Schuettpelz L G, Borgerding J N, Christopher M J, Gopalan P K, Romine M P, Herman A C, Woloszynek J R, Greenbaum A M, Link D C
Department of Pediatrics, Washington University School of Medicine, Saint Louis, MO, USA.
Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, Saint Louis, MO, USA.
Leukemia. 2014 Sep;28(9):1851-60. doi: 10.1038/leu.2014.68. Epub 2014 Feb 12.
Recent studies demonstrate that inflammatory signals regulate hematopoietic stem cells (HSCs). Granulocyte colony-stimulating factor (G-CSF) is often induced with infection and has a key role in the stress granulopoiesis response. However, its effects on HSCs are less clear. Herein, we show that treatment with G-CSF induces expansion and increased quiescence of phenotypic HSCs, but causes a marked, cell-autonomous HSC repopulating defect associated with induction of Toll-like receptor (TLR) expression and signaling. The G-CSF-mediated expansion of HSCs is reduced in mice lacking TLR2, TLR4 or the TLR signaling adaptor MyD88. Induction of HSC quiescence is abrogated in mice lacking MyD88 or in mice treated with antibiotics to suppress intestinal flora. Finally, loss of TLR4 or germ-free conditions mitigates the G-CSF-mediated HSC repopulating defect. These data suggest that low-level TLR agonist production by commensal flora contributes to the regulation of HSC function and that G-CSF negatively regulates HSCs, in part, by enhancing TLR signaling.
近期研究表明，炎症信号可调节造血干细胞（HSCs）。粒细胞集落刺激因子（G-CSF）常因感染而被诱导产生，在应激粒细胞生成反应中起关键作用。然而，其对造血干细胞的影响尚不清楚。在此，我们表明，用G-CSF处理可诱导表型造血干细胞的扩增并增加其静止状态，但会导致明显的、细胞自主性的造血干细胞重建缺陷，这与Toll样受体（TLR）表达及信号传导的诱导有关。在缺乏TLR2、TLR4或TLR信号转导衔接蛋白MyD88的小鼠中，G-CSF介导的造血干细胞扩增减少。在缺乏MyD88的小鼠或用抗生素处理以抑制肠道菌群的小鼠中，造血干细胞静止状态的诱导被消除。最后，TLR4缺失或无菌条件可减轻G-CSF介导的造血干细胞重建缺陷。这些数据表明，共生菌群产生的低水平TLR激动剂有助于调节造血干细胞功能，并且G-CSF部分通过增强TLR信号传导对造血干细胞产生负调节作用。
