1015 – HUMAN HAEMATOPOIETIC STEM AND PROGENITOR CELL LANDSCAPES: LOCATION MATTERS

Abstract

In adults, most hematopoietic stem and progenitor cells (HSPCs) reside within the bone marrow (BM), giving rise to all mature blood cells. Yet at any given time, a small proportion of HSPCs circulates in peripheral blood (PB), and under severe stress and disease, the spleen can significantly contribute to blood production. However, the cellular, molecular and functional composition of circulating and extramedullary HSPC pools remains unexplored. Here I will discuss the single cell characterisation of the adult human HSPC pool found in spleen and non-mobilised PB, comparing and contrasting it to BM. Using matched and unmatched samples from deceased and living donors, we profiled more than 50,000 single CD34+ HSPCs by scRNA-seq and 3,900 single phenotypic haematopoietic stem cells / multipotent progenitors (HSC/MPPs) in functional assays. In BM, we find a topography of the hematopoietic hierarchy that supports continuous HSPC proliferation and blood production. In contrast, the cellular configuration in extramedullary tissues is positioned for lineage-primed demand-adapted haematopoiesis, including a molecularly distinct subset of HSC/MPPs not found in BM. We also find steady-state non-mobilised PB is dominated by quiescent HSC-like cells and non-proliferative early progenitors functionally restricted to erythrocyte and megakaryocyte production. PB HSC/MPPs thus sustain a unique differentiation potential and configuration in healthy conditions, but which become imbalanced with age and in haematological conditions. Overall these data identify extramedullary cellular reservoirs for demand-adapted haematopoiesis and provide a framework of clinical relevance.