Quantification of intrinsic regulatory factors refines human hematopoietic progenitor definitions and reveals early erythroid lineage priming

Hematopoietic stem and progenitor cell (HSPC) transplantation is an essential therapy for the treatment of hematological conditions, but finer definitions of human HSPC subsets with associated function could enable better tuning of grafts and more routine application in patients with lower risks. To deeply characterize human HSPCs, we quantified 41 surface proteins and functional regulators on millions of CD34+ and CD34- cells, spanning four primary human hematopoietic tissues: bone marrow, mobilized peripheral blood, cord blood, and fetal liver. We propose more granular definitions of HSPC subsets and provide new, detailed differentiation trajectories of erythroid and myeloid lineages. These aspects of our revised human hematopoietic model were validated with corresponding epigenetic analysis and in vitro clonal differentiation assays. Overall, we demonstrate the utility of using molecular regulators as surrogates for cellular identity and functional potential, providing a framework for description, prospective isolation, and cross-tissue comparison of HSPCs in humans. Chromatin accessibility profiling through ATAC sequencing of human bone marrow progenitors after sorting for specific populations in the erythrocyte and myeloid development stages