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Stem Cells

G-CSF regulates hematopoietic stem cell activity, in part, through activation of Toll-like receptor signaling

Leukemia volume 28, pages 1851–1860 (2014)Cite this article

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Abstract

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.

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Acknowledgements

We thank J Tucker-Davis for animal care. We also thank the Alvin J Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, MO, USA, for the use of the Siteman Flow Cytometry Core, which provided cell sorting and analysis service. The Siteman Cancer Center is supported in part by an NCI Cancer Center Support Grant #P30 CA91842. This work was supported by the NIH grant RO1 HL60772 (to DCL), Alex's Lemonade Stand Foundation (to LGS), the Children's Discovery Institute of Washington University and St Louis Children's Hospital (to LGS), and Hyundai Motor America (Hyundai Hope on Wheels scholar award to LGS). LGS is a scholar of the Child Health Research Center of Excellence in Developmental Biology at Washington University School of Medicine (K12-HD076224).

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Authors and Affiliations

  1. Department of Pediatrics, Washington University School of Medicine, Saint Louis, MO, USA

    L G Schuettpelz, M P Romine & A C Herman

  2. Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, Saint Louis, MO, USA

    J N Borgerding, M J Christopher, J R Woloszynek, A M Greenbaum & D C Link

  3. Department of Medicine, University of Florida, Gainesville, FL, USA

    P K Gopalan

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  1. L G Schuettpelz
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Correspondence to D C Link.

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Author Contributions

LGS designed the research, performed the research, analyzed data and wrote the paper. JNB performed the research and analyzed data. MJC designed the research, performed the research and analyzed data. PKG performed the research. MPR performed the research. ACH performed the research. JRW performed the research. AMG designed the research. DCL designed the research, analyzed data and wrote the paper.

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Schuettpelz, L., Borgerding, J., Christopher, M. et al. G-CSF regulates hematopoietic stem cell activity, in part, through activation of Toll-like receptor signaling. Leukemia 28, 1851–1860 (2014). https://doi.org/10.1038/leu.2014.68

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