The Scientist

Stem cells found in the bone marrow and blood of adult mice can restock ovaries with new egg cells, US scientists report in this week's Cell.

"This work demonstrates there is an adult stem cell pool in mammalian females whose primary role is to generate new oocytes, and quite strikingly, it doesn't exist in the ovaries," senior author Jonathan Tilly from Massachusetts General Hospital told The Scientist.

The new findings build on a study Tilly and colleagues conducted in 2004, in which they discovered–contrary to biological dogma–that female mice could produce new egg cells, suggesting the existence of female germline stem cells. When the researchers destroyed oocyte-containing follicles in mice with doxorubicin, hundreds of new oocytes were generated in only 24 hours, far more than expected from the relatively small number of cells in the ovaries expressing the primordial germ cell marker SSEA1.

Tilly and colleagues then looked for a germline stem cell reservoir outside the ovaries. Gene expression analyses for germ cell markers Mvh, Oct4, Dazl, Stella, Fragilis, and Nobox revealed all were expressed in bone marrow isolated from adult female mice. Further studies revealed that Mvh, Dazl, Stella, and Fragilis were expressed together in the same cells.

To see if bone marrow could generate oocytes, the researchers transplanted bone marrow from adult wild-type mice into mice sterilized with chemotherapy drugs cyclophosphamide and busulfan. The ovaries of the recipient mice possessed several hundred oocyte-containing follicles at all stages of development from one to seven days after transplantation, and researchers continued to see oocytes in ovaries more than 11 months later. Matching results were seen in transplants to Atm-deficient mice, which lack the ability to produce mature germ cells.

If bone marrow houses germline stem cells, Tilly and colleagues reasoned that progeny from these cells were likely to migrate to the ovaries via the blood. To test this, the researchers used mice with green fluorescent protein (GFP) expression linked with Oct4, a gene that, in adult mice, is restricted to germ cells. Blood transfusions from these fertile mice led to GFP-labeled oocytes appearing within the ovaries of sterilized wild-type and genetically sterile mice within two days.

"This is rock solid evidence for the revolutionary concept that eggs can originate in bone marrow. The most important follow-up study now is to confirm whether these eggs can resolve in pregnancies," Kutluk Oktay of Cornell University, New York, who did not participate in this study, told The Scientist.

But Ri-Cheng Chian of McGill University in Montreal, Canada, who did not participate in this study, cautioned that Tilly and colleagues' results "were based on morphology, the number of follicles, and expression of germ cell and oocyte specific markers in the transplanted ovaries. Most scientists may want to see strong evidence that the oocytes are generated by transplanted germ cells derived from bone marrow and peripheral blood." He also noted the accuracy of germline-restricted GFP staining could be called into question. "This finding needs to be confirmed by others."

The researchers also found Mvh, Dazl, and Stella in the bone marrow and blood of human women ages 23 to 36. If humans also carry a supply of germline stem cells outside the ovaries, "it opens a huge potential for women to preserve their fertility before toxic cancer treatments" using cells harvested and cryopreserved before chemotherapy or radiotherapy, Chian told The Scientist.

If researchers can raise human oocytes in culture from bone marrow or blood-borne stem cells, "that could prove useful in somatic cell nuclear transfer for therapeutic cloning," Tilly added. Also, since oocytes are totipotent, "it might be interesting to see if we can trick these cells to producing cells of other lineages."