A central dogma of reproductive biology has been that mammalian females lose the capacity for oogenesis during fetal life, such that a non-renewable oocyte stockpile is endowed at birth. This reserve of oocytes then declines during postnatal life, eventually leaving the ovaries barren of germ cells (driving menopause in women). We recently challenged this dogma by showing in mice that oocyte production persists in adult life, raising the possibility that, like in the fly, mammalian oogenesis is sustained in adult life by germline stem cells (GSCs). We have since shown in adult female mice that germ cells reside in bone marrow, and that bone marrow transplantation (BMT) rescues oocyte production in sterile recipient adult females. Further, peripheral blood of adult female mice contains germ cells that generate oocytes. To further characterize the role that bone marrow-derived GSCs (BMGSCs) and their progenitors play in ovarian function and failure in mammalian females, we propose: 1) to use flow cytometry to fractionate bone marrow-derived cells into subpopulations containing or lacking germ cells, and to characterize the functional activity of these putative BMGSCs;2) to evaluate if BMT restores the long-term reproductive potential of wild-type female mice sterilized in young adulthood by chemotherapy;3) to determine if bone marrow derived from adult male donors, rather than sex-matched (female) donors, generates 'oocytes'in sterilized wild-type female mice following transplantation, and if these 'oocytes'are competent for fertilization, embryogenesis and birth of offspring;4) to examine if bone marrow derived from aged (versus young) female mice possesses a reduced complement of GSCs, and consequently fails to rescue oocyte production in chemotherapy-sterilized adult wild-type female mice following BMT;and 5) to test if ovaries of aged female mice lose the ability or competency to accept circulating germ cell progenitors derived from young donors, or to support new oocyte and follicle production once BMGSC progenitors engraft into the ovaries. We envision that completion of this work will significantly advance our understanding of the biology and function of female GSCs. Furthermore, in light findings shown herein that germline markers are expressed in bone marrow and peripheral blood of adult human females, our ultimate goal is to develop GSC-based strategies to regenerate the oocyte pool in women as a means to restore fertility or postpone ovarian failure under normal and pathological conditions.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Method to Extend Research in Time (MERIT) Award (R37)
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Development - 1 Study Section (DEV)
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Fuldner, Rebecca A
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Massachusetts General Hospital
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Safdar, Adeel; Annis, Sofia; Kraytsberg, Yevgenya et al. (2016) Amelioration of premature aging in mtDNA mutator mouse by exercise: the interplay of oxidative stress, PGC-1?, p53, and DNA damage. A hypothesis. Curr Opin Genet Dev 38:127-132
Woods, Dori C; Tilly, Jonathan L (2015) Autologous Germline Mitochondrial Energy Transfer (AUGMENT) in Human Assisted Reproduction. Semin Reprod Med 33:410-21
Park, Eun-Sil; Tilly, Jonathan L (2015) Use of DEAD-box polypeptide-4 (Ddx4) gene promoter-driven fluorescent reporter mice to identify mitotically active germ cells in post-natal mouse ovaries. Mol Hum Reprod 21:58-65
Woods, Dori C; Tilly, Jonathan L (2015) Woods and Tilly reply. Nat Med 21:1118-21
Tilly, Jonathan L; Sinclair, David A (2013) Germline energetics, aging, and female infertility. Cell Metab 17:838-50
Park, Eun-Sil; Woods, Dori C; Tilly, Jonathan L (2013) Bone morphogenetic protein 4 promotes mammalian oogonial stem cell differentiation via Smad1/5/8 signaling. Fertil Steril 100:1468-75
Woods, Dori C; Tilly, Jonathan L (2013) An evolutionary perspective on adult female germline stem cell function from flies to humans. Semin Reprod Med 31:24-32
Woods, Dori C; White, Yvonne A R; Niikura, Yuichi et al. (2013) Embryonic stem cell-derived granulosa cells participate in ovarian follicle formation in vitro and in vivo. Reprod Sci 20:524-35
Woods, Dori C; White, Yvonne A R; Tilly, Jonathan L (2013) Purification of oogonial stem cells from adult mouse and human ovaries: an assessment of the literature and a view toward the future. Reprod Sci 20:7-15
Woods, Dori C; Tilly, Jonathan L (2013) Isolation, characterization and propagation of mitotically active germ cells from adult mouse and human ovaries. Nat Protoc 8:966-88

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