Molecular transitions in early progenitors during human cord blood hematopoiesis

Hematopoietic stem cells (HSCs) give rise to diverse cell types in the blood system, yet our molecular understanding of the early trajectories that generate this enormous diversity in humans remains incomplete. Here, we leverage Drop‐seq, a massively parallel single‐cell RNA sequencing (scRNA‐seq) approach, to individually profile 20,000 progenitor cells from human cord blood, without prior enrichment or depletion for individual lineages based on surface markers. Our data reveal a transcriptional compendium of progenitor states in human cord blood, representing four committed lineages downstream from HSC, alongside the transcriptional dynamics underlying fate commitment. We identify intermediate stages that simultaneously co‐express “primed” programs for multiple downstream lineages, and also observe striking heterogeneity in the early molecular transitions between myeloid subsets. Integrating our data with a recently published scRNA‐seq dataset from human bone marrow, we illustrate the molecular similarity between these two commonly used systems and further explore the chromatin dynamics of “primed” transcriptional programs based on ATAC‐seq. Finally, we demonstrate that Drop‐seq data can be utilized to identify new heterogeneous surface markers of cell state that correlate with functional output.