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Developmental trajectory of pre-hematopoietic stem cell formation from endothelium

By Qin Zhu, Peng Gao, Joanna Tober, Laura Bennett, Changya Chen, Yasin Uzun, Yan Li, Melanie Mumau, Wenbao Yu, Bing He, Nancy A Speck, Kai Tan

Posted 20 Nov 2019
bioRxiv DOI: 10.1101/848846 (published DOI: 10.1182/blood.2020004801)

Hematopoietic stem and progenitor cells (HSPCs) differentiate from hemogenic endothelial (HE) cells through an endothelial to hematopoietic cell transition (EHT). Newly formed HSPCs accumulate in intra-arterial clusters (IACs) before colonizing the fetal liver. To examine the cell and molecular transitions during the EHT, and the heterogeneity of HSPCs within IACs, we profiled ∼37,000 cells from the caudal arteries of embryonic day 9.5 (E9.5) to E11.5 mouse embryos by single-cell transcriptome and chromatin accessibility sequencing. We identified an intermediate developmental stage prior to HE that we termed pre-HE, 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. Distinct developmental trajectories within IAC cells result in two populations of CD45+ HSPCs; an initial wave of lympho-myeloid-biased progenitors, followed by precursors of hematopoietic stem cells (pre-HSCs).

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