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Blood
08 13, 2020;136 (7): 845-856.

Developmental trajectory of prehematopoietic stem cell formation from endothelium.

Qin 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
Author Information
  1. Qin Zhu: Genomics and Computational Biology Graduate Group, University of Pennsylvania, Philadelphia, PA.
  2. Peng Gao: Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA; and.
  3. Joanna Tober: Department of Cell and Developmental Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, and.
  4. Laura Bennett: Department of Cell and Developmental Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, and.
  5. Changya Chen: Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA; and.
  6. Yasin Uzun: Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA; and.
  7. Yan Li: Department of Cell and Developmental Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, and.
  8. Elizabeth D Howell: Department of Cell and Developmental Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, and.
  9. Melanie Mumau: Department of Cell and Developmental Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, and.
  10. Wenbao Yu: Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA; and.
  11. Bing He: Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA; and.
  12. Nancy A Speck: Department of Cell and Developmental Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, and.
  13. Kai Tan: Genomics and Computational Biology Graduate Group, University of Pennsylvania, Philadelphia, PA.
PMID: 32392346 DOI: 10.1182/blood.2020004801

Abstract

Hematopoietic 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.

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Grants

  1. R01 HL091724/NHLBI NIH HHS
  2. R01 HD089245/NICHD NIH HHS
  3. R01 HG006130/NHGRI NIH HHS
  4. T32 HD083185/NICHD NIH HHS
  5. R01 GM108716/NIGMS NIH HHS
  6. T32 DK007780/NIDDK NIH HHS
  7. R21 AI133261/NIAID NIH HHS
  8. F31 HL150952/NHLBI NIH HHS
  9. T32 HL007439/NHLBI NIH HHS

MeSH Term

Animals
Cell Differentiation
Core Binding Factor Alpha 2 Subunit
Embryo, Mammalian
Endothelium
Female
Gene Dosage
Gene Expression Regulation, Developmental
Hemangioblasts
Hematopoiesis
Hematopoietic Stem Cells
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Pregnancy
RNA-Seq

Chemicals

Core Binding Factor Alpha 2 Subunit
Runx1 protein, mouse
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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