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

• Published in: Leukemia Vol. 26; no. 11; pp. 2375 - 2383
• Main Authors: Singh, P, Hu, P, Hoggatt, J, Moh, A, Pelus, L M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2012; Nature Publishing Group
• Subjects: 631/136/532/1542; 631/250/2504/223/1699; 631/80/82/23; 692/700/565/1331; Adhesion; Animals; Antibodies; Apoptosis; Apoptosis - physiology; Base Sequence; Biological and medical sciences; Biomedical materials; Bone marrow; Bone Marrow Cells - immunology; Cancer Research; Cell adhesion; Cell adhesion & migration; Cell adhesion molecules; Cell differentiation; Cell Lineage; Cell proliferation; Chemokines; Cloning; Coculture Techniques; Colony-stimulating factor; Critical Care Medicine; Cytokines; DNA Primers; Egress; Granulocyte colony-stimulating factor; Granulocyte Colony-Stimulating Factor - administration & dosage; Granulocytes; Hematologic and hematopoietic diseases; Hematology; Hematopoietic stem cells; Hematopoietic Stem Cells - immunology; Immunology; Intensive; Internal Medicine; Leukemia; Leukocytes (granulocytic); Leukocytes (neutrophilic); Macrophages; Medical sciences; Medicine; Medicine & Public Health; Mesenchyme; Mice; Molecular Sequence Data; Monocytes; Neutropenia; Neutrophils; Neutrophils - cytology; Niches; Oncology; original-article; Osteoprogenitor cells; Peripheral blood; Physiological aspects; Polymerase Chain Reaction; Progenitor cells; Reactive oxygen species; Retention; SDF-1 protein; Stem cell factor; Stem cells; Transplants & implants; Vascular cell adhesion molecule 1; United States; Indiana; United States > US; Indianapolis Indiana; neutrophil expansion; G-CSF; osteolineage cells; HSPC mobilization; hematopoietic niche disruption and ROS; Hematology; Stem cell; Rodentia; Granulocyte; Hematopoietic cell; Mobilization; Vertebrata; Granulocyte colony stimulating factor; Mammalia; Mouse; Cell death; Animal; Bone marrow; Neutrophil; Expansion; Apoptosis
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2012.117

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.