ATF4 plays a pivotal role in the development of functional hematopoietic stem cells in mouse fetal liver

Blood. 2015 Nov 19;126(21):2383-91. doi: 10.1182/blood-2015-03-633354. Epub 2015 Sep 17.

Abstract

The fetal liver (FL) serves as a predominant site for expansion of functional hematopoietic stem cells (HSCs) during mouse embryogenesis. However, the mechanisms for HSC development in FL remain poorly understood. In this study, we demonstrate that deletion of activating transcription factor 4 (ATF4) significantly impaired hematopoietic development and reduced HSC self-renewal in FL. In contrast, generation of the first HSC population in the aorta-gonad-mesonephros region was not affected. The migration activity of ATF4(-/-) HSCs was moderately reduced. Interestingly, the HSC-supporting ability of both endothelial and stromal cells in FL was significantly compromised in the absence of ATF4. Gene profiling using RNA-seq revealed downregulated expression of a panel of cytokines in ATF4(-/-) stromal cells, including angiopoietin-like protein 3 (Angptl3) and vascular endothelial growth factor A (VEGFA). Addition of Angptl3, but not VEGFA, partially rescued the repopulating defect of ATF4(-/-) HSCs in the culture. Furthermore, chromatin immunoprecipitation assay in conjunction with silencing RNA-mediated silencing and complementary DNA overexpression showed transcriptional control of Angptl3 by ATF4. To summarize, ATF4 plays a pivotal role in functional expansion and repopulating efficiency of HSCs in developing FL, and it acts through upregulating transcription of cytokines such as Angptl3 in the microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / genetics
  • Activating Transcription Factor 4 / metabolism*
  • Angiopoietin-Like Protein 3
  • Angiopoietin-like Proteins
  • Angiopoietins / genetics
  • Angiopoietins / metabolism
  • Animals
  • Cell Movement / physiology*
  • Fetus / cytology
  • Fetus / embryology*
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / metabolism*
  • Liver / cytology
  • Liver / embryology*
  • Mice
  • Mice, Knockout
  • Stem Cell Niche / physiology*
  • Stromal Cells / cytology
  • Stromal Cells / metabolism
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Angiopoietin-Like Protein 3
  • Angiopoietin-like Proteins
  • Angiopoietins
  • Angptl3 protein, mouse
  • Atf4 protein, mouse
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • Activating Transcription Factor 4