Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
Department of Haematology and Wellcome and MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
Nature. 2019 Oct;574(7778):365-371. doi: 10.1038/s41586-019-1652-y. Epub 2019 Oct 9.
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.
在胎儿肝脏中进行的明确造血作用支持造血干细胞和多能祖细胞（HSC/MPP）的自我更新和分化，但在人类中仍未得到很好的定义。在这里，我们使用大约 140,000 个肝脏细胞和 74,000 个皮肤、肾脏和卵黄囊细胞的单细胞转录组谱分析，确定了人类在发育过程中血液和免疫细胞的组成。我们从 HSC/MPP 推断出分化轨迹，并评估组织微环境对血液和免疫细胞发育的影响。我们揭示了胎儿皮肤中的生理红细胞生成以及卵黄囊中存在肥大细胞、自然杀伤细胞和先天淋巴细胞前体。我们证明了胎儿肝脏中造血成分在妊娠期间从主要是红细胞向造血的转变，伴随着 HSC/MPP 分化潜力的平行变化，我们通过功能验证了这一点。我们整合的胎儿肝脏造血图谱为研究儿科血液和免疫疾病提供了蓝图，并为利用 HSC/MPP 的治疗潜力提供了参考。
