Heparin-Binding EGF-like Growth Factor and Enteric Neural Stem Cell Transplantation in the Prevention of Experimental Necrotizing Enterocolitis

BACKGROUND: Necrotizing enterocolitis (NEC) is associated with loss of neurons and glial cells in the enteric nervous system (ENS). Our goal was to determine whether enteric neural stem cell (NSC) transplantation, in conjunction with heparin binding-epidermal growth factor-like growth factor (HB-EGF), could protect against experimental NEC. METHODS: In vitro, HB-EGF effect on NSC proliferation and migration, and the receptors utilized by HB-EGF to exert these effects, were determined. In vivo, mouse pups were exposed to experimental NEC and treated with either NSC alone, HB-EGF alone, NSC+HB-EGF, or HB-EGF over-expressing NSC. NSC engraftment and differentiation into neurons in the ENS, intestinal injury, intestinal permeability and intestinal motility were determined. RESULTS: HB-EGF promotes NSC proliferation via ErbB-1 receptors and enhances NSC migration via ErbB-1, ErbB-4 and Nardilysin receptors. HB-EGF significantly enhanced the engraftment of transplanted NSC into the ENS during NEC. NSC transplantation significantly reduced NEC incidence and improved gut barrier function and intestinal motility, and these effects were augmented by simultaneous administration of HB-EGF or by transplantation of HB-EGF-over-expressing NSC. CONCLUSIONS: HB-EGF promotes NSC proliferation and migration. HB-EGF and NSC reduce intestinal injury and improve gut barrier function and intestinal motility in experimental NEC. Combined HB-EGF and NSC transplantation may represent a potential future therapy to prevent NEC.