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.

Agency
National Institute of Health (NIH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
7R37AG012279-19
Application #
8606381
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Fuldner, Rebecca A
Project Start
Project End
Budget Start
Budget End
Support Year
19
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Northeastern University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
Woods, Dori C; Tilly, Jonathan L (2015) Autologous Germline Mitochondrial Energy Transfer (AUGMENT) in Human Assisted Reproduction. Semin Reprod Med 33:410-21
Woods, Dori C; Tilly, Jonathan L (2015) Woods and Tilly reply. Nat Med 21:1118-21
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
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) Isolation, characterization and propagation of mitotically active germ cells from adult mouse and human ovaries. Nat Protoc 8:966-88
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) An evolutionary perspective on adult female germline stem cell function from flies to humans. Semin Reprod Med 31:24-32
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

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