Control of pituitary stem cell activity in human and mouse through modulation of YAP/TAZ signalling

The pituitary gland is an organ situated beneath the brain that controls important functions in humans and animals such a growth, metabolism, our response to stress as well as puberty and reproduction. It does so by producing factors that are called pituitary hormones, which are released into the blood and distributed throughout the body. An imbalance in hormone levels can result in serious health problems affecting the functions regulated by the pituitary. Disruption of the normal production and secretion can develop as a result of pituitary diseases, among which a condition called hypopituitarism where the organ fails and too little hormone is secreted, or pituitary tumours which may produce excess hormones but also crush surrounding healthy pituitary resulting in hypopituitarism as well as damaging the brain and affecting vision. In addition, the levels of hormones decline as we get older, contributing to the normal deterioration of bodily functions that characterise ageing. Since it is important to maintain steady hormone levels, the pituitary contains and replenishes specialised cells throughout life that are responsible for producing hormones. These hormone-producing cells are derived from stem cells that express a factor called SOX2. Our research and that from others has shown that the function of these SOX2 stem cells declines with age in mice, which may contribute to the loss of pituitary function. Additionally, it has shown that abnormal function of SOX2 stem cells can result in tumours of the pituitary. The main goal of our research is to study the mechanisms that control SOX2 stem cell function and to ultimately discover new ways to activate or inhibit SOX2 function in pituitary diseases as needed. Our research in mouse has already significantly contributed in understanding SOX2 stem cells and identified other factors that can activate these stem cells and stimulate them to divide, either to produce new hormone-secreting cells or to cause pituitary tumours by dividing uncontrollably. In this proposal, I will combine diverse state-of-the-art techniques to dissect the mechanisms underlying these two opposite functions in mouse and in addition, I will investigate whether such mechanisms are conserved in the human pituitary. The latter is a necessary step if we want to develop and apply regenerative medicine approaches to patients with hypopituitarism or during ageing, and to inhibit such activation in pituitary tumours.

Our recent work has demonstrated a central role for YAP/TAZ signalling in SOX2+ pituitary stem cells (PSCs), in promoting self-renewal and repressesing differentiation (Lodge et al. 2019). We have shown that levels of signalling are critical, and can lead to either homeostatic activation of SOX2+ PSCs resulting in normal differentiation of new hormone-producing cells, or paradoxically pituitary tumourigenesis. Our preliminary data support that a reduction in YAP/TAZ signalling can contribute to reduced PSC activity with age. Understanding the mechanisms by which YAP/TAZ regulate PSCs, their interaction with other pathways of known importance in this process and the validity of the findings in the human pituitary remain to be addressed. Here we will employ molecular and genetic approaches to dissect the mechanisms underlying SOX2+ PSC fate and how these are altered during ageing and in pituitary disease. Specifically, we will address the interplay between YAP/TAZ and WNT signalling, another critical pathway involved in PSC fate (Andoniadou et al. 2013, preliminary data) in their concerted regulation of PSCs. Moreover, we will extend these studies to the human pituitary to assess the degree of conservation and provide data of relevance for future development of novel regenerative approaches. Altogether, this research will reveal important insights into the function of YAP/TAZ signalling in PSC biology and regulation with potential translational implications in the field of pituitary disease.

The long-term beneficiaries of this research include patients suffering from pituitary disorders and their families as well as health care providers and social workers. The research will contribute to the understanding of the mechanisms underlying certain pituitary disorders. Similarly, organisations such as charities working with patients and their families, providing lay summaries and information on medical conditions, are likely to find the results from this study of use for inclusion in their communications, which will in turn help improve social welfare and well-being. The results stemming from this project after the end of its term are likely to be used in translational applications to develop potential treatments for pituitary disorders such as hypopituitarism and pituitary tumours.
This research will contribute towards increasing public awareness regarding the role of stem cells in normal tissues as well as their contribution to disease, and help to promote the understanding of science. This new knowledge and scientific advancement can be used by beneficiaries in the third sector, such as those in education. It is anticipated that it would be of interest to the general public, third sector workers e.g. teachers, workers in charities promoting science, school-age children as part of their curriculum or for promoting science as a career choice. Alongside generation of knowledge and the generation high quality and aesthetically pleasing images expected to derive from this work, we aim to promote the endocrine system and the pituitary gland through a short interactive exhibit bringing together KCL artists in residence, STEMNet, the Pituitary Society scientists and Science Gallery London.