Umemoto Terumasa, Matsuzaki Yu, Shiratsuchi Yoshiko, Hashimoto Michihiro, Yoshimoto Takayuki, Nakamura-Ishizu Ayako, Petrich Brian, Yamato Masayuki, Suda Toshio
International Research Center for Medical Science, Kumamoto University, Kumamoto, Japan
International Research Center for Medical Science, Kumamoto University, Kumamoto, Japan.
EMBO J. 2017 Aug 15;36(16):2390-2403. doi: 10.15252/embj.201796771. Epub 2017 Jul 3.
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.
造血稳态依赖于造血干细胞（HSC）的维持，造血干细胞在特殊的骨髓（BM）微环境中受到调控。当造血干细胞感知外部刺激时，它们的黏附状态对于决定造血干细胞的细胞命运可能至关重要。细胞表面分子整合素αvβ3通过造血干细胞与细胞外基质和微环境细胞的黏附而被激活。整合素β3信号传导将造血干细胞维持在微环境中。在此，我们通过一种新型的造血干细胞明确表型分析，展示了促炎细胞因子干扰素-γ（IFNγ）和β3整合素信号传导对小鼠造血干细胞功能的协同负调控作用。在IFNγ存在的情况下，整合素αvβ3抑制造血干细胞功能，而受损的整合素β3信号传导减轻了IFNγ对造血干细胞的依赖性负面作用。在IFNγ刺激期间，整合素β3信号传导通过丝氨酸磷酸化增强了STAT1介导的基因表达。这些发现表明，整合素β3信号传导增强了IFNγ对造血干细胞的抑制作用，这表明在骨髓微环境中通过整合素αvβ3的细胞黏附作为一种依赖于环境的信号调节剂，在稳态和炎症条件下调节造血干细胞功能。
