Heparin-binding EGF-like growth factor protects intestinal stem cells from injury in a rat model of necrotizing enterocolitis

Abstract

Necrotizing enterocolitis (NEC) is an often catastrophic disease that typically affects premature newborns. Although the exact etiology of NEC is uncertain, the disease is associated with formula feeding, bacterial colonization of the gut, hypoxia, and hypoperfusion. In light of the pathogenesis of NEC, the integrity and function of the intestinal mucosa plays a major defensive role against the initiation of NEC. Various forms of intestinal injury, including NEC, injure the intestinal epithelial cell (IEC) lineages, including the intestinal stem cells (ISCs), thereby disrupting the normal homeostasis needed to maintain gut barrier function. In the current study we examined the effects of HB-EGF administration on enterocytes, goblet cells, neuroendocrine cells and intestinal stem cells in a newborn rat model of experimental NEC. We also examined the cytoprotective effects of heparin-binding EGF-like growth factor (HB-EGF) on intestinal stem cells in in vitro cell cultures and in ex vivo crypt-villous organoid cultures. We found that HB-EGF protects all intestinal epithelial cell lineages, including intestinal stem cells, from injury. We further found that HB-EGF protects isolated intestinal stem cells from hypoxic injury in vitro, and promotes intestinal stem cell activation and survival, and the expansion of crypt transit amplifying cells, in ex vivo crypt-villous organoid cultures. The protective effects of HB-EGF were dependent upon EGF receptor activation, and were mediated via the MEK1/2 and PI3K signaling pathways. These results demonstrate that the intestinal cytoprotective effects of HB-EGF are mediated, at least in part, through its ability to protect intestinal stem cells from injury.

Toll-like Receptor 4 Is Expressed on Intestinal Stem Cells and Regulates Their Proliferation and Apoptosis via the p53 Up-regulated Modulator of Apoptosis

“…It is tempting to now speculate that TLR4 may play a parallel role in the mammalian host by regulating the oxidative burst or by modifying the JAK-STAT and JNK pathways, which have been shown to play important roles in the regulation of gut stem cells in mice and humans (38,39). Although a large set of extracellular ligands have been shown to govern intestinal stem cell turnover, including Wnt ligands (40 -42) and members of the epidermal growth factor receptor (EGFR) superfamily (43)(44)(45), these findings suggest that lipopolysaccharide and potentially other extracellular bacterial products may be included in this list. We now suggest that at baseline, TLR4 is present on the intestinal stem cells in part to confer a survival advantage to the host in the setting of exposure to bacterial products, and only when TLR4 signaling becomes exaggerated, such as after a hypoxic insult or in the setting of prematurity that characterizes NEC, does TLR4 activation lead to deleterious effects of apoptosis and impaired proliferation.…”

Enteric nervous system abnormalities are present in human necrotizing enterocolitis: potential neurotransplantation therapy

“…Experimental NEC was induced as we have described previously [15,16]. Rat pups were delivered on day 21 of gestation by Cesarean section from timed pregnant rats (Harlan Sprague–Dawley, Indianapolis, IN, USA).…”

ErbB small molecule tyrosine kinase inhibitor (TKI) induced diarrhoea: Chloride secretion as a mechanistic hypothesis

“…Specifically, they are abundantly expressed on the basolateral membranes of healthy intestinal epithelial cells and are crucial for essential normal functions and development in the gut [30,31]. For example, ErbB receptors activated on intestinal epithelial cells cause a cascade of complex signalling pathways resulting in maintenance of mucosal integrity via induction of mucus and prostaglandin synthesis, promotion of enterocyte migration, prevention of intestinal epithelial cell apoptosis, decreasing bacterial translocation and preservation of gut barrier function after injury [32,33].…”