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

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.

Mechanisms of G-CSF-mediated hematopoietic stem and progenitor mobilization.

Under normal conditions, the great majority of hematopoietic stem/progenitors cells (HSPCs) reside in the bone marrow. The number of HSPCs in the circulation can be markedly increased in response to a number of stimuli, including hematopoietic growth factors, myeloablative agents and environmental stresses such as infection. The ability to 'mobilize' HSPCs from the bone marrow to the blood has been exploited clinically to obtain HSPCs for stem cell transplantation and, more recently, to stimulate therapeutic angiogenesis at sites of tissue ischemia. Moreover, there is recent interest in the use of mobilizing agents to sensitize leukemia and other hematopoietic malignancies to cytotoxic agents. Key to optimizing clinical mobilizing regimens is an understanding of the fundamental mechanisms of HSPC mobilization. In this review, we discuss recent advances in our understanding of the mechanisms by which granulocyte colony-stimulating factor (G-CSF), the prototypical mobilizing agent, induces HSPC mobilization.