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

• Published in: Laboratory investigation 2012-03, Vol.92 (3), p.331-344
• Main Authors: Chen, Chun-Liang, Yu, Xiaoyi, James, Iyore O-A, Zhang, Hong-yi, Yang, Jingyuan, Radulescu, Andrei, Zhou, Yu, Besner, Gail E
• Format: Article
• Language: English
• Subjects: AC133 Antigen; Animals; Animals, Newborn; Antigens, CD - metabolism; Biological and medical sciences; Biotechnology; Cell Survival; Disease Models, Animal; Drug Evaluation, Preclinical; Enterocolitis, Necrotizing - drug therapy; Enterocytes - drug effects; epithelial cells; ErbB Receptors - metabolism; Female; Fundamental and applied biological sciences. Psychology; Gastroenterology. Liver. Pancreas. Abdomen; Glycoproteins - metabolism; Goblet Cells - drug effects; HB-EGF; Heparin-binding EGF-like Growth Factor; Hypoxia - metabolism; Hypoxia - pathology; Intercellular Signaling Peptides and Proteins - pharmacology; Intercellular Signaling Peptides and Proteins - therapeutic use; intestine; Intestines - pathology; Investigative techniques, diagnostic techniques (general aspects); Laboratory Medicine; LGR5; MAP Kinase Signaling System; Medical sciences; Medicine; Medicine & Public Health; Neuroendocrine Cells - drug effects; Other diseases. Semiology; Pathology; Peptides - metabolism; Pregnancy; prominin-1; Rats; Rats, Sprague-Dawley; research-article; stem cells; Stem Cells - drug effects; Stem Cells - metabolism; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/labinvest.2011.167

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 has 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 heparin-binding EGF-like growth factor (HB-EGF) administration on enterocytes, goblet cells, neuroendocrine cells and ISCs in a newborn rat model of experimental NEC. We also examined the cytoprotective effects of HB-EGF on ISCs in in vitro cell cultures and in ex vivo crypt-villous organoid cultures. We found that HB-EGF protects all IEC lineages, including ISCs, from injury. We further found that HB-EGF protects isolated ISCs from hypoxic injury in vitro, and promotes ISC 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 on EGF receptor activation, and were mediated via the MEK1/2 and PI3K signaling pathways. These results show that the intestinal cytoprotective effects of HB-EGF are mediated, at least in part, through its ability to protect ISCs from injury.