Donor Marrow Can Restore Fertility In Female Mice, MGH Researchers
Confirm
Article Date: 04 Aug 2007 - 14:00 PDT
A new study from Massachusetts General Hospital (MGH) researchers
confirms that female mice that receive bone marrow transplantation
after fertility-destroyin
pregnancies throughout their normal reproductive life. The report in
the 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 (http://www.vcrb.
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-destroyin
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-
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-
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.
------------
Article adapted by Medical News Today from original press release.
------------
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 (http://www.massgene
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 Partners HealthCare
HealthCare System, a Boston-based integrated health care delivery
system.
Source: Sue McGreevey
Massachusetts General Hospital
http://www.medicaln
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The CNS Healing Group
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