title: Analysis of liver repair mechanisms in Alagille syndrome and biliary atresia reveals a role for notch signaling.
abstract: Patients with Alagille syndrome (AGS), a genetic disorder of Notch signaling, suffer from severe ductopenia and cholestasis, but progression to biliary cirrhosis is rare. Instead, in biliary atresia (BA) severe cholestasis is associated with a pronounced "ductular reaction" and rapid progression to biliary cirrhosis. Given the role of Notch in biliary development, we hypothesized that defective Notch signaling would influence the reparative mechanisms in cholestatic cholangiopathies. Thus we compared phenotype and relative abundance of the epithelial components of the hepatic reparative complex in AGS (n = 10) and BA (n = 30) using immunohistochemistry and computer-assisted morphometry. BA was characterized by an increase in reactive ductular and hepatic progenitor cells, whereas in AGS, a striking increase in intermediate hepatobiliary cells contrasted with the near absence of reactive ductular cells and hepatic progenitor cells. Hepatocellular mitoinhibition index (p21(waf1)/Ki67) was similar in AGS and BA. Fibrosis was more severe in BA, where portal septa thickness positively correlated with reactive ductular cells and hepatic progenitor cells. AGS hepatobiliary cells failed to express hepatic nuclear factor (HNF) 1beta, a biliary-specific transcription factor. These data indicate that Notch signaling plays a role in liver repair mechanisms in postnatal life: its defect results in absent reactive ductular cells and accumulation of hepatobiliary cells lacking HNF1beta, thus being unable to switch to a biliary phenotype.
authors.affiliation: CeLiveR, Gastroenterology and Liver Transplant Unit, Ospedali Riuniti di Bergamo, Bergamo, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Fabris
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Cadamuro
authors.forename: Maria
authors.initials: M
authors.lastname: Guido
authors.forename: Carlo
authors.initials: C
authors.lastname: Spirli
authors.forename: Romina
authors.initials: R
authors.lastname: Fiorotto
authors.forename: Michele
authors.initials: M
authors.lastname: Colledan
authors.forename: Giuliano
authors.initials: G
authors.lastname: Torre
authors.forename: Daniele
authors.initials: D
authors.lastname: Alberti
authors.forename: Aurelio
authors.initials: A
authors.lastname: Sonzogni
authors.forename: Lajos
authors.initials: L
authors.lastname: Okolicsanyi
authors.forename: Mario
authors.initials: M
authors.lastname: Strazzabosco
mesh_terms: D000293:Adolescent; D000328:Adult; D016738:Alagille Syndrome / Q000378:metabolism / Q000473:pathology*; D001656:Biliary Atresia / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D002648:Child; D002675:Child, Preschool; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis; D005260:Female; D051539:Hepatocyte Nuclear Factor 1-beta / Q000032:analysis; D022781:Hepatocytes / Q000737:chemistry / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D053539:Keratin-19 / Q000032:analysis; D053552:Keratin-7 / Q000032:analysis; D019394:Ki-67 Antigen / Q000032:analysis; D008099:Liver / Q000737:chemistry / Q000473:pathology* / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology; D008115:Liver Regeneration; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D051880:Receptors, Notch / Q000502:physiology*; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000502:physiology
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C496495:HNF1B protein, human; D053539:Keratin-19; D053552:Keratin-7; D019394:Ki-67 Antigen; D051880:Receptors, Notch; D051539:Hepatocyte Nuclear Factor 1-beta