Decoding human fetal liver haematopoiesis
Dorin-Mirel Popescu,#1 Rachel A. Botting,#1 Emily Stephenson,#1 Kile Green,1 Simone Webb,1 Laura Jardine,1 Emily F. Calderbank,2 Krzysztof Polanski,3 Issac Goh,1 Mirjana Efremova,3 Meghan Acres,1 Daniel Maunder,1


Definitive haematopoiesis in the fetal liver supports self-renewal and differentiation of haematopoietic stem cells/multipotent progenitors (HSC/MPPs) but remains poorly defined in humans. Using single cell transcriptome profiling of ~140,000 liver and ~74,000 skin, kidney and yolk sac cells, we identify the repertoire of human blood and immune cells during development. We infer differentiation trajectories from HSC/MPPs and evaluate the impact of tissue microenvironment on blood and immune cell development. We reveal physiological erythropoiesis in fetal skin and the presence of mast cells, NK and ILC precursors in the yolk sac. We demonstrate a shift in fetal liver haematopoietic composition during gestation away from being erythroid-predominant, accompanied by a parallel change in HSC/MPP differentiation potential, which we functionally validate. Our integrated map of fetal liver haematopoiesis provides a blueprint for the study of paediatric blood and immune disorders, and a valuable reference for harnessing the therapeutic potential of HSC/MPPs.