Dorin-Mirel Popescu, Rachel A Botting, Emily Stephenson, Kile Green, Simone Webb, Laura Jardine, Emily F Calderbank, Krzysztof Polanski, Issac Goh, Mirjana Efremova, Meghan Acres, Daniel Maunder, Peter Vegh, Yorick Gitton, Jong-Eun Park, Roser Vento-Tormo, Zhichao Miao, David Dixon, Rachel Rowell, David McDonald, James Fletcher, Elizabeth Poyner, Gary Reynolds, Michael Mather, Corina Moldovan, Lira Mamanova, Frankie Greig, Matthew D Young, Kerstin B Meyer, Steven Lisgo, Jaume Bacardit, Andrew Fuller, Ben Millar, Barbara Innes, Susan Lindsay, Michael J T Stubbington, Monika S Kowalczyk, Bo Li, Orr Ashenberg, Marcin Tabaka, Danielle Dionn, Timothy L Tickle, Michal Slyper, Orit Rozenblatt-Rosen, Andrew Filby, Peter Carey, Alexandra-Chloe Villani, Anindita Roy, Aviv Regev, Alain Ch<c3><a9>dotal, Irene Roberts, Berthold Gottgens, Sam Behjati, Elisa Laurenti, Sarah A Teichmann, Muzlifah Haniffa
Definitive haematopoiesis in the fetal liver supports self-renewal and differentiation of haematopoietic stem cells and multipotent progenitors (HSC/MPPs) but remains poorly defined in humans. Here, using single-cell transcriptome profiling of approximately 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 influence of the tissue microenvironment on blood and immune cell development. We reveal physiological erythropoiesis in fetal skin and the presence of mast cells, natural killer and innate lymphoid cell precursors in the yolk sac. We demonstrate a shift in the haemopoietic composition of fetal liver during gestation away from being predominantly erythroid, accompanied by a parallel change in differentiation potential of HSC/MPPs, 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 reference for harnessing the therapeutic potential of HSC/MPPs.