HOXB4 Promotes Hemogenic Endothelium Formation without Perturbing Endothelial Cell Development

Stem Cell Reports. 2018 Mar 13;10(3):875-889. doi: 10.1016/j.stemcr.2018.01.009. Epub 2018 Feb 15.


Generation of hematopoietic stem cells (HSCs) from pluripotent stem cells, in vitro, holds great promise for regenerative therapies. Primarily, this has been achieved in mouse cells by overexpression of the homeotic selector protein HOXB4. The exact cellular stage at which HOXB4 promotes hematopoietic development, in vitro, is not yet known. However, its identification is a prerequisite to unambiguously identify the molecular circuits controlling hematopoiesis, since the activity of HOX proteins is highly cell and context dependent. To identify that stage, we retrovirally expressed HOXB4 in differentiating mouse embryonic stem cells (ESCs). Through the use of Runx1(-/-) ESCs containing a doxycycline-inducible Runx1 coding sequence, we uncovered that HOXB4 promoted the formation of hemogenic endothelium cells without altering endothelial cell development. Whole-transcriptome analysis revealed that its expression mediated the upregulation of transcription of core transcription factors necessary for hematopoiesis, culminating in the formation of blood progenitors upon initiation of Runx1 expression.

Keywords: EHT; HOXB4; RUNX1; hemangioblast; hematopoietic specification; hematopoietic stem cells; hemogenic endothelium; pluripotent stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / physiology
  • Cells, Cultured
  • Core Binding Factor Alpha 2 Subunit / metabolism
  • Embryonic Stem Cells / metabolism
  • Embryonic Stem Cells / physiology
  • Endothelial Cells / metabolism*
  • Endothelial Cells / physiology*
  • Endothelium / metabolism*
  • Endothelium / physiology*
  • Gene Expression Profiling / methods
  • Hematopoiesis / physiology*
  • Hematopoietic Stem Cells / metabolism
  • Hematopoietic Stem Cells / physiology
  • Homeodomain Proteins / metabolism*
  • Mice
  • Pluripotent Stem Cells / metabolism
  • Pluripotent Stem Cells / physiology
  • Transcription Factors / metabolism*
  • Transcription, Genetic / physiology
  • Up-Regulation / physiology


  • Core Binding Factor Alpha 2 Subunit
  • Homeodomain Proteins
  • Hoxb4 protein, mouse
  • Transcription Factors