# Origins and Functions of Mammalian Female Germline Stem Cells

> **NIH NIH R01** · NORTHEASTERN UNIVERSITY · 2020 · $317,176

## Abstract

PROJECT SUMMARY
Based on the well-documented relationship that exists between ovarian function and women’s health, for
decades hormone therapy was considered by many as the standard-of-care for the management, and even the
prevention, of post-menopausal health complications. However, recent clinical trials have raised concerns over
hormone therapy and increased risks for coronary heart disease, stroke, blood clots, and cancer. While the
general thinking behind hormone therapy – viz. provision of ovarian hormones lost at menopause would serve
as a ‘replacement’ for failed ovarian function – seems reasonable, it is perhaps not surprising that replacement
of only one (estrogen) or two (estrogen-progestin) of the multitude of bioactive factors produced by the ovaries
during reproductive life would ultimately prove insufficient. We have been working on the idea that ‘ovarian
therapy’ would serve as a far better ‘replacement’ for alleviating health consequences of failed ovarian function
with age. We eventually generated a mouse model that maintains an adequate reserve of oocyte-containing
follicles, and an ensuing continuation of ovarian function, well into advanced chronological ages. Long-term
follow-up work showed this strategy indeed yielded immense health benefits in aging females without an
increase in cancer in any tissue. While we were excited to demonstrate this key proof-of-concept in mammals,
there was a major downside: the “gene knockout” approach used was not amenable for translation to women.
Nonetheless, the work underscored the importance of continuing efforts to elucidate mechanisms underlying
endowment and depletion of oocyte-containing follicles in the context of ovarian aging. This led us to discover
the existence of female germline or oogonial stem cells (OSCs) in mice and then in humans, and the role these
cells play in supporting ovarian function during adulthood. Of the many new areas this paradigm shift opened,
one of the most exciting revolves around the use of regenerative medicine to extend functional ovarian lifespan
into later ages of life. Achieving this, however, will require a detailed understanding of cues that drive OSC
differentiation, and how aging impacts on these cues such that the ability of ovaries to sustain their oocyte
reserves becomes compromised with age. To this end we found that application of mechanical ‘strain’ to OSCs
activates their differentiation into oocytes. We also found that ovarian matrix proteins, which directly influence
biomechanical properties of tissue, not only decline with age but also serve as direct activators of OSC
differentiation. Here we have designed a number of in-vitro and in-vivo studies to rigorously test the hypothesis
that progressive loss of mouse and human OSC function in ovaries with age is directly tied to a reduction in
biomechanical stimulatory signaling occurring concomitant with aging-associated changes in matrix proteins.
Completion of these studies will both suppo...

## Key facts

- **NIH application ID:** 9930000
- **Project number:** 5R01AG012279-24
- **Recipient organization:** NORTHEASTERN UNIVERSITY
- **Principal Investigator:** Jonathan Lee Tilly
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $317,176
- **Award type:** 5
- **Project period:** 1995-09-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9930000

## Citation

> US National Institutes of Health, RePORTER application 9930000, Origins and Functions of Mammalian Female Germline Stem Cells (5R01AG012279-24). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9930000. Licensed CC0.

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