Macrophage-Lineage Cells Negatively Regulate the Hematopoietic Stem Cell Pool in Response to Interferon Gamma at Steady State and During Infection.
Macrophage-Lineage Cells Negatively Regulate the Hematopoietic Stem Cell Pool in Response to Interferon Gamma at Steady State and During Infection.
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DOI：
10.1002/stem.2040
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发表时间：
2015-07
期刊：
影响因子：
--
通讯作者：
MacNamara KC
中科院分区：
文献类型：
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作者：
McCabe A;Zhang Y;Thai V;Jones M;Jordan MB;MacNamara KC
骨髓（BM）驻留巨噬细胞（M β）调节造血干细胞（HSC）动员，但其对HSC功能的影响尚未研究。我们证明，BM驻留的M β s的耗尽会增加HSC的增殖以及静止的HSC库。同时，在细菌感染期间，BM驻留的M β选择性增加，我们观察到HSC数量减少。此外，在感染过程中消耗或减少M β s的策略可以防止HSC损失并挽救HSC功能。我们以前发现，在感染过程中HSC的短暂损失是干扰素γ（IFNγ）依赖的。我们现在证明，IFNγ信号特异性地在巨噬细胞中是至关重要的减少HSC池和维持BM驻留的巨噬细胞在感染期间。除了感染期间BM HSC和祖细胞（HSPC）的IFNγ依赖性损失外，IFNγ还减少了循环HSPC数量。重要的是，在感染条件下，AMD 3100或G-CSF诱导的干细胞动员受损。综上所述，我们的数据表明IFNγ作用于作为HSC池的负调节剂的M β，以在感染期间驱动BM和外周HSC的损失。我们的研究结果表明，调节BM驻留M β数量可以影响体内HSC功能，这可能对血液学条件和HSC移植方案的改进有治疗意义。
Bone marrow (BM) resident macrophages (Mϕs) regulate hematopoietic stem cell (HSC) mobilization, however their impact on HSC function has not been investigated. We demonstrate that depletion of BM resident Mϕs increases HSC proliferation as well as the pool of quiescent HSCs. At the same time, during bacterial infection where BM resident Mϕs are selectively increased we observe a decrease in HSC numbers. Moreover, strategies that deplete or reduce Mϕs during infection prevent HSC loss and rescue HSC function. We previously found that the transient loss of HSCs during infection is interferon-gamma (IFNγ)-dependent. We now demonstrate that IFNγ signaling specifically in Mϕs is critical for both the diminished HSC pool and maintenance of BM resident Mϕs during infection. In addition to the IFNγ-dependent loss of BM HSC and progenitor cells (HSPCs) during infection, IFNγ reduced circulating HSPC numbers. Importantly, under infection conditions AMD3100 or G-CSF-induced stem cell mobilization was impaired. Taken together our data show that IFNγ acts on Mϕs, which are a negative regulator of the HSC pool, to drive the loss in BM and peripheral HSCs during infection. Our findings demonstrate that modulating BM resident Mϕ numbers can impact HSC function in vivo, which may be therapeutically useful for hematologic conditions and refinement of HSC transplantation protocols.