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


  • Potential conflict of interest: Nothing to report.

  • This work was supported by the Interuniversity Attraction Pole (IAP) Programme (Belgian Science Policy, to O.D., P.C., and F.L.), the D.G. Higher Education and Scientific Research of the French Community of Belgium (to F.L.), the Alphonse and Jean Forton Fund (to O.D. and F.L.), the Fonds de la Recherche Scientifique Médicale (Belgium, to F.L.), the European Community (EUNEFRON, GA#201590, to O.D.), and the National Institutes of Health (DK55534; to L.G.W.). M.P. was a recipient of “Bettencourt Schueller prix d'élan pour la recherche” and “Equipe Fondation pour la Recherche Médicale”. C.E.P. is Senior Research Associate of the FRS-FNRS (Fonds National de la Recherche Scientifique).

  • §

    See Editorial on Page 1795


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. (HEPATOLOGY 2011;)