Abstract
Early menopause and infertility often occur in female cancer patients after chemotherapy (CTx). For these patients, oocyte/embryo cryopreservation or ovarian tissue cryopreservation is the current modality for fertility preservation. However, the above methods are limited in the long-term protection of ovarian function, especially for fertility preservation (very few females with cancer have achieved pregnancy with cryopreserved ovarian tissue or eggs until now). In addition, the above methods are subject to their scope (females with no husband or prepubertal females with no mature oocytes). Thus, many females who suffer from cancers would not adopt the above methods pre- and post-CTx due to their uncertainty, safety and cost-effectiveness. Therefore, millions of women have achieved long-term survival after thorough CTx treatment and have desired to rescue their ovarian function and fertility with economic, durable and reliable methods. Recently, some studies showed that mice with infertility caused by CTx can produce normal offspring through intraovarian injection of exogenous female germline stem cells (FGSCs). Though exogenous FGSC can be derived from mice without immune rejection in the same strain, it is difficult to obtain human female germline stem cells (hFGSCs), and immune rejection could occur between different individuals. In this study, infertility in mice was caused by CTx, and the ability of FGSCs to restore ovarian function or even produce offspring was assessed. We had successfully isolated and purified the FGSCs from adult female mice two weeks after CTx. After infection with GFP-carrying virus, the FGSCs were transplanted into ovaries of mice with infertility caused by CTx. Finally, ovarian function was restored and the recipients produced offspring long-term. These findings showed that mice with CTx possessed FGSCs, restoring ovarian function and avoiding immune rejection from exogenous germline stem cells.
Highlights
According to the 2012 GLOBOCAN statistics, approximately 8.2 million cancer patients died and 14.1 million new cases of cancer were diagnosed in 2012 worldwide
Considering the small number of the separated cells and the inevitable damage during the process of isolation, we cultured the digested cells from 8 ovaries for 3–4 days, when the cell density reached confluence on the six-well plate and with the cell number increasing to 8–10×105; these cells were used for magnetic activated cell sorting (MACS) and 2% (1.6–2×104) positive cells were obtained with the antibody of Fragilis
The purified female germline stem cells (FGSCs) grew in clusters during the early stage of the subculture, and in grape-like shapes for subsequent passages, with a high nuclear-to-cytoplasm ratio during the culture (Fig 1A–1D), which was consistent with previous reports
Summary
According to the 2012 GLOBOCAN statistics, approximately 8.2 million cancer patients died and 14.1 million new cases of cancer were diagnosed in 2012 worldwide. The long-term side effects of exposure to chemotherapy treatments in women often lead to damage to ovarian function and can even induce amenorrhea as well as infertility [3,4,5]. A huge breakthrough for ovarian function protection and fertility preservation will not occur unless a new promising method of transplantation of FGSCs appears. Stem-cell transplantation can be used as a novel method for the treatment of ovarian failure [12]. Because there are so many women, especially young females, who undergo chemotherapy and suffer from ovarian damage, we sought to determine whether FGSCs exist and whether stem-cell transplantation could be considered as a therapeutic option to restore ovarian function and infertility caused by CTx using a mouse model of CTx-induced ovarian failure
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