Finding that stem cells in the bone marrow can regenerate egg cells reverses dogma.

When Jonathan Tilly claimed in March 2004 that stem cells could replenish the supply of eggs in a mammalian ovary, experts in the field balked. But his claim in July that those stem cells may reside not in the ovary but in the bone marrow, and that they might circulate in blood, has shocked critics into downright disbelief.

Tilly's new work posits that stem cells in the bone marrow can travel through the blood to regenerate oocytes in a mouse ovary (Cell 122, 303–315; 2005). His group at the Massachusetts General Hospital has found that mice with barren ovaries that received blood transfusions began producing new egg cells within days.

There are so many inconsistencies between the first paper and this one, it makes it very difficult to believe in these findings. David Albertini, University of Kansas

The study challenges the long-held view that mammals are born with a limited number of eggs that declines with age. Among experts, it has inspired, at best, cautious optimism and, at worst, vehement denial. But it is also challenging the field to reexamine one of its most sacred dogmas.

“There are so many inconsistencies between the first paper and this one, it makes it very difficult to believe in these findings,” says David Albertini of the University of Kansas, referring to Tilly's earlier work, which suggested that the stem cells reside in the outer covering of ovaries (Nature 428, 145–150; 2004). When the researchers could not isolate the stem cells from ovaries, Tilly says, their data led them to the ovarian blood supply, and then to the bone marrow.

The team transplanted blood from normal female mice engineered to produce green fluorescent protein to mice that had been sterilized by chemotherapy, a genetic mutation or both. In each case, the recipient ovaries gained fluorescent green egg cells. Bone marrow transplants also restored oocytes, although more slowly. But whether those eggs can be fertilized to produce fluorescent offspring is yet to be determined. That result would largely mollify the critics.

Tilly's work also hints that the ovary may alert the bone marrow when oocyte numbers run low. The expression of a gene marker used to track bone marrow stem cells fluctuates with the mouse's estrous cycle and disappears altogether when the ovaries are removed. The researchers suggest that ovaries send an unknown molecular signal to regulate egg development.

“Therapeutically, such a factor would be a gold mine to increase the oocyte stockpile or jumpstart new egg production,” says Tilly, adding that if the work translates to humans, it could lead to ways to prolong women's fertility or delay menopause.

But talk of human implications frustrates critics who say the work must first be reproduced. “Relieving menopause is a long jump forward,” says Jeffrey Chang, a reproductive endocrinologist at the University of California, San Diego. Chang says he appreciates the research, but “it's important not to over-interpret their work.”

Kutluk Oktay, a fertility expert at Weill Cornell Medical Center in New York, says anecdotal evidence from his patients suggests Tilly's observations might hold true in people. But “people expect duplication of this study, and that may take someone else five years,” Oktay says.

Because the work raises fundamental questions, five years is too long, experts say. But the work's controversial nature may make scientists reluctant to take on projects that confirm or counter Tilly's work, they note.

Tilly says it is “most revealing” that no one has published data refuting his hypothesis in the 18 months following the Nature paper. He says some colleagues set the burden of proof incredibly high, suggesting that he should have asked another lab to confirm his work in parallel. “If you are still critical,” he says, “get into the lab and prove us wrong.”