With implications for mothers-to-be, doctors in Boston are turning the long-held belief that women are born with all the eggs they'll ever have upside down. In a study published last month,1 a team of researchers at Massachusetts General Hospital and Harvard Medical School claim they've uncovered a previously unrecognized form of stem cell that can replenish the ovaries with a fresh supply of eggs.
Revolutionary or Preliminary?
The results are "really revolutionizing how we think about female reproductive function," explained Jonathan Tilly, PhD, director of the Vincent Center for Reproductive Biology at Massachusetts General Hospital and the study's chief investigator.
But other experts question the study's results, contending that there has never been any direct evidence of the existence of these stem cells.
Tilly and his colleagues used mice to locate the stem cells, found in the animals' bone marrow and blood. The study is a follow-up to one published last year in which the researchers reported the first preliminary evidence that ovaries of mice can be renewed with new eggs in adulthood.2
"Here we show that adult mouse ovaries can produce hundreds of new oocytes [eggs] within 24 hours, reinforcing the primary conclusion from our earlier work that initially challenged the dogma of a fixed component of oocytes at birth," wrote Tilly and his team.
Significance of Stem Cells
Stem cells are primitive cells that form before we're born. They have the ability to transform themselves into many different cells in the body. Stem cells serve as a repair system, of sorts, and can divide limitlessly to replenish diseased or damaged cells, such as those of the muscle, blood, or brain.3
It's thought that bone marrow is the ultimate repository of the body's stem cell supply. Blood cells are known to be produced from bone marrow-derived stem cells, as well as those of bone, cartilage, and fat. Bone marrow stem cells are currently the only type of stem cell currently being used to treat disease, such as with the use of a bone marrow transplant procedure. More advanced techniques involving the harvesting of stem cells from bone marrow are being used to treat leukemia, lymphoma, and several inherited blood disorders.4
Genetic Markers Observed
In this study, Tilly and his team claimed the presence of several genetic markers normally found in germ cells, the master cells in the body that give rise to egg and sperm cells, point to the existence of the stem cells that they claim exist in bone marrow and blood in mice. These genetic markers, they say, also exist in humans.
Contrasting with entrenched beliefs about egg production, the investigators found that bone marrow or blood cell transplants appeared to completely revive the ovaries of female mice that were sterilized by chemotherapy. Just 24 hours after they were sterilized, the mice reportedly had new egg cells and follicles, the group of cells in which an egg is housed and eventually released from the ovary. Some of the eggs were not observed directly. Instead, the genetic markers that the researchers claim indicated their presence were observed.
"Bone marrow transplantation restores [egg] production in wild-type mice sterilized by chemotherapy … which are otherwise incapable of making [eggs]," Tilly and his colleagues wrote.
When they compared normal mice to those that had been sterilized two months after the bone marrow transplants, Tilly's group found that the ovaries in both groups appeared nearly identical.
Are the New Eggs Viable?
Though it's not yet clear whether the egg cells produced following the bone marrow transplants will become mature and fertilized, giving rise to viable mouse pups, the findings are a significant first step toward investigating this potential for restoring fertility, Tilly and his associates stress. "Although the fertilizability and developmental competency of the bone marrow and peripheral blood-derived-oocytes remain to be established, their morphology [appearance], enclosure within follicles, and expression of germ-cell- and-oocyte-specific markers collectively support that these cells are bona fide oocytes," the research team reported.
Additionally, the activity of the germ cell markers fluctuated regularly with each mouse's estrous cycle (equivalent to a menstrual cycle), much like the cyclical rise and fall of certain hormones, the investigators noted. Other results of the study suggest that the mice's ovaries are sending signals to the bone marrow, readying the stem cells to travel to the ovary and restock its egg cell supply, the team noted.
Menopause Postponed?
Further, the findings imply that ovarian restoration in this fashion could postpone the hormonal effects of menopause and could represent an alternative to hormone replacement therapy. But that hypothesis needs to be further tested, the investigators pointed out.
The researchers have another caveat. "It is important to emphasize that we do not yet know if the oocytes produced as a result of bone marrow transplantation or peripheral blood cell transplantation are competent for fertilization, embryonic development, and the generation of viable offspring," they stressed. As such, experiments are still needed to "rigorously test this".
Critics: Give us More Proof
Despite the encouraging results, some experts are not convinced. "Just give us one shred of evidence these cells … actually produce a viable oocyte," said David F. Albertini, PhD, The Hall Professor of Molecular Medicine at the Kansas University Medical Center, in a telephone interview.
"We, as reproductive scientists, would actually [accept] much less than the birth of a baby or even the production of a fertilized egg [as evidence], and yet no evidence has been forthcoming," Albertini said.
He says genetic markers don't serve as direct evidence of the existence of these eggs, nor whether they were derived from stem cells found in bone marrow. "When you look at the images in the paper, as many of us have certainly scrutinized, there is little to convince someone that these are normal follicular structures," Albertini stated.
He says the follicles and eggs reported by the research team were more likely what would be seen in ovaries that have lost their eggs through normal degenerative processes.
Further, Albertini argues that the cells could be those of the immune system, responding to the injury of the mice's ovaries following chemotherapy used in the study. "You can't dispute that there are some cells that came from bone marrow that have entered into the ovary," he said. "But they could also be bone marrow-derived macrophages or monocytes, which you would expect to go into not just the ovary, but any tissue."
Macrophages and monocytes are cells of the immune system formed in the bone marrow that protect the body from infection. These cells would travel to the ovary as a form of injury response, he said.
Finally, Albertini points out that the development of follicles, which then mature and produce eggs, "takes weeks" to occur in mice, "and they're suggesting that this is happening within a day."
"There's a huge time warp between what they're reporting and what normal, healthy animals do," he said.
1. Johnson J, Bagley J, Skaznik-Wikiel M et al. Oocyte generation in adult Mammalian ovaries by putative germ cells in bone marrow and peripheral blood. Cell 2005 July 29;122(2):303-15.
2. Johnson J, Canning J, Kaneko T, Pru JK, Tilly JL. Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature 2004 Mar 11;428(6979):145-50.
3. National Institutes of Health. Stem Cell Basics. Available at: http://stemcells.nih.gov/info/basics/. Accessed August 2, 2005.
4. National Institutes of Health. Stem Cell Basics. Frequently Asked Questions. Available at: http://stemcells.nih.gov/info/faqs.asp. Accessed August 2, 2005.
John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include overseeing health news coverage for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications.
