A new study from Massachusetts General Hospital (MGH) researchers confirms that female mice that receive bone marrow transplantation after fertility-destroying chemotherapy can go on to have successful pregnancies throughout their normal reproductive life.
The report in the August 1 Journal of Clinical Oncology verifies that donor marrow can restore fertility in female mice through an as-yet unidentified mechanism. While donor-derived egg cells or oocytes were observed in the ovaries of marrow recipients, all pups born were from the recipients' own eggs.
"Consistent with our past work, cells derived from the donor bone marrow are getting into the ovaries and developing into immature oocytes," says Jonathan Tilly, PhD, director of the Vincent Center for Reproductive Biology at MGH, the study's senior author. "Although these oocytes derived from marrow cells don't appear competent, at least thus far, to make fertilizable eggs, marrow does contribute something that allows a resumption of fertility in female mice sterilized by chemotherapy."
In a 2005 paper published in the journal Cell, Tilly's group found that the ovaries of female mice that had received bone marrow or blood cell transplants after fertility-destroying doses of chemotherapy appeared normal and contained immature oocytes expressing a marker protein indicating they came from the donor cells. This report followed a 2004 Nature paper, also from Tilly"s team, reporting that female mice continued producing eggs well into adulthood, in contrast to the long-held belief that female mammals are born with a finite supply of eggs that is depleted throughout life. Both those papers have been extremely controversial, and the current study was designed to follow up the 2005 paper and to address criticisms raised by other researchers.
In the current study, adult female mice treated with infertility-inducing chemotherapy received bone marrow transplants from non-treated, healthy adult females either one week or two months after chemotherapy. The mice were then housed with healthy adult males and followed for 7 months, a time period in which a group of control females achieved at least five successful pregnancies each. Both the males and the donor females were black in coat color while the recipient females were white-coated. As a result, the coat color of any pups would indicate the source of egg cells used to make the offspring, with tan coats signifying eggs from the recipients and black coats indicating that the eggs had come from marrow donors.
Of the 10 females that received bone marrow transplants one week after chemotherapy, all but one achieved several successful pregnancies during the study period. One gave birth to four litters, one gave birth to five litters, and seven gave birth to six litters of pups. All pups were offspring of the recipients. In a comparison group of 13 females that did not receive marrow after chemotherapy, 10 did become pregnant, but none delivered more than three litters.
Additional experiments indicated that mice receiving transplants one week after chemotherapy had better fertility outcomes than did those transplanted at eight weeks. Similarly, resuming mating sooner after transplantation also improved fertility rates. When chemotherapy doses were increased to levels expected to cause death in half the mice, those that also received bone marrow transplants had improved rates of both survival and long-term fertility.
The coat-color results of the mating trial indicated that the transplanted marrow's contribution to restoring fertility did not involve cells destined to becoming fertilizable eggs. To further investigate this observation, the MGH-Vincent researchers gave chemotherapy-treated females marrow from transgenic females that express a green fluorescent protein (GFP) marker only on germline cells, which are precursor cells involved in producing oocytes. Two months after the transplant, the researchers observed GFP-marked oocytes in immature follicles within recipient ovaries. However, donor-derived oocytes made up less than 2 percent of the total number of oocytes contained within follicles, and no mature follicles contained GFP-marked cells.