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MGH researchers confirm that bone marrow restores fertility in female mice
Donor-derived egg cells present in ovaries, but all offspring are from marrow recipients' own eggs

BOSTON - July 31, 2007 - 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.

Among the published reports raising objections to the previous work of Tilly's group - none of which actually attempted to duplicate those experiments - one theorized that GFP-marked cells observed in recipient ovaries in the 2005 Cell paper might be donor immune cells rather than oocytes. To address that conjecture, the MGH-Vincent team isolated immune cells from normal mice, from the germline-only GFP strain used in their experiments, and from a strain of mice expressing GFP in all cells. Careful analysis confirmed that no immune cells from the germline-only GFP strain contained the marker protein, making it highly unlikely that GFP-labeled cells in the ovaries of females receiving germline-only-labeled marrow were anything other than oocytes. This was further confirmed by experiments showing that isolated immune cells did not express the oocyte-specific marker genes previously used by Tilly's group to identify the marrow-derived oocytes.

Tilly and his colleague note that, since agents that protect fertility most likely would need to be given before chemotherapy to be effective, whatever the donor marrow contributes probably acts by restoring rather than preserving fertility. "Right now, we really don't know exactly what it is in marrow that restores recipient oocyte production and rescues long-term fertility. However, we do know without question that immature oocytes can be generated from cells in adult bone marrow, but they are probably not critical to the fertility rescue observed after the transplants."

Since the 2005 Cell paper, Tilly points out, three studies have been published by other groups showing that, similar to his team's work in females, bone marrow cells from adult male mice or from men can be coaxed to make immature sperm cells, both in lab dishes and after transplantation into the testes. "Clearly, something is going on here regarding the ability of stem cells in bone marrow to produce immature egg and sperm cells, and we need to figure out what it is," he says. Tilly is an associate professor of Obstetrics, Gynecology and Reproductive Biology at Harvard Medical School.

The first author of the study is Ho-Joon Lee, PhD, of the MGH-Vincent Center for Reproductive Biology. Co-authors are Kaisa Selesniemi, PhD, Yuichi Niikura, PhD, and Teruko Niikura, also of MGH-Vincent; and Rachael Klein and David Dombkowski of the MGH Center for Regenerative Medicine. The work was supported by grants from the National Institutes of Health, Sea Breeze Foundation, JM Foundation and Vincent Memorial Research Funds.

Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine. MGH and Brigham and Women's Hospital are founding members of of Partners HealthCare HealthCare System, a Boston-based integrated health care delivery system.




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