HDAC1 and HDAC2 Modulate TGF-β Signaling during Endothelial-to-Hematopoietic Transition

Stem Cell Reports. 2018 Apr 10;10(4):1369-1383. doi: 10.1016/j.stemcr.2018.03.011.

Abstract

The first hematopoietic stem and progenitor cells are generated during development from hemogenic endothelium (HE) through trans-differentiation. The molecular mechanisms underlying this endothelial-to-hematopoietic transition (EHT) remain poorly understood. Here, we explored the role of the epigenetic regulators HDAC1 and HDAC2 in the emergence of these first blood cells in vitro and in vivo. Loss of either of these epigenetic silencers through conditional genetic deletion reduced hematopoietic transition from HE, while combined deletion was incompatible with blood generation. We investigated the molecular basis of HDAC1 and HDAC2 requirement and identified TGF-β signaling as one of the pathways controlled by HDAC1 and HDAC2. Accordingly, we experimentally demonstrated that activation of this pathway in HE cells reinforces hematopoietic development. Altogether, our results establish that HDAC1 and HDAC2 modulate TGF-β signaling and suggest that stimulation of this pathway in HE cells would be beneficial for production of hematopoietic cells for regenerative therapies.

Keywords: AGM; HDAC1; HDAC2; TGF-β signaling; embryonic stem cells; endothelial-to-hematopoietic transition; epigenetic; hematopoietic stem cells; hemogenic endothelium; in vitro differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamides / pharmacology
  • Cell Differentiation / drug effects
  • Dioxoles / pharmacology
  • Endothelial Cells / cytology*
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Gene Deletion
  • Hemangioblasts / cytology
  • Hematopoiesis* / drug effects
  • Histone Deacetylase 1 / deficiency
  • Histone Deacetylase 1 / metabolism*
  • Histone Deacetylase 2 / deficiency
  • Histone Deacetylase 2 / metabolism*
  • Histone Deacetylase Inhibitors / pharmacology
  • Mice
  • Signal Transduction* / drug effects
  • Transforming Growth Factor beta / metabolism*

Substances

  • 4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide
  • Benzamides
  • Dioxoles
  • Histone Deacetylase Inhibitors
  • Transforming Growth Factor beta
  • Hdac1 protein, mouse
  • Hdac2 protein, mouse
  • Histone Deacetylase 1
  • Histone Deacetylase 2