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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / radiation effects
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Apoptosis Regulatory Proteins / biosynthesis
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Bone Marrow / radiation effects
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Bone Marrow Cells / radiation effects
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Cells, Cultured
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Epidermal Growth Factor / metabolism*
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Epidermal Growth Factor / pharmacology*
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ErbB Receptors / antagonists & inhibitors
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ErbB Receptors / metabolism*
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Erlotinib Hydrochloride
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Female
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Hematopoiesis*
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Hematopoietic Stem Cells / physiology
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Hematopoietic Stem Cells / radiation effects*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Protein Kinase Inhibitors / pharmacology
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Quinazolines / pharmacology
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Radiation Injuries, Experimental / drug therapy*
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Regeneration*
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Signal Transduction / radiation effects
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Tumor Suppressor Proteins / biosynthesis
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Whole-Body Irradiation
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bcl-2 Homologous Antagonist-Killer Protein / genetics
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bcl-2-Associated X Protein / genetics
Substances
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Apoptosis Regulatory Proteins
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Bak1 protein, mouse
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Bax protein, mouse
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PUMA protein, mouse
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Protein Kinase Inhibitors
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Quinazolines
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Tumor Suppressor Proteins
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bcl-2 Homologous Antagonist-Killer Protein
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bcl-2-Associated X Protein
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Epidermal Growth Factor
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Erlotinib Hydrochloride
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EGFR protein, mouse
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ErbB Receptors