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

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 induce MPC and OB apoptosis leading to reduced production of BM HSPC retention factors including stromal cell derived factor-1 (SDF-1), stem cell factor (SCF) and vascular cell adhesion molecule-1(VCAM-1). Blockade of neutrophil reactive oxygen species (ROS) 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.