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 transplants1,2,3,4,5,6,7,8,9. 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 time2. 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.
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This work was supported by a Cincinnati Children's Hospital Medical Center Translational Research Initiative Award to H.G. and M.A.R., grants from the US National Institutes of Health, HL076604 and DK077762 to H.G., AG024950 and HD060915 to G.V.Z. and an American Heart Association established investigator award to T.D.L.C. (0740069N). H.G. is a New Investigator in Aging, and G.V.Z. is a Senior Scholar in Aging of The Ellison Medical Foundation. A.S. is a recipient of the Lady Tata Memorial Trust Fellowship Award. We would like to thank T. Weaver and M.-D. Filippi for discussions and critical comments on the manuscript. We would like to thank B. Hardie for advice on the erlotinib experiments and the Comprehensive Mouse and Cancer Core as well as the Flow Cytometry Core at CCHMC for help with the experiments and OSI Pharmaceuticals for providing erlotinib.
M.A.R. and H.G. are listed on a patent application [AU: About what aspect of this work?] to the US Patent Office filed by the Cincinnati Children's Hospital Medical Center.
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