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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.

journal_name

Nat Med

journal_title

Nature medicine

authors

Ryan MA,Nattamai KJ,Xing E,Schleimer D,Daria D,Sengupta A,Köhler A,Liu W,Gunzer M,Jansen M,Ratner N,Le Cras TD,Waterstrat A,Van Zant G,Cancelas JA,Zheng Y,Geiger H

doi

10.1038/nm.2217

subject

Has Abstract

pub_date

2010-10-01 00:00:00

pages

1141-6

issue

10

eissn

1078-8956

issn

1546-170X

pii

nm.2217

journal_volume

16

pub_type

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