Pharmacological inhibition of EGFR signaling enhances G-CSF-induced hematopoietic stem cell mobilization.
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.
Ryan
Marnie A
MA
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, Ohio, USA.
Nattamai
Kalpana J
KJ
Xing
Ellen
E
Schleimer
David
D
Daria
Deidre
D
Sengupta
Amitava
A
Köhler
Anja
A
Liu
Wei
W
Gunzer
Matthias
M
Jansen
Michael
M
Ratner
Nancy
N
Le Cras
Timothy D
TD
Waterstrat
Amanda
A
Van Zant
Gary
G
Cancelas
Jose A
JA
Zheng
Yi
Y
Geiger
Hartmut
H
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
D016179:Granulocyte Colony-Stimulating Factor; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020764:cdc42 GTP-Binding Protein