065. THE MAMMALIAN OOCYTE: FROM BENCH TO CLINIC

Abstract

The mature mammalian oocyte is the central link between generations. It is not only responsible for the transfer of the female genome between generations, but also largely determines embryo and early fetal developmental potential. For any female, oocytes are in limited supply and are easily damaged, such that the availability of high quality or developmentally competent oocytes is a fundamental rate-limiting factor in female fertility. This is particularly relevant in Australian society today with the steadily rising age to first conception which adversely affects oocyte quality and female fertility. Yet despite years of research and clinical IVF we still have a poor understanding of the molecular and cellular processes that control oocyte quality. It is clear that oocytes acquire developmental competence in the ovarian follicle. The acquisition of competence necessitates communication between the oocyte and maternal systems, a process which endows developmental potential as the oocyte grows and matures inside the follicle. At the cellular level this is achieved by bi-directional communication between oocytes and their companion somatic cells [1]. Over the past 10 years my laboratory has focused heavily on the nature of these oocyte-somatic communication axes and their impact on oocyte quality. Over this period, our work and that of others has shaped a new paradigm in ovarian biology, which is that the oocyte is not passive in the follicle, but rather that it actively directs the differentiation of its neighbouring somatic cells into cumulus cells through the secretion of GDF9 and BMP15 growth factors [2]. In doing so, oocytes dictate the function of their neighboring cumulus cells, directing them to perform functions needed for the appropriate growth and development of the oocyte. For example, cumulus cells supply oocytes with an array of nutrients, substrates and regulatory molecules such as cAMP, many directly through gap-junctions. These communication axes establish and maintain an elaborate and intricate local oocyte-cumulus auto regulatory loop that is required to enable post-fertilisation development. A clear clinical application of this new knowledge is in Artificial Reproductive Technologies, in particular oocyte in vitro maturation (IVM) [3]. IVM biotechnologies have the capacity to capture the vast supply of oocytes in the mammalian ovary and generate mature oocytes in vitro. Generating offspring using IVM is already a clinically and commercially viable biotechnology in livestock breeding programs, particularly in cattle. IVM is a particularly attractive technology for the treatment of human infertility, as it removes the need for expensive and potentially harmful ovarian hyperstimulation protocols used in clinical IVF. However, widespread application of IVM in humans requires an increase in efficiency and further examination of safety of the technology. Recent work from my laboratory has increased IVM success rates in animals by using GDF9 and BMP15 in IVM [2, 3] and by developing a new system of “Induced-IVM” that more closely resembles the mechanisms of oocyte maturation in vivo. Most recently, the latter approach has led to substantial increases in embryo yield and pregnancy outcomes to levels equivalent to hormone-stimulated IVF [4]. The next challenge is to adapt these new approaches to clinical/field conditions to provide new opportunities for infertile women and for the development of a wide range of reproductive biotechnologies.