Function and Regulation of the Pituitary Stem Cell Compartment in Mammals

The pituitary gland is a central regulator of physiological processes such as metabolism, reproduction, growth and the stress response. The anterior pituitary is responsible for the continuous production of six hormones, and when the specialised cell populations responsible for their production are depleted or impaired, levels of hormone can become insufficient, a condition known as hypopituitarism. This condition affects up to 1 in 4000 individuals and is associated with considerable morbidity and mortality. Known examples are genetic dwarfism, due to lack of growth hormone leading to failure of the child to thrive or failure to enter puberty, which is caused by lack of gonadotrophins. Similarly an over-proliferation of cells in the pituitary gland leads to tumours, which in turn can damage healthy pituitary tissue resulting in hypopituitarism, something which can also develop from damage during surgery and treatment. Most of these tumours have devastating effects on the quality of life of the survivors, causing a high burden to families, carers and social services. Often, these patients encounter difficulties in employment and being active community members. My research aims to understand better the basic biology underlying how these human conditions arise, with the ultimate goal of developing safer and better treatments.

The pituitary gland contains stem cells which give rise to new hormone-producing cells throughout life. However, how these cells are involved in the continuing function of the gland and the molecules controlling cell specification remain unknown. My research has demonstrated that WNT signalling factors, an essential group of proteins orchestrating normal development, play a role in the regulation of the pituitary stem cell compartment. This proposal aims to gain insights into stem cell biology using the pituitary gland as a model. Combining mouse genetics with live imaging of this organ, we will reveal how pituitary stem cells function and how WNT signalling is involved in regulating cell decisions by providing instructive cues. As the WNT pathway is closely linked to stem cell involvement in numerous human tumours and cancers, my research will have an important impact on elucidating the different roles of stem cells that could contribute to these conditions. This work will benefit the scientific community by providing advances in stem cell biology, which can in turn lead to better disease management and treatments for devastating human disorders.

Pituitary progenitor/stem cells (PSCs) have been identified using in vitro and in vivo techniques and have been show to contribute to all hormone-producing cell types of the gland. These cells are mostly quiescent and are not solely responsible for the essential turn-over that takes place in the anterior pituitary throughout life. My preliminary research has identified that PSCs are a source of WNT ligands capable of activating surrounding cells. I have found that rapidly dividing progenitors which do turn-over the anterior pituitary, can activate the WNT/beta-catenin signalling pathway and express the pathway target Axin2. We will investigate the role of WNT signalling in pituitary homeostasis in vivo, by genetic deletion of the pathway in different uncommitted cell populations. The contribution of PSCs or progenitors will reveal the typical adaptive capacity of the gland to respond to specific physiological demand. Using novel mouse models, we will characterise the identity of WNT-responsive and WNT-secreting cells and reveal the source of signals through mapping Wnt expression using ultra-sensitive mutliplex in situ hybridisation. Through gene expression profiling by RNA-Seq, we aim to identify novel pathways involved in the control of PSC and progenitor cell compartments, opening up new avenues to understand regulation of homeostasis. To do this we will utilise genetic tools enabling cell purification of PSCs based on expression of known genes that mark populations containing PSCs. Our hypothesis is that WNT ligands control self-renewal and differentiation and we will test this through cutting-edge ex vivo imaging of the whole pituitary. Using a series of mouse models identifying the different populations, we will reveal the consequences of altering levels of signalling on cell fates and divisions. Overall, this proposal will reveal important insights into the biology and regulation of PSCs, information that can be invaluable to tackle treatment of human 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, may find the results from this study of use for inclusion in their communications, which will in turn help improve social welfare and well-being. Through research downstream of this proposal, i.e. utilizing the results from this project after the end of its term, there may be the development of potential treatments for pituitary disorders. 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 the generation of knowledge, high quality and aesthetically pleasing images as well as dynamic videos of cell interactions are expected to derive from this work, which can promote science if used for public events such as by museums, galleries and STEM events promoting science and research.