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Normal Hemopoiesis

Expansion of bone marrow neutrophils following G-CSF administration in mice results in osteolineage cell apoptosis and mobilization of hematopoietic stem and progenitor cells

Leukemia volume 26, pages 2375–2383 (2012)Cite this article

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Abstract

Proliferation and differentiation of hematopoietic stem/progenitor cells (HSPC) within bone marrow (BM) niches are regulated by adhesion molecules and cytokines produced by mesenchymal stem/progenitor cells (MPC) and osteoblasts (OB). HSPCs that egresses to peripheral blood are widely used for transplant and granulocyte-colony stimulating factor (G-CSF) is used clinically to induce mobilization. The mechanisms, through which G-CSF regulates HSPC trafficking, however, are not completely understood. Herein we show that G-CSF-driven neutrophil expansion alters the BM niche that leads to HSPC mobilization. Alcam−Sca-1+MPC and Alcam+Sca-1− OB are reduced coincident with mobilization, which correlates inversely with BM neutrophil expansion. In mice made neutropenic by the neutrophil-specific anti-Ly6G antibody, G-CSF-mediated reduction in MPC and OB is attenuated and mobilization reduced without an effect on monocytes/macrophages. Neutrophils, expanded in response to G-CSF-induced MPC and OB apoptosis leading to reduced production of BM HSPC retention factors, including stromal cell-derived factor-1, stem cell factor and vascular cell adhesion molecule-1. Blockade of neutrophil reactive oxygen species attenuates G-CSF-mediated MPC and OB apoptosis. These data show that the expansion of BM neutrophils by G-CSF contributes to the transient degradation of retention mechanisms within the BM niche, facilitating enhanced HSPC egress/mobilization.

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Acknowledgements

This work was supported by NIH grants HL069669 and HL096305 (to LMP) and partially supported by National Institute of Diabetes and Digestive and Kidney Diseases Center for Excellence in Molecular Hematology grant P30 DK090948. JH was supported sequentially by NIH Training Grants DK07519 and HL007910. Flow cytometry was performed in the Flow Cytometry Resource Facility of the Indiana University Simon Cancer Center (NCI P30 CA082709). This study was also supported by US Public Health Service grants HL069669, and HL096305 from the National Institutes of Health (to LMP).

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  1. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA

    P Singh, P Hu, J Hoggatt, A Moh & L M Pelus

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Correspondence to L M Pelus.

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Singh, P., Hu, P., Hoggatt, J. et al. Expansion of bone marrow neutrophils following G-CSF administration in mice results in osteolineage cell apoptosis and mobilization of hematopoietic stem and progenitor cells. Leukemia 26, 2375–2383 (2012). https://doi.org/10.1038/leu.2012.117

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