BACKGROUND AND AIMS: Repair from biliary damages requires the biliary specification of hepatic progenitor cells and the remodeling of ductular reactive structures into branching biliary tubules. We hypothesized that the morphogenetic role of Notch signaling is maintained during the repair process and have addressed this hypothesis using pharmacologic and genetic models of defective Notch signaling. METHODS AND RESULTS: Treatment with DDC (3,5-diethoxycarbonyl1,4-dihydrocollidine) or ANIT (alpha-naphthyl-isothiocyanate) was used to induce biliary damage in wild-type mice and in mice with a liver-specific defect in the Notch-2 receptor (Notch-2-cko) or in RPB-Jk. Hepatic progenitor cells, ductular reaction and mature ductules were quantified using K19 and SOX-9. In DDC-treated wild-type mice, pharmacologic Notch inhibition with dibenzazepine decreased the number of both ductular reaction and hepatic progenitor cells. Notch-2-cko mice treated with DDC or ANIT accumulated hepatic progenitor cells that failed to progress into mature ducts. In RBP-Jκ-cko mice, mature ducts and hepatic progenitor cells were both significantly reduced with respect to similarly treated wild-type mice. The mouse progenitor cell line BMOL cultured on Matrigel, formed a tubular network allowing the study of tubule formation in vitro; γ-secretase inhibitor treatment and siRNAs silencing of Notch-1, Notch2 or Jagged1 significantly reduced both the length and the number of tubular branches. CONCLUSIONS: These data demonstrate that Notch signaling plays an essential role in biliary repair. Lack of Notch-2 prevents biliary tubule formation, both in vivo and in vitro. Lack of RBP-Jk inhibits the generation of biliary-committed precursors and tubule formation.
Fiorotto, R., Raizner, A., Morell, C., Torsello, B., Scirpo, R., Fabris, L., et al. (2013). Notch signaling regulates tubular morphogenesis during repair from biliary damage in mice. JOURNAL OF HEPATOLOGY, 59(1), 124-130 [10.1016/j.jhep.2013.02.025].
|Citazione:||Fiorotto, R., Raizner, A., Morell, C., Torsello, B., Scirpo, R., Fabris, L., et al. (2013). Notch signaling regulates tubular morphogenesis during repair from biliary damage in mice. JOURNAL OF HEPATOLOGY, 59(1), 124-130 [10.1016/j.jhep.2013.02.025].|
|Tipo:||Articolo in rivista - Articolo scientifico|
|Carattere della pubblicazione:||Scientifica|
|Presenza di un coautore afferente ad Istituzioni straniere:||Si|
|Titolo:||Notch signaling regulates tubular morphogenesis during repair from biliary damage in mice|
|Autori:||Fiorotto, R; Raizner, A; Morell, C; Torsello, B; Scirpo, R; Fabris, L; Spirli, C; Strazzabosco, M|
STRAZZABOSCO, MARIO (Ultimo)
|Data di pubblicazione:||2013|
|Rivista:||JOURNAL OF HEPATOLOGY|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.jhep.2013.02.025|
|Appare nelle tipologie:||01 - Articolo su rivista|