Egg drop: A donor-derived cell (brown) is seen in the ovary of the bone marrow transplant recipient, but it is unclear whether the cell is an oocyte.

Are women born with a fixed supply of eggs that cannot be replenished? That is still an open question.

Scientists have sought answers with studies on mice, but after three years, the debate about whether mice can regenerate eggs is far from settled, and work from Jonathan Tilly's laboratory at Massachusetts General Hospital (MGH) continues to fuel disagreement in the field.

Tilly's group reported in 2005 that stem cells in the bone marrow replenish the egg supply in mice, suggesting adult females can make new eggs under the right conditions (Nat. Med. 11, 911; 2005). His results were met with widespread skepticism.

The following year, another group, also at MGH, showed that mice receiving bone marrow transplants failed to ovulate—or release from the ovary for fertilization—donor-derived eggs (Nature 441, 795; 2006), seemingly refuting Tilly's work.

The burden of proof our critics want is a moving target. Jonathan Tilly, Massachusetts General Hospital

Tilly's group has now come back with yet another study, reporting in August that bone marrow transplants restore fertility in chemotherapy–treated mice, but that the pups born are from the transplant recipient's own eggs (J. Clin. Oncol. 25, 3198–3204; 2007).

“I feel pretty darn comfortable that there is regeneration,” says Tilly. “But the real point of this paper is to tell people that stem cell–based technologies do hold future promise for ovarian rescue.”

A few formerly critical peers, such as Evelyn Telfer of the University of Edinburgh, concede that this work raises interesting questions, but note that how the transplanted stem cells might help ovaries without actually contributing functional eggs remains a mystery.

Critics chalk up the improved fertility to the transplanted cells restoring the recipient's overall health, or contributing a factor that helps eggs that survive the chemotherapy.

“[The new work] is inconsistent with Tilly's two prior papers, and there's no evidence that this idea [of regeneration] is not just a figment of one's imagination,” says David Keefe, chair of obstetrics and gynecology at the University of South Florida in Tampa.

The high stakes—potentially overturning the long-held paradigm that female mammals are born with a fixed pool of eggs, and providing methods to preserve fertility—has led to particularly passionate arguments from both sides.

Tilly points to recent studies in mice that show no decline in egg numbers with age, and indicate that bone marrow–derived cells can generate sperm. Keefe and colleagues have in turn reported that adult human ovaries don't express genes involved in meiosis or oogenesis.

One finding from Tilly's work stubbornly remains unresolved: the identity of the donor-derived cells that make their way into recipient ovaries. Tilly argues that the cells are immature eggs that may somehow help support ovulation of the recipient's eggs.

Telfer agrees that the cells appear to be immature oocytes enclosed in a follicle structure, and that the 'helper cell' idea is plausible. But she stops short of supporting the idea of regeneration. “The [recipient eggs] are there from the start,” she says.

Keefe contends that the donor cells may in fact be immune cells, cleaning up after chemotherapy-induced cell death, and have nothing to do with fertility.

Not surprisingly, Tilly rejects that suggestion. “The burden of proof our critics want is a moving target—it has morphed toward the point that unless we produce a baby, these cells aren't oocytes.”

Still, Tilly admits that these cells may be peripheral to the restored fertility, and other transplanted cells could be involved in restoring signals that support the ovary's stem cell niche.

That's consistent with ovarian transplants that have restored natural fertility to the once-menopausal ovaries of human cancer survivors, says Kutluk Oktay, a reproductive endocrinologist at Weill Cornell Medical College in New York City.

“The ovarian transplant might provide the niche that the other ovary is lacking. A bone marrow transplant might be doing something similar,” says Oktay. “This paper continues the discussion—it both confirms and refutes Tilly's earlier work. But that's how science works.”