title: Pharmacological inhibition of EGFR signaling enhances G-CSF-induced hematopoietic stem cell mobilization.
abstract: 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. 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. 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.
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, Ohio, USA.
authors.forename: Marnie A
authors.initials: MA
authors.lastname: Ryan
authors.forename: Kalpana J
authors.initials: KJ
authors.lastname: Nattamai
authors.forename: Ellen
authors.initials: E
authors.lastname: Xing
authors.forename: David
authors.initials: D
authors.lastname: Schleimer
authors.forename: Deidre
authors.initials: D
authors.lastname: Daria
authors.forename: Amitava
authors.initials: A
authors.lastname: Sengupta
authors.forename: Anja
authors.initials: A
authors.lastname: Köhler
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Matthias
authors.initials: M
authors.lastname: Gunzer
authors.forename: Michael
authors.initials: M
authors.lastname: Jansen
authors.forename: Nancy
authors.initials: N
authors.lastname: Ratner
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Le Cras
authors.forename: Amanda
authors.initials: A
authors.lastname: Waterstrat
authors.forename: Gary
authors.initials: G
authors.lastname: Van Zant
authors.forename: Jose A
authors.initials: JA
authors.lastname: Cancelas
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.forename: Hartmut
authors.initials: H
authors.lastname: Geiger
mesh_terms: D000818:Animals; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000502:physiology; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D015398:Signal Transduction; D020764:cdc42 GTP-Binding Protein / Q000502:physiology
chemical_list: D016179:Granulocyte Colony-Stimulating Factor; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020764:cdc42 GTP-Binding Protein