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−/−; Baxflox/– 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.
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This work was supported in part by National Heart, Lung and Blood Institute grant HL-086998-01 (J.P.C.), National Institute of Allergy and Infectious Diseases (NIAID) grant AI-067798-06 (J.P.C.) and a pilot project from the NIAID Centers for Medical Countermeasures grant AI-067798-01 (D.G.K.). P.L.D. was supported by US National Institutes of Health training grant T32 HL0070757-33, the Barton Haynes Award and a Duke Cancer Center Seed Grant (Duke University).
The authors declare no competing financial interests.
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Doan, P., Himburg, H., Helms, K. et al. Epidermal growth factor regulates hematopoietic regeneration after radiation injury. Nat Med 19, 295–304 (2013). https://doi.org/10.1038/nm.3070
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