title: PDX-1/Hes-1 interactions determine cholangiocyte proliferative response to injury in rodents: possible implications for sclerosing cholangitis.
abstract: OBJECTIVE
  Cholangiocyte proliferation plays a role in the progression of cholangiopathies, in particular in primary sclerosing cholangitis. The mechanisms regulating cholangiocyte proliferation are still undefined. Pancreatic Duodenal Homeobox protein 1 (PDX-1) is expressed by reactive cholangiocytes. In the adult pancreas, PDX-1 regulates the proliferative response to injury of ductal cells. Its effects can be counteracted by Hairy and enhancer of split 1 (Hes-1). We aimed at studying whether PDX-1/Hes-1 interactions regulate cholangiocyte proliferation in response to injury.
  
  
  METHODS
  The effect of the loss of PDX-1 on cholangiocyte proliferation was studied in vitro. In vivo PDX-1-heterozygous (+/-) mice were subjected to either DDC feeding (a model of sclerosing cholangitis) or to bile duct ligation (BDL). PDX-1/Hes-1 interactions on cell proliferation were determined by exposure to All-trans Retinoic Acid (At-RA), an inductor of Hes-1.
  
  
  RESULTS
  In vitro, cholangiocyte proliferation was undetectable in cells pre-treated with PDX-1 siRNA. In vivo, increases in bile duct mass and collagen deposition observed after DDC feeding or BDL were significantly reduced in PDX-1(+/-) mice. Hes-1 expression is reduced in proliferating cholangiocytes; At-RA induced a dose-dependent increase in Hes-1 and a decrease in PDX-1 expression. At-RA neutralized the increases in PDX-1 expression and cell proliferation, both in vitro and in vivo in DDC mice. PDX-1 is overexpressed and Hes-1 downregulated in cholangiocytes isolated from PSC livers.
  
  
  CONCLUSIONS
  Hes-1 downregulation allows PDX-1 to act as a major determinant of cholangiocyte proliferation in response to cholestatic injury. These findings provide novel mechanistic insights into the pathophysiology of cholangiopathies.
authors.affiliation: Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy. m.marzioni@univpm.it
authors.forename: Marco
authors.initials: M
authors.lastname: Marzioni
authors.forename: Stefania
authors.initials: S
authors.lastname: Saccomanno
authors.forename: Laura
authors.initials: L
authors.lastname: Agostinelli
authors.forename: Chiara
authors.initials: C
authors.lastname: Rychlicki
authors.forename: Samuele
authors.initials: S
authors.lastname: De Minicis
authors.forename: Irene
authors.initials: I
authors.lastname: Pierantonelli
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
authors.forename: Peter
authors.initials: P
authors.lastname: Fickert
authors.forename: Tobias
authors.initials: T
authors.lastname: Müller
authors.forename: Kumar
authors.initials: K
authors.lastname: Shanmukhappa
authors.forename: Luciano
authors.initials: L
authors.lastname: Trozzi
authors.forename: Cinzia
authors.initials: C
authors.lastname: Candelaresi
authors.forename: Gianluca Svegliati
authors.initials: GS
authors.lastname: Baroni
authors.forename: Antonio
authors.initials: A
authors.lastname: Benedetti
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001659:Biliary Tract / Q000293:injuries / Q000378:metabolism* / Q000473:pathology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D015209:Cholangitis, Sclerosing / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D015870:Gene Expression; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000072056:Transcription Factor HES-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D015534:Trans-Activators; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse; C084010:pancreatic and duodenal homeobox 1 protein