title: 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.
authors: Department of Medicine, Division of Hematologic Malignancies and Cellular Therapy, Durham, North Carolina, USA.
authors: Phuong L
authors: PL
authors: Doan
authors: Heather A
authors: HA
authors: Himburg
authors: Katherine
authors: K
authors: Helms
authors: J Lauren
authors: JL
authors: Russell
authors: Emma
authors: E
authors: Fixsen
authors: Mamle
authors: M
authors: Quarmyne
authors: Jeffrey R
authors: JR
authors: Harris
authors: Divino
authors: D
authors: Deoliviera
authors: Julie M
authors: JM
authors: Sullivan
authors: Nelson J
authors: NJ
authors: Chao
authors: David G
authors: DG
authors: Kirsch
authors: John P
authors: JP
authors: Chute
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D001853:Bone Marrow / Q000528:radiation effects; D001854:Bone Marrow Cells / Q000528:radiation effects; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000378:metabolism* / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D005260:Female; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000502:physiology / Q000528:radiation effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D011833:Radiation Injuries, Experimental / Q000188:drug therapy*; D012038:Regeneration; D015398:Signal Transduction / Q000528:radiation effects; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis; D014916:Whole-Body Irradiation; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; C488588:PUMA protein, mouse; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D025521:Tumor Suppressor Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D004815:Epidermal Growth Factor; D000069347:Erlotinib Hydrochloride; C541485:EGFR protein, mouse; D066246:ErbB Receptors
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