2 It is proposed that the condition of DPM arises from a persistence or lack of remodeling of the embryonic ductal plate normally observed during IHBD formation. ARPKD, autosomal recessive polycystic kidney disease;

DPM, ductal plate malformation; HNF, hepatocyte nuclear factor; IHBD, intrahepatic bile duct; PDS, primitive ductal structure; SOX9, SRY-related HMG box transcription factor 9; TβRII, transforming growth factor receptor type II; ZO-1, zonula occludens-1. From a developmental point of view, the cells that contribute to the IHBD system are a subpopulation of hepatoblast bipotential progenitors located near portal veins. This subpopulation of hepatoblasts forms a band of potential cholangiocytes, termed a ductal plate, encircling the portal veins. Remodeling of ductal plates into IHBDs start at the oldest ductal plates surrounding the larger BTK pathway inhibitor portal veins near the hilum and is thought to move toward the periphery of liver following the portal vein system. The ductal plate cells

that remain unincorporated into an IHBD then involute. If the unincorporated ductal plate cells do not receive or are deaf to the proper signals, they may contribute BYL719 to DPM. Thus, there is a level of coordination that must regulate sequential tubulogenesis and regression of the ductal plates along portal veins within the three-dimensional space of the liver Unoprostone to connect the entire IHBD system to the extrahepatic ductal system. This indicates that careful orchestration of signals between epithelial and mesenchymal cells is required to guide IHBD formation.3 In this issue of HEPATOLOGY, the report by Raynaud et al.4 gives the general term DPM a new set of classifications according

to distinct defects in biliary tubulogenesis. This article reassesses how DPM observed in human congenital liver disease might result from various tubulogenesis defects in light of a defined transient asymmetry step identified during the process of mouse IHBD maturation.5 This step delineates the structure surrounding a forming lumen as either a primitive ductal structure (PDS) or a mature duct. PDS is composed of two cell types as distinguished by the presence or absence of marker expression (SRY-related HMG box transcription factor 9 [SOX9], hepatocyte nuclear factor 4 [HNF4], and transforming growth factor receptor type II [TβRII]) compared to a mature duct. The PDS is asymmetrical; cells on the portal vein side of the lumen express the marker SOX9, compared to cells on the parenchymal side that express HNF4 and TβRII. A mature duct is symmetrical, composed of cells expressing SOX9. To evaluate DPM, the authors focused their investigation on differentiation, polarity, and ciliogenesis in mouse models and human cases of DPM. Raynaud et al.