A central dogma of reproductive biology has been that mammalian females lose the capacity for oogenesis during fetal development, such that a non-renewable stockpile of oocytes is endowed in the ovaries at birth. This reserve of oocytes is depleted during juvenile and adult life, eventually leaving the ovaries barren of genn cells. In humans, exhaustion of the oocyte pool occurs around the fifth decade of life, driving the menopause. In 2004, we published a study with mice that challenged this dogma [1]. Follow-up work not only supported this earlier study but also suggested a possible extra-ovarian source of oocyte-producing stem cells in adult females [2]. Specifically, we showed that bone marrow (BM)- derived cells express several germline markers and that BM transplantation (BMT) rescues oocyte production in adult mice rendered sterile by chemotherapy (busulfan plus cyclophosphamide) or a genetic mutation {Atm gene knockout). Cell tracking confirmed the presence of donor-derived immature oocytes in ovaries of transplanted females [2]. The PI therefore hypothesized that ovarian failure in aging females results from an age-related decline in the number or function of oocyte-producing stem cells (hereafter referred to as germline stem cells or GSCs) in adult females, or an age-related deterioration of the ovarian environment that impairs the ability of BM-derived germ cells to support oogenesis.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Fuldner, Rebecca A
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Northeastern University
Schools of Arts and Sciences
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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
Imudia, Anthony N; Wang, Ning; Tanaka, Yoshihiro et al. (2013) Comparative gene expression profiling of adult mouse ovary-derived oogonial stem cells supports a distinct cellular identity. Fertil Steril 100:1451-8
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
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; 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
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; 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
White, Yvonne A R; Woods, Dori C; Takai, Yasushi et al. (2012) Oocyte formation by mitotically active germ cells purified from ovaries of reproductive-age women. Nat Med 18:413-21
Selesniemi, Kaisa; Lee, Ho-Joon; Muhlhauser, Ailene et al. (2011) Prevention of maternal aging-associated oocyte aneuploidy and meiotic spindle defects in mice by dietary and genetic strategies. Proc Natl Acad Sci U S A 108:12319-24
Wang, Ning; Tilly, Jonathan L (2010) Epigenetic status determines germ cell meiotic commitment in embryonic and postnatal mammalian gonads. Cell Cycle 9:339-49

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