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Epidermal growth factor regulates hematopoietic regeneration after radiation injury.
Abstract
The mechanisms that regulate hematopoietic stem cell (HSC) regeneration after myelosuppressive
injury are not well understood. We identified epidermal growth factor (EGF) to be
highly enriched in the bone marrow serum of mice bearing deletion of Bak and Bax in
TIE2-expressing cells in Tie2Cre; Bak1(-/-); Bax(flox/-) mice. These mice showed radioprotection
of the HSC pool and 100% survival after a lethal dose of total-body irradiation (TBI).
Bone marrow HSCs from wild-type mice expressed functional EGF receptor (EGFR), and
systemic administration of EGF promoted the recovery of the HSC pool in vivo and improved
the survival of mice after TBI. Conversely, administration of erlotinib, an EGFR antagonist,
decreased both HSC regeneration and the survival of mice after TBI. Mice with EGFR
deficiency in VAV-expressing hematopoietic cells also had delayed recovery of bone
marrow stem and progenitor cells after TBI. Mechanistically, EGF reduced radiation-induced
apoptosis of HSCs and mediated this effect through repression of the proapoptotic
protein PUMA. Our findings show that EGFR signaling regulates HSC regeneration after
myelosuppressive injury.
Type
Journal articleSubject
AnimalsApoptosis
Apoptosis Regulatory Proteins
Bone Marrow
Bone Marrow Cells
Cells, Cultured
Epidermal Growth Factor
Erlotinib Hydrochloride
Female
Hematopoiesis
Hematopoietic Stem Cells
Mice
Mice, Inbred C57BL
Mice, Knockout
Protein Kinase Inhibitors
Quinazolines
Radiation Injuries, Experimental
Receptor, Epidermal Growth Factor
Regeneration
Signal Transduction
Tumor Suppressor Proteins
Whole-Body Irradiation
bcl-2 Homologous Antagonist-Killer Protein
bcl-2-Associated X Protein
Permalink
https://hdl.handle.net/10161/14156Published Version (Please cite this version)
10.1038/nm.3070Publication Info
Doan, Phuong L; Himburg, Heather A; Helms, Katherine; Russell, J Lauren; Fixsen, Emma;
Quarmyne, Mamle; ... Chute, John P (2013). Epidermal growth factor regulates hematopoietic regeneration after radiation injury.
Nat Med, 19(3). pp. 295-304. 10.1038/nm.3070. Retrieved from https://hdl.handle.net/10161/14156.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Nelson Jen An Chao
Donald D. and Elizabeth G. Cooke Cancer Distinguished Research Professor
My research interests are in two broad areas, clinical hematopoietic stem cell and
cord blood transplantation and in the laboratory studies related to graft vs. host
disease and immune reconstitution. On the clinical side we are currently conducting
approximately 50 different clinical protocols ranging from preparatory regimens, supportive
care studies and disease specific protocols. Most of these clinical studies are centered
around studies of the sources of stem cells and the methods to
John Patrick Chute
Adjunct Professor in the Department of Medicine
Phuong Linh Doan
Associate Professor of Medicine
Emma Fixsen
Assistant Professor of Dermatology
David Guy Kirsch
Barbara Levine University Distinguished Professor
My clinical interests are the multi-modality care of patients with bone and soft tissue
sarcomas and developing new sarcoma therapies. My laboratory interests include utilizing
mouse models of cancer to study cancer and radiation biology in order to develop new
cancer therapies in the pre-clinical setting.
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