Compared to their age-matched peers, the five-year relative survival rate of cancer patients is now at 68%, improved from 50% thirty years ago. At least one in 250 women of reproductive age are cancer survivors. Today, 90% of these young women will be cured of their cancer. Unfortunately, the chemotherapies that save their life are fertility-threatening;in particular, alkylating agents and platinum-based drugs are highly associated with post-treatment infertility as they cause DNA damage to the oocytes that comprise the ovarian reserve. Most young women with cancer are highly interested in trying to preserve their fertility so they might have children in the future [1, 2]. The cryopreservation and autotransplantation of ovarian tissue is emerging as a powerful approach for preserving fertility for patients that are losing ovarian function. Ovarian tissue transplantation has preserved fertility (at least 22 live births to date);however, for cancer patients, transplantation may not be possible due to the risk of re-seeding disease.
In Aim 1 ofthe proposed research, we refine the procedures for follicle isolation to enable large-scale recovery of primordial follicles, and subsequently investigate the engraftment and function by transplanted follicles within a range of biomaterials. The transplantation of early stage follicles is challenged by the potential to disrupt cell-cell interactions within the follicle during the isolation and encapsulation process, as well as the lack of mechanical support and paracrine factors from the stromal cells following transplantation. Preliminary studies indicate that a biomaterial for follicle transplantation can protect the graft following transplantation, provide a conduit between the host and transplanted follicles, and deliver factors that can locally promote engraftment. Graft longevity is a key consideration in clinical transplantation, and our preliminary studies indicate significant activation of follicles into the growing pool, thereby depleting the tissue of early stage follicles which are necessary for long-term graft function.
For Aim 2, we propose to investigate strategies to modulate the initial recruitment of follicles that would deplete the ovarian reserve, and thereby enhance the duration of graft function.
For Aim 3, we investigate the transplantation of follicles from post-pubertal animals, and determine the contribution of age and obesity of the recipient on the engraftment and function of transplanted follicles. The use of post-pubertal follicles simulates the physiological transplant settings found in humans. Furthermore, transplanting a common follicle population into ovaries of a normal cycling mouse, an aged mouse, or obese mouse can identify the impact of the ovarian environment due to aging or obesity on follicle development in vivo. Finally, in Aim 4, we investigate the transplantation of ovarian follicles from mice with metastatic disease, which simulates the clinical situation of re-seeding cancer cells. We will investigate our isolation procedures to determine the extent to which cancer cells are present, and adapt procedures to remove metastatic cells while maintaining follicle viability.
Cancer patients often have their fertility compromised by the chemotherapy regimens that are designed to save their life. The cryopreservation and autotransplantation of ovarian tissue is emerging as a powerful approach for preserving fertility for patients that are losing ovarian function. We propose to investigate strategies for the transplantation of individually isolated follicles, as opposed to ovarian tissue transplantation, with follicles delivered to minimize the risk of re-seeding cancer cells that may be present within the vasculature or stroma of the ovary.
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|Tagler, David; Makanji, Yogeshwar; Tu, Tao et al. (2014) Promoting extracellular matrix remodeling via ascorbic acid enhances the survival of primary ovarian follicles encapsulated in alginate hydrogels. Biotechnol Bioeng 111:1417-29|
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|Smith, Rachel M; Shikanov, Ariella; Kniazeva, Ekaterina et al. (2014) Fibrin-mediated delivery of an ovarian follicle pool in a mouse model of infertility. Tissue Eng Part A 20:3021-30|
|Pavone, Mary Ellen; Hirshfeld-Cytron, Jennifer; Tingen, Candace et al. (2014) Human ovarian tissue cortex surrounding benign and malignant lesions. Reprod Sci 21:582-9|
|Shea, Lonnie D; Woodruff, Teresa K; Shikanov, Ariella (2014) Bioengineering the ovarian follicle microenvironment. Annu Rev Biomed Eng 16:29-52|
|Lyttle, B; Bernardi, L; Pavone, M E (2014) Ovarian cancer in endometriosis: clinical and molecular aspects. Minerva Ginecol 66:155-64|
|De Vos, Michel; Smitz, Johan; Woodruff, Teresa K (2014) Fertility preservation in women with cancer. Lancet 384:1302-10|
|Laronda, Monica M; Duncan, Francesca E; Hornick, Jessica E et al. (2014) Alginate encapsulation supports the growth and differentiation of human primordial follicles within ovarian cortical tissue. J Assist Reprod Genet 31:1013-28|
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