Notch signaling regulates tubular morphogenesis during repair from biliary damage in mice

Romina Fiorotto, Aileen Raizner, Carola M. Morell, Barbara Torsello, Roberto Scirpo, Luca Fabris, Carlo Spirli, Mario Strazzabosco

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

Background & 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 Treatment with DDC (3,5-diethoxycarbonyl-1,4- 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. Results 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-Jk-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, Notch-2 or Jagged-1 significantly reduced both the length and 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.

Original languageEnglish (US)
Pages (from-to)124-130
Number of pages7
JournalJournal of Hepatology
Volume59
Issue number1
DOIs
StatePublished - Jul 1 2013
Externally publishedYes

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Keywords

  • Alagille syndrome
  • Cholangiocytes
  • Ductular reaction
  • GSI
  • Liver repair
  • Notch signaling

ASJC Scopus subject areas

  • Hepatology

Cite this

Fiorotto, R., Raizner, A., Morell, C. M., Torsello, B., Scirpo, R., Fabris, L., Spirli, C., & Strazzabosco, M. (2013). Notch signaling regulates tubular morphogenesis during repair from biliary damage in mice. Journal of Hepatology, 59(1), 124-130. https://doi.org/10.1016/j.jhep.2013.02.025