Epidermal growth factor regulates hematopoietic regeneration after radiation injury

Abstract

The mechanisms which regulate HSC regeneration following myelosuppressive injury are not well understood. We identified epidermal growth factor (EGF) to be highly enriched in the bone marrow (BM) serum of mice bearing deletion of Bak and Bax in Tie2+ cells (Tie2Cre;Bak1−/−;Baxfl/− mice), which displayed radioprotection of the HSC pool and 100% survival following lethal dose total body irradiation (TBI). BM HSCs from wild type mice expressed functional EGFR and systemic administration of EGF promoted the recovery of the HSC pool in vivo and the improved survival of mice following TBI. Conversely, administration of erlotinib, an EGFR antagonist, significantly decreased both HSC regeneration and mice survival following TBI. VavCre;EGFRfl/+ mice also demonstrated delayed recovery of BM stem/progenitor cells following TBI compared to VavCre;EGFR+/+ mice. Mechanistically, EGF reduced radiation-induced apoptosis of HSCs and mediated this effect via repression of the proapoptotic protein, PUMA. EGFR signaling regulates HSC regeneration following myelosuppressive injury.

Loss of β-catenin triggers oxidative stress and impairs hematopoietic regeneration

“…This set of genes included several implicated in self-renewal and regeneration. For example, loss of b-catenin led to a significant twofold to threefold down-regulation of EGF and EGFR (Doan et al 2013), Jag1 (Neves et al 2006), Xray radiation resistance associated 1 (Xrra-1) (Mesak et al 2003), and the Aryl hydrocarbon receptor (Ahr) (Casado et al 2011). Interestingly, the deletion of b-catenin triggered a down-regulation of catalase (Fig.…”

Transmembrane protein 88: a Wnt regulatory protein that specifies cardiomyocyte development

“…Development 140 (18) Bioinformatics analysis of gene ontology show that gene clusters greater than twofold upregulated in the TMEM88 KD cells included the Notch signaling pathway (Kim et al, 2013), EGF signaling (Doan et al, 2013), regulation of cell proliferation, mesenchymal and mesodermal developmental, and, most interestingly, genes involved in hematopoiesis and blood vessel development (supplementary material Table S6). The endothelial potential of these cells was validated by qPCR of specific genes involved in development of hemato-endothelial lineages (Fig.…”

Protein tyrosine phosphatase–σ regulates hematopoietic stem cell–repopulating capacity

“…RTKs regulate the maintenance, differentiation, and malignant transformation of hematopoietic stem cells (HSCs) (1)(2)(3)(4)(5). The activity of RTKs is counterbalanced through the action of receptor protein tyrosine phosphatases (PTPs), which dephosphorylate receptor and intracellular kinases (6,7).…”