Blood formation is co-ordinately maintained by functionally heterogenous haematopoietic stem cells (HSC) and multipotent progenitors, as demonstrated by many decades of mechanistic work in animal models. The past 20 years have also seen major breakthroughs in how patients with haematological diseases are treated in parallel to great progress in our understanding of human haematopoiesis. However, a complete framework of how it unfolds across the human lifespan, a key pre-requisite to understand ageing, clonal haemopoiesis, disease risk and leukaemia development, is still lacking. Over the years, my group have used single cell transcriptomics, whole-genome sequencing and functional assays to understand the diversity of HSC behaviours over a human lifetime. In this talk I first will discuss how we have also uncovered unique HSPC compositions, transcriptional identities and skewing of differentiation at extramedullary sites, such as non-mobilised peripheral blood and spleen. Second, I will present data pertinent to the complex effects of pro-inflammatory signals on human HSC differentiation trajectories that extend beyond emergency myelopoiesis. Finally, I will discuss some recent insights into how ageing profoundly reduces clonality in the human HSC pool.<\/p>\n
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