive years.
Still, isolating stem cells via fluorescence is "the real advance, and for me the exciting thing about this work," said Justin Lathia, an assistant professor of cell biology at the Cleveland Clinic's Lerner Research Institute.
"We're now seeing a transition from having to study stem cells in mice to [being able to] isolate them as a single cell," said Lathia, who was not involved in the new study.
A technique to isolate stem cells is especially important with ovarian stem cells, since they're so rare in the ovary, he noted.
Lathia adds that he wasn't particularly surprised by the new study's results, since "the idea of ... stem cells from the ovary has been out there."
He noted that the team didn't follow through to see if a mouse or human could be born from an egg produced by a stem cell, though that's not necessarily a "huge thing."
Gaining Control of the Biological Clock
In the distant future, the discovery could greatly improve women's health, Tilly said.
For instance, finding these new cells in the human ovary could one day help scientists delay or halt menopause in women—something Tilly and his team have already done in a mouse.
By genetically engineering a mouse to maintain its egg-cell reserve as it aged, the team stopped what "in the lab we jokingly call the 'mouseopause,'" he said. (Read more about stem cells in National Geographic magazine.)
The rejuvenated mouse later avoided many of the health problems associated with ovary failure, such as osteoporosis and muscle loss—the same problems that affect post-menopausal women.
"If we could gain control of the [human] female biological clock ... you could arguably delay the time of ovary failure, the primary force behind menopause."
What's more, scientists down the road could potentially use a woman's egg stem cells to create an "unlimited supply" of eggs, which could improve or even replace difficult fertility treatments.
"I don't want to give the idea that we can make a million eggs from a woman tomorrow," Tilly cautioned.
But "the future looks bright in providing women with more options to think about as they go through their lives."
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