Integrin αvβ3 enhances the suppressive effect of interferon-γ on hematopoietic stem cells

EMBO J. 2017 Aug 15;36(16):2390-2403. doi: 10.15252/embj.201796771. Epub 2017 Jul 3.

Abstract

Hematopoietic homeostasis depends on the maintenance of hematopoietic stem cells (HSCs), which are regulated within a specialized bone marrow (BM) niche. When HSC sense external stimuli, their adhesion status may be critical for determining HSC cell fate. The cell surface molecule, integrin αvβ3, is activated through HSC adhesion to extracellular matrix and niche cells. Integrin β3 signaling maintains HSCs within the niche. Here, we showed the synergistic negative regulation of the pro-inflammatory cytokine interferon-γ (IFNγ) and β3 integrin signaling in murine HSC function by a novel definitive phenotyping of HSCs. Integrin αvβ3 suppressed HSC function in the presence of IFNγ and impaired integrin β3 signaling mitigated IFNγ-dependent negative action on HSCs. During IFNγ stimulation, integrin β3 signaling enhanced STAT1-mediated gene expression via serine phosphorylation. These findings show that integrin β3 signaling intensifies the suppressive effect of IFNγ on HSCs, which indicates that cell adhesion via integrin αvβ3 within the BM niche acts as a context-dependent signal modulator to regulate the HSC function under both steady-state and inflammatory conditions.

Keywords: IFNγ; STAT1; hematopoietic stem cells; integrin αvβ3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation*
  • Gene Expression Regulation
  • Hematopoietic Stem Cells / physiology*
  • Integrin alphaVbeta3 / metabolism*
  • Interferon-gamma / metabolism*
  • Mice
  • Phosphorylation
  • Protein Processing, Post-Translational
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction

Substances

  • IFNG protein, mouse
  • Integrin alphaVbeta3
  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • Interferon-gamma