A team of Harvard scientists is claiming the discovery of a reservoir of cells that appear capable of replenishing the ovaries of sterilized mice, possibly providing new ways to help infertile women have babies.
While cautioning that more research is needed to confirm that similar cells exist in women and that they can safely restore fertility, the researchers said the findings could revolutionize the understanding of female reproduction and the power to manipulate it.
"This may launch a new era in how to think about female infertility and menopause," said Jonathan L. Tilly, a reproductive biologist at Harvard Medical School and Massachusetts General Hospital in Boston who led the research. It is being published in tomorrow's issue of the journal Cell.
Other researchers agreed that the findings could have profound implications, but several expressed caution and skepticism, saying many key questions remain about whether the researchers have proved their claims.
"This is really exciting and a revolutionary idea. The implications are potentially huge," said Lawrence Nelson of the National Institute of Child Health and Human Development. "But before this could have any type of application to humans, a whole lot of work has to be done. We have to be careful not to get ahead of ourselves."
But Tilly said he was confident of his findings, which could, for example, enable women to bank egg-producing cells when they are young in case they have health problems that leave them infertile or they get too old.
"In theory, these cells could provide an insurance policy. We could harvest them and store them away for 20 years. Then you put them back in, and they are going to do exactly what they are supposed to — find the ovaries and generate new eggs" to restore fertility, Tilly said.
Applications for menopause
The discovery could also lead to ways to prevent, delay or reverse menopause, perhaps by stimulating dormant cells in the bone marrow or "tweaking" the ovaries to accept them, Tilly said. It may also be possible to transplant them from one woman to another, he said.
In addition, because the cells appear to be a particularly versatile type of adult stem cell, they could provide an alternative to those obtained from embryos, avoiding the political and ethical debates raging around the use of those cells.
"The implications are mind-boggling, really," Tilly said.
The research is a follow-up to results the team reported in March 2004, when it claimed it had shown that mice can produce eggs throughout their lives. For decades, scientific dogma has been that female mammals such as mice and humans are born with a finite number of eggs. To alleviate doubts about their original claim, the researchers conducted another round of experiments, which they said confirm the findings and explain how it might work.
First, the scientists sterilized female mice with a cancer chemotherapy drug that destroyed eggs in the ovaries but spared any egg-producing cells elsewhere. They tested the animals' ovaries 12 to 24 hours later and found signs their egg supply was rapidly regenerating. Two months later, the animals' ovaries looked normal, and they remained that way for life.
After tests indicated the source of the cells may lie in the animals' bone marrow, the researchers infused marrow from healthy mice into those that were either genetically engineered to be infertile or had been made infertile with chemotherapy. Two months later, the recipients' ovaries looked normal, whereas those that had not received the transplants remained barren, the researchers reported. Blood transfusions produced similar results, they said.
The researchers then infused blood into infertile mice from animals that had been genetically engineered so that their reproductive stem cells glowed fluorescent green. Within two days, green egg cells appeared in the recipients' ovaries, which the researchers said indicated the cells had traveled through the blood to the ovaries.
Finally, the researchers screened human bone marrow and blood from healthy women and found that both tested positive for biological markers indicating the presence of immature reproductive cells.
"Mice and humans appear to be the same — they appear to have a set of genes in bone marrow consistent with ... cells that can make themselves a new egg," Tilly said.
Could explain pregnancies in transplant patients
The findings could help explain previously mysterious cases of women sterilized by cancer treatment who spontaneously became pregnant after receiving bone marrow transplants, Tilly said. This may happen only rarely because some, but not all, techniques used to process bone marrow before transplantation may destroy the cells in some cases, he speculated.
The research triggered a mixture of excitement, caution and deep skepticism.
"It's quite amazing," said Hans Schoeler of the Max Planck Institute in Germany. "The idea that cells from bone marrow may be a reservoir for egg cells would be quite astonishing."
But Schoeler and other researchers cautioned that many crucial questions remained. Several researchers had doubts about some of the techniques the researchers used. Others were puzzled by the speed with which the ovaries appeared to be repopulated with eggs. Many pointed out that the researchers had failed to show the eggs were viable, the mice were ovulating or that they could give birth to healthy offspring.
"I'm very skeptical," said David F. Albertini of the University of Kansas Medical Center in Kansas City, Kan. "There are a lot of holes in the research."
Tilly attributed the skepticism to the radical nature of the findings and said he already had work underway to address the concerns, including breeding studies aimed at producing healthy offspring.
"We hope we will have the answers very soon," Tilly said.