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Bone Marrow Transplantation Generates Immature Oocytes and Rescues Long-Term Fertility in a Preclinical Mouse Model of Chemotherapy-Induced Premature Ovarian Failure

Ho-Joon Lee, Kaisa Selesniemi, Yuichi Niikura, Teruko Niikura, Rachael Klein, David M. Dombkowski, Jonathan L. Tilly

From the Vincent Center for Reproductive Biology and Center for Regenerative Medicine, Massachusetts General Hospital/Harvard Medical School, Boston, MA

Address reprint requests to Jonathan L. Tilly, PhD, Massachusetts General Hospital, THR-901B, 55 Fruit St, Boston, MA 02114; e-mail: jtilly{at}partners.org

Purpose Although early menopause frequently occurs in female cancer patients after chemotherapy (CTx), bone marrow (BM) transplantation (BMT) has been linked to an unexplained return of ovarian function and fertility in some survivors. Studies modeling this in mice have shown that BMT generates donor-derived oocytes in CTx-treated recipients. However, a subsequent report claimed that ovulated eggs are not derived from BM and that BM-derived oocytes reported previously are misidentified immune cells. This study was conducted to further clarify the impact of BMT on female reproductive function after CTx using a preclinical mouse model.

Methods Female mice were administered CTx followed by BMT using coat color-mismatched female donors. After housing with males, the number of pregnancies and offspring genotype were recorded. For cell tracking, BM from germline-specific green fluorescent protein-transgenic mice was transplanted into CTx-treated wild-type recipients. Immune cells were sorted from blood and analyzed for germline markers.

Results BMT rescued long-term fertility in CTx-treated females, but all offspring were derived from the recipient germline. Cell tracking showed that donor-derived oocytes were generated in ovaries of recipients after BMT, and two lines of evidence dispelled the claim that these oocytes are misidentified immune cells.

Conclusion These data from a preclinical mouse model validate a testable clinical strategy for preserving or resurrecting ovarian function and fertility in female cancer patients after CTx, thus aligning with recommendations of the 2005 National Cancer Institute Breast Cancer Progress Review Group and President's Cancer Panel to prioritize research efforts aimed at improving the quality of life in cancer survivors.

Supported by Grant No. R37-AG012279 from the National Institutes of Health, Sea Breeze Foundation, JM Foundation, and Vincent Memorial Research Funds.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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