One of the challenges to the application of stem cells as therapeutics in regenerative medicine is the status of the microenvironment to which the stem cell therapy will be applied. Unfortunately, these specialized environments are frequently damaged or degenerated with age or insult. A damaged environment may not support stem cell repopulation following therapy, or may induce aberrant cellular function resulting in undesirable pathologies. Restorative efforts become even more complicated in multifunctional organs with cells having multiple phenotypes, such as female ovaries. Ovaries are dynamic organs with multiple cellular phenotypes derived from multiple lineages. For example, the gonad itself is generated from a population of somatic cells from the embryonic genital ridge, whereas germ cells are of extra-gonadal origin, migrating to the newly formed gonad shortly after its formation. In the neonate, surviving germ cells in the ovaries are arrested in the late diplotene stage of meiosis and enclosed by pre-granulosa cells of somatic cell linage in structures termed follicles. As such, regenerative efforts directed at rejuvenating female fertility or ovarian function in the aged or damaged ovary by targeting only one cell type may have limited success, due to the necessity to restore multiple cellular phenotypes. The goal of this study is to restore a healthy ovarian environment in the aged or damaged ovary through the generation of specialized somatic cells derived from embryonic stem (ES) and induced pluripotent stem (iPS) cells. Using ES and IPS cells derived from TgOG2 transgenic mice with germline-specific expression of GFP, transduced with a somatic cell-specific expression of DsRed, both somatic and germ cell populations can be distinguished in vitro. Specifically, Aim I will identify and characterize ovarian specific somatic cells in vitro, while Aim II will use transplantation of isolated germline and somatic cell populations derived from ES and iPS cells into aged or chemically damaged ovaries to restore follicle formation in vivo. Using a marker specific for ovarian somatic cells, F0XL2 (a FOX winged-helix forkhead gene transcription factor), a sub-population of differentiated ES and iPS cells can be identified and isolated. These isolated somatic cells can then be transplanted into follicle depleted adult mouse ovaries. Somatic cells are required for follicle formation, and ultimately steroid hormone production and ovulation, thus comprising a critical component of the ovarian environment. Increasing the healthy somatic cell population in the aged or damaged ovary represents an eariy, yet crucial, step in restoration of ovarian function. It is thought that by restoring this environment, which is damaged by. aging, that ovarian function can be prolonged or restored, ultimately alleviating the menopause.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F06-E (20))
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Murthy, Mahadev
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Massachusetts General Hospital
United States
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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
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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 (2012) The next (re)generation of ovarian biology and fertility in women: is current science tomorrow's practice? Fertil Steril 98:3-10
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
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Woods, Dori C; White, Yvonne A R; Dau, Caroline et al. (2011) TLR4 activates NF-κB in human ovarian granulosa tumor cells. Biochem Biophys Res Commun 409:675-80