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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Fuldner, Rebecca A
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Northeastern University
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Woods, Dori C; Khrapko, Konstantin; Tilly, Jonathan L (2018) Influence of Maternal Aging on Mitochondrial Heterogeneity, Inheritance, and Function in Oocytes and Preimplantation Embryos. Genes (Basel) 9:
Truman, Alisha M; Tilly, Jonathan L; Woods, Dori C (2017) Ovarian regeneration: The potential for stem cell contribution in the postnatal ovary to sustained endocrine function. Mol Cell Endocrinol 445:74-84
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
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
Tilly, Jonathan L; Sinclair, David A (2013) Germline energetics, aging, and female infertility. Cell Metab 17:838-50
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

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