A classification of ductal plate malformations based on distinct pathogenic mechanisms of biliary dysmorphogenesis.

Abstract

UNLABELLED:

Ductal plate malformations (DPMs) are developmental anomalies considered to result from lack of ductal plate remodeling during bile duct morphogenesis. In mice, bile duct development is initiated by the formation of primitive ductal structures lined by two cell types, namely ductal plate cells and hepatoblasts. During ductal plate remodeling, the primitive ductal structures mature to ducts as a result from differentiation of the ductal plate cells and hepatoblasts to cholangiocytes. Here, we report this process is conserved in human fetal liver. These findings prompted us to evaluate how DPMs develop in three mouse models, namely mice with livers deficient in hepatocyte nuclear factor 6 (HNF6), HNF1β, or cystin-1 (cpk [congenital polycystic kidney] mice). Human liver from a patient with a HNF1B/TCF2 mutation, and from fetuses affected with autosomal recessive polycystic kidney disease (ARPKD) were also analyzed. Despite the epistatic relationship between HNF6, HNF1β, and cystin-1, the three mouse models displayed distinct morphogenic mechanisms of DPM. They all developed biliary cysts lined by cells with abnormal apicobasal polarity. However, the absence of HNF6 led to an early defect in ductal plate cell differentiation. In HNF1β-deficient liver, maturation of the primitive ductal structures was impaired. Normal differentiation and maturation but abnormal duct expansion was apparent in cpk mouse livers and in human fetal ARPKD.

CONCLUSION:

DPM is the common endpoint of distinct defects initiated at distinct stages of bile duct morphogenesis. Our observations provide a new pathogenic classification of DPM.

• Authors: Peggy Raynaud, Joshua Tate, Céline Callens, Sabine Cordi, Patrick Vandersmissen, Rodolphe Carpentier, Christine Sempoux, Olivier Devuyst, Christophe E Pierreux, Pierre Courtoy, Karin Dahan, Katty Delbecque, Sébastien Lepreux, Marco Pontoglio, Lisa M Guay-Woodford, Frédéric P Lemaigre
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 53 Issue 6 Pg. 1959-66 (Jun 2011) ISSN: 1527-3350 [Electronic] United States
• PMID: 21391226 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 American Association for the Study of Liver Diseases.

Chemical References

• Biomarkers
• Cys1 protein, mouse
• HNF1B protein, human
• Hepatocyte Nuclear Factor 6
• Hnf1b protein, mouse
• Membrane Proteins
• Onecut1 protein, mouse
• Hepatocyte Nuclear Factor 1-beta

Topics

• Animals
• Bile Ducts, Intrahepatic (abnormalities, embryology, pathology)
• Biomarkers (metabolism)
• Cell Differentiation (physiology)
• Congenital Abnormalities (classification, etiology, physiopathology)
• Disease Models, Animal
• Hepatocyte Nuclear Factor 1-beta (metabolism)
• Hepatocyte Nuclear Factor 6 (metabolism)
• Humans
• Liver (embryology, metabolism, pathology)
• Membrane Proteins (metabolism)
• Mice
• Mice, Mutant Strains
• Morphogenesis (physiology)
• Polycystic Kidney Diseases (congenital, metabolism, physiopathology)
• Polycystic Kidney, Autosomal Recessive (metabolism, physiopathology)