HEMATOPOIESIS AND STEM CELLS| AUGUST 13, 2020
Developmental trajectory of prehematopoietic stem cell formation from endotheliumQin Zhu, Peng Gao, Joanna Tober, Laura Bennett, Changya Chen, Yasin Uzun, Yan Li, Elizabeth D. Howell, Melanie Mumau, Wenbao Yu, Bing He, Nancy A. Speck, Kai Tan
Blood (2020) 136 (7): 845–856.
https://doi.org/10.1182/blood.2020004801
Key PointsSingle-cell analyses determine the trajectory from endothelial cells to pre-HSCs, with defined intermediate stages.
Hemogenic endothelial cells in the arteries produce 2 waves of CD45+ cells; an early wave of progenitors followed by pre-HSCs.
AbstractHematopoietic stem and progenitor cells (HSPCs) in the bone marrow are derived from a small population of hemogenic endothelial (HE) cells located in the major arteries of the mammalian embryo. HE cells undergo an endothelial to hematopoietic cell transition, giving rise to HSPCs that accumulate in intra-arterial clusters (IAC) before colonizing the fetal liver. To examine the cell and molecular transitions between endothelial (E), HE, and IAC cells, and the heterogeneity of HSPCs within IACs, we profiled ∼40 000 cells from the caudal arteries (dorsal aorta, umbilical, vitelline) of 9.5 days post coitus (dpc) to 11.5 dpc mouse embryos by single-cell RNA sequencing and single-cell assay for transposase-accessible chromatin sequencing. We identified a continuous developmental trajectory from E to HE to IAC cells, with identifiable intermediate stages. The intermediate stage most proximal to HE, which we term pre-HE, is characterized by increased accessibility of chromatin enriched for SOX, FOX, GATA, and SMAD motifs. A developmental bottleneck separates pre-HE from HE, with RUNX1 dosage regulating the efficiency of the pre-HE to HE transition. A distal candidate Runx1 enhancer exhibits high chromatin accessibility specifically in pre-HE cells at the bottleneck, but loses accessibility thereafter. Distinct developmental trajectories within IAC cells result in 2 populations of CD45+ HSPCs; an initial wave of lymphomyeloid-biased progenitors, followed by precursors of hematopoietic stem cells (pre-HSCs). This multiomics single-cell atlas significantly expands our understanding of pre-HSC ontogeny.
Subjects:
Hematopoiesis and Stem Cells
Topics:
cd45 antigens, chromatin, embryo, endothelium, hematopoietic stem cells, rna, small cytoplasmic, stem cells, wave - physical agent, enhancer of transcription, endothelial cells
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