A new US study has cast serious doubt on controversial research that suggested bone marrow stem cells can produce new eggs in adult mice. Last year, a team based at Massachusetts General Hospital reported in the journal Cell that the eggs of mice rendered sterile could regenerate within 24 hours, following bone marrow transplants. However, in a new paper published online by Nature, scientists based at Harvard University and the Joslin Diabetes Center say they have found no evidence to back up the claims.
The Massachusetts researchers found that when they destroyed egg-containing follicles with the drug doxorubicin, hundreds of new eggs appeared within 24 hours. The scientists also transplanted bone marrow from healthy mice into mice sterilised with two chemotherapy drugs, cyclophosphamide and busulfan. They found that new egg cells appeared in the ovaries of the treated mice one to seven days after transplantation, with egg cells still present 11 months later. The researchers got similar results when they transplanted bone marrow from normal mice into animals incapable of producing mature germ cells.
The results caused a sensation when they were published, since they appeared to contradict the long-held belief that female mammals are born with a lifetime's supply of eggs. Instead, they provided evidence for the existence of 'ovary stem cells' that continue to make new eggs throughout the animal's life. At the time, team leader Jonathon Tilly said: 'Everyone had missed finding female germline stem cells because they are not in the ovaries, where everyone would have looked for them', Now, it seems that such stem cells may not actually exist - at least not in bone marrow.
In the latest study, the researchers wanted to find out if the new eggs reported in Tilly's study could be ovulated (released from the ovary), and whether or not ovary regeneration by bone marrow cells was a normal process. The team used 'parabiotic' mice - pairs of animals that have the skin between their front and hind legs sewn together, so they share a blood circulatory system. One mouse in each pair was normal, while the other had been genetically altered to produce green fluorescent protein (GFP) in all its tissues. Eve after eight months of sharing their blood, the normal mice produced no eggs tagged with GFP, and the GFP mice produced no normal eggs. This, say the scientists, is proof that circulating bone marrow stem cells do not normally produce new eggs.
The team carried out another experiment, in which one mouse in each pair had received chemotherapy drugs to destroy its own eggs. But again, the researchers found no evidence of the damaged ovaries being replenished with cells from the other mouse. 'This is a pretty powerful denial of the idea that new eggs form and contribute to fertility', said co-author Roger Gosden, of Cornell University in New York. Other scientists agree: 'It incontestably shows that the Tilly work is simply not true', David Albertini of Kansas University told Nature.
But Tilly says the new research does not contradict his own findings, since he looked at immature eggs still in the ovary, whereas the latest study focussed on ovulated eggs. He says that replenished, immature egg cells could still be crucial to fertility, even if they are never released by the ovary. Gosden concedes that dormant egg stem cells, which can be 'brought back to life' in the lab, could still exist. 'I think the Tilly group might be right to some extent on that one', he said.