Pharmacological inhibition of EGFR signaling enhances G-CSF–induced hematopoietic stem cell mobilization

For bone marrow transplantation, donor hematopoietic cells are routinely mobilized from the bone marrow to the peripheral blood by the cytokine G-CSF. By studying mouse strains that respond to G-CSF with varying degrees of mobilization, Marnie A. Ryan et al . discovered that the epidermal growth factor receptor, acting in bone marrow cells, restrains this response. An inhibitor of epidermal growth factor receptor activity augmented G-CSF–induced mobilization in mice, suggesting that this approach might be clinically useful in bone marrow transplantation. Mobilization of hematopoietic stem and progenitor cells (HSPCs) from bone marrow into peripheral blood by the cytokine granulocyte colony–stimulating factor (G-CSF) has become the preferred source of HSPCs for stem cell transplants 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 . However, G-CSF fails to mobilize sufficient numbers of stem cells in up to 10% of donors, precluding autologous transplantation in those donors or substantially delaying transplant recovery time 2 . Consequently, new regimens are needed to increase the number of stem cells in peripheral blood upon mobilization. Using a forward genetic approach in mice, we mapped the gene encoding the epidermal growth factor receptor ( Egfr ) to a genetic region modifying G-CSF–mediated HSPC mobilization. Amounts of EGFR in HSPCs inversely correlated with the cells' ability to be mobilized by G-CSF, implying a negative role for EGFR signaling in mobilization. In combination with G-CSF treatment, genetic reduction of EGFR activity in HSPCs (in waved-2 mutant mice) or treatment with the EGFR inhibitor erlotinib increased mobilization. Increased mobilization due to suppression of EGFR activity correlated with reduced activity of cell division control protein-42 (Cdc42), and genetic Cdc42 deficiency in vivo also enhanced G-CSF–induced mobilization. Our findings reveal a previously unknown signaling pathway regulating stem cell mobilization and provide a new pharmacological approach for improving HSPC mobilization and thereby transplantation outcomes.