Gene regulatory networks underlying intrinsic properties in human hematopoietic stem cell ontogeny

Human hematopoiesis starts at early yolk sac and undergoes site- and stage-specific changes over development. However, the gene regulatory networks (GRN) that drive the developmental changes in naive hematopoietic stem/progenitor cells (HSPCs) remain poorly understood. Here, we analyzed single-cell transcriptome of human naive HSPCs in different developmental stages, including yolk-sac (YS), AGM, fetal liver (FL), umbilical cord blood (UCB) and adult peripheral blood (PB) mobilized HSPCs. These stage-specific HSPCs display differential intrinsic properties, such as metabolism, self-renewal, differentiating potentialities etc. We generated highly co-related GRN modules underlying the differential HSC key properties. Particularly, we identified GRNs and key regulators controlling lymphoid potentiality, self-renewal and aerobic respiration in human HSCs. Introducing selected regulators promotes establishing key HSC functions in HSPCs derived from human pluripotent stem cells. Therefore, GRNs underlying key intrinsic properties of human HSCs provide a valuable guide to generate fully functional HSCs in vitro. 10X Single-cell RNASeq of FACS-sorted Lin-CD34+CD38- HSPCs mobilized in human umbilical cord blood (CB-HSPCs).