Novel mechanisms of theca cell growth in the ovarian follicle of cattle

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Over the last 50 years, there has been a major decline in fertility in dairy cattle worldwide, such that 70% of the average North American dairy herd is subfertile. This represents a major loss of genetic diversity and huge economic and environmental costs. The long-term goal of my NSERC research program is to understand the mechanisms of infertility in cattle, in order to propose solutions for the Canadian dairy industry. Infertility in females is mostly caused by problems at the level of the ovary, and my research focuses on the follicle, a fluid-filled structure that contains the egg (oocyte). Several follicles start to grow synchronously at the beginning of an estrous cycle, but in species such as cattle and horses, only one grows large enough to release an egg at ovulation; the remainder regress. The reasons why follicles regress are not clear, but likely involves a complex series of hormonal interactions within the follicle. The follicle contains three major cell types, the oocyte, granulosa cells and theca cells, and there has been a lot of research into the hormonal interactions between these cell types. Theca cells reside in a fibrous layer that also contains blood capillaries and connective tissue. My lab has been investigating a factor ('FGF18') that is secreted by the theca cell layer and that causes granulosa cell death, and we recently discovered that this factor is secreted not by theca cells but by the cells of the blood capillaries (endothelial cells). These cells are controlled by hormones and also by physical forces, including being stretched within growing tissues. As the growing follicle expands by 10% per day, we hypothesize that theca cells are also subject to biophysical forces that shape their function. In this next phase of my program, we will (1) establish a 'stretch' model of bovine theca cells in culture, (2) determine the main pathways regulated by stretch in theca cells, and (3) discover novel signaling from theca cells in response to stretch. To achieve these goals, my team of graduate students will develop a method for 'stretching' theca cells in culture, and determine how theca cells detect and respond to biophysical force. We will then identify novel factors secreted by theca cells in response to stretch, and determine the effect that these factors have on granulosa cell health and growth of the follicle. This research may provide new approaches to improving fertility in cattle, and potentially to other species that undergo the same type of follicle growth, including sheep, horses and endangered species.