Heparin-Binding Epidermal Growth Factor-Like Growth Factor: Hypoxia-Inducible ExpressionIn Vitroand Stimulation of NeurogenesisIn VitroandIn Vivo

Abstract

Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) is found in cerebral neurons, and its expression is increased after hypoxic or ischemic injury, which also stimulates neurogenesis. To investigate the possible role of HB-EGF in hypoxic-ischemic induction of neurogenesis, we measured its expression, effects, and target receptors in embryonic murine cerebral cortical cultures and in adult rat brain. Hypoxia increased HB-EGF expression by approximately 50% in cortical cultures, where expression was associated with mature and immature neurons. HB-EGF (5-100 ng/ml) stimulated by approximately 80% the incorporation of bromodeoxyuridine (BrdU) into cultured cells that expressed the HB-EGF receptors epidermal growth factor receptor (EGFR)/avian erythroblastic leukemia viral oncogene homolog 1 (ErbB1) and N-arginine dibasic convertase (NRDc). Intracerebroventricular administration of HB-EGF in adult rats increased BrdU labeling in the subventricular zone and in the subgranular zone of dentate gyrus, where EGFR/ErbB1 and NRDc were also expressed and where ischemia-induced neurogenesis is observed. We conclude that HB-EGF stimulates neurogenesis in proliferative zones of the adult brain that are also affected in ischemia and that it does so by interacting with EGFR/ErbB1 and possibly NRDc. Therefore, HB-EGF may help to trigger proliferation of neuronal precursors in brain after hypoxic or ischemic injury.

ADAM-17/Tumor Necrosis Factor-α-Converting Enzyme Inhibits Neurogenesis and Promotes Gliogenesis from Neural Stem Cells

“…Although the mechanism is not fully understood, the concomitance of the two EGFR states within the SVZ is probably implemented by a specific spatial organization allowing the creation of microdomains where either proliferation or differentiation takes place preferentially, as it has been well documented for the generation of blood cells from hematopoietic precursors in the bone marrow [63]. This hypothesis is supported by a series of experiments showing that when EGF, TGF-a, or HB-EGF are infused into the cerebral ventricles, exposing the whole SVZ to nonphysiological concentrations of EGFR ligands, there is an expansion of the SVZ with increased proliferation of nestin-expressing cells, increased migration of progenitors toward surrounding regions [24,26,33,64], and preferential differentiation into astrocytes [26,27] and oligodendrocytes [28,65]. A similar situation has been reported in a rat model of cerebral ischemia, in which ADAM-17 was upregulated in the SVZ and produced an expansion of the proliferating NPCs without increased neurogenesis [44].…”

Reduced EGFR signaling in progenitor cells of the adult subventricular zone attenuates oligodendrogenesis after demyelination

“…Growth factors that are secreted by endothelial cells (Gama Sosa et al, 2007;Rosenstein and Krum, 2006) as well as by other glial cells (Aschner, 1996;Suzumura et al, 2006;Sen and Levison, 2006) during development and under pathological conditions (Ferrer et al, 1996;Lisovoski et al, 1997;Jin et al, 2002;Covey and Levison, 2007) are crucial regulators of progenitor cell mobilization. Previous reports demonstrated upregulation of several growth factors in the CC after demyelination, including HB-EGF and TGF-alpha (Ferrer et al, 1996;Lisovoski et al, 1997;Aguirre et al, 2007).…”

Changes of cell proliferation and differentiation in the developing brain of mouse

“…The mice's genetical deficiency in bFGF exhibit a significant reduction of neurogenesis [13,14] . Heparin-binding epidermal growth factor (HB-EGF) can stimulate the neurogenesis [15] . Furthermore, the increase of brain-derived neurotrophic factor (BDNF), erythropoietin, or EGF may augment neurogenesis [16][17][18] .…”