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Integrin αvβ3 enhances the suppressive effect of interferon-γ on hematopoietic stem cells. (EMBO J, July 2017)

Umemoto T1, Matsuzaki Y2, Shiratsuchi Y3, Hashimoto M2, Yoshimoto T4, Nakamura-Ishizu A5, Petrich B6, Yamato M3, Suda T1,5.

Author information
1 International Research Center for Medical Science, Kumamoto University, Kumamoto, Japan umemoto@kumamoto-u.ac.jp csits@nus.edu.sg.
2 International Research Center for Medical Science, Kumamoto University, Kumamoto, Japan.
3 Institute of Advanced Medical Bioscience and Engineering, Tokyo Women’s Medical University, Tokyo, Japan.
4 Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan.
5 Cancer Science Institute of Singapore, National University of Singapore, Singapore City, Singapore.
6 Department of Pediatrics and Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA, USA.

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.

PMID: 28673932