Determining haematopoietic stem cell activity for biomedical discovery (360G-Wellcome-302479_Z_23_Z)

Haematopoietic stem cells (HSCs) are a rare but incredibly important cell type. Just ~100,000 HSCs generate all the cells of the blood and immune systems, which constitute 90% of the cells within our bodies. HSCs are also clinically significant with HSC transplantation being the mainstay treatment for the most severe disorders of haematopoiesis ranging from immunodeficiencies to myeloid and lymphoid malignancies. Despite their importance, their paucity and lack of a tractable ex vivo culture system means that the mechanisms that regulate HSC activity are incompletely understood. I recently pioneered a polymer-based culture system that for the first-time supports long-term ex vivo HSC expansion and provides the basis for a new tractable ex vivo stem cell model of haematopoiesis. My career development award will leverage this model to determine mechanisms regulating human HSC activity. The specific aims of this research programme are to (1) define cellular mechanisms of HSC expansion, (2) identify intrinsic and extrinsic factors influencing human HSC expansion potential, (3) determine functional regulators of HSC expansion, and (4) discover molecular mechanisms of HSC differentiation. These biological insights will facilitate improvements in clinical treatments including the development of new cell and gene therapies and the identification of disease-specific therapeutic targets.