Activation of the developmental pathway neurogenin-3/microRNA-7a regulates cholangiocyte proliferation in response to injury

• DOI: 10.1002/hep.27262
• Publication Date: 2014-06-13T07:58:03Z
• Authors: Marco Marzioni; Laura Agostinelli; Cinzia Candelaresi; Stefania Saccomanno; Samuele De Minicis; Luca Maroni; Eleonora Mingarelli; Chiara Rychlicki; Luciano Trozzi; Jesus M. Banales; Antonio Benedetti; Gianluca Svegliat...
• Keywords: Cholangiocyte

The activation of the biliary stem-cell signaling pathway hairy and enhancer split 1/pancreatic duodenal homeobox-1 (Hes-1/PDX-1) in mature cholangiocytes determines cell proliferation. Neurogenin-3 (Ngn-3) is required for pancreas development ductal neogenesis. PDX-1-dependent Ngn-3 initiates differentiation program by inducing microRNA (miR)−7 expression. Here we investigated role on cholangiocyte Expression levels miR-7 isoforms were tested from normal cholestatic human livers. was knocked-down vitro rat short interfering RNA (siRNA). In vivo , wild-type Ngn-3-heterozygous (+/−) mice subjected to 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding (a model sclerosing cholangitis) or bile duct ligation (BDL). liver, expressed specifically primary cholangitis (PSC) patients DDC BDL, but not mouse miR-7a-1 miR-7a-2 isoforms, miR-7b, increased compared ones. cholangiocytes, siRNA against blocked proliferation stimulated exendin-4. addition, knockdown neutralized overexpression insulin growth factor-1 (IGF1; promitotic effector) observed after exposure exendin-4, that PDX-1 VEGF-A/C. Oligonucleotides anti-miR-7 inhibited exendin-4-induced did affect synthesis. Biliary hyperplasia collagen deposition induced BDL significantly reduced +/− wild-type. Conclusion : Ngn-3-dependent miR-7a a determinant These findings indicate reacquisition molecular profile typical organ essential biological response injury cholangiocytes. (Hepatology 2014;60:1324–1335)