Defining the microenvironment that will enable a long-term bioprosthetic ovary transplant

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PROJECT SUMMARY/ABSTRACT The ovaries contain a finite resource of potential eggs and sex hormone-producing cells, and therefore, life- saving cancer treatments that irradiate or chemically induce cell death within the ovaries will likely result in premature ovarian insufficiency (POI) with reduced ovarian hormones and infertility. The option to have biological children, is a key quality of life measure for cancer survivors. Women with POI will experience co-morbidities associated with loss of ovarian hormones and a shorter life expectancy. The only method for fertility preservation for pediatric patients, who do not yet make eggs, is ovarian tissue cryopreservation (OTC). This tissue can then be transplanted back to restore fertility and hormone function. However, only 20 – 30% of transplants result in livebirth and it produces an average of 2 – 5 years of hormone restoration, leaving many without biological children and decades of post-cancer survival without essential hormone production. One major contributor to the shortened function of transplanted ovarian tissue is the significant spike in activation of the ovarian reserve (primordial follicles) and subsequent depletion, at least in part, due to the disruption in the microenvironment. Additionally, some patients have metastatic disease within the ovary and therefore cannot use that tissue in its current form. Therefore, a safe, long-term solution for fertility and hormone restoration would involve isolating the ovarian cells that are essential for function from potential cancer cells and housing them in a microenvironment that maintains the bank of potential eggs and prolongs hormone production. We have previously developed an engineered 3D printed scaffold that restored fertility and hormone function in mice. We will test the hypothesis that the matrisome imposes biochemical and physical cues that controls primordial follicle activation. Additionally, we predict that the contribution of stromal cells is necessary for full folliculogenesis. We will use cow ovaries as mono-ovulatory models of human ovaries. In Aim 1, we will investigate the biochemical cues of the matrisome and how they regulate primordial follicle activation, by defining the matrisome proteins that exist in the ovary and modulating candidate proteins that may be key to controlling primordial follicle activation through extracellular inhibition or induction of intracellular pathways. In Aim 2, we will investigate the physical properties of the ovary and how they control primordial follicle quiescence, by defining the native stiffness of the ovarian microenvironment and monitoring how primordial follicles response to different physical properties in culture. In Aim 3, we will investigate the role of stromal cells in folliculogenesis supported by a transplantable scaffold. We will define the matrisome proteins and paracrine factors that are secreted by stromal cells and investigate how they contribute to folliculogenesis within a 3D printed bioprosthetic scaffold in a transplant model. The aims in this application will build on our previous successes and a bioprosthetic ovary, defined by the results here, would improve current options for fertility and hormone restoration for women.