Gallbladder wall abnormality in biliary atresia of mouse Sox17+/- neonates and human infants

Biliary atresia (BA) is characterized by the inflammation and obstruction of the extrahepatic bile ducts (EHBDs) in newborn infants. SOX17 is a master regulator of the fetal EHBDs formation. In mouse Sox17+/- BA models, SOX17 reduction causes cell-autonomous epithelial shedding together with the ectopic appearance of SOX9-positive cystic duct-like epithelia in the gallbladder walls, resulting in the BA-like symptoms during the perinatal period. However, the similarities with the human BA gallbladders are still unclear. In the present study, we conducted the phenotypic analysis with the Sox17+/- BA neonate mice, in order to compare with the gallbladder wall phenotype of human BA infants. The most characteristic phenotype of the Sox17+/- BA gallbladders is the ectopic appearance of SOX9-positive peribiliary glands (PBGs), so-called pseudopyloric glands (PPGs). Next we examined SOX17/SOX9 expression profiles of human gallbladders in thirteen BA infants. Among them, five BA cases showed a loss or drastic reduction of SOX17-positive signals throughout the whole region of gallbladder epithelia (SOX17-low group). Even in the remaining eight gallbladders (SOX17-high group), the epithelial cells near the decidual sites were frequently reduced in the SOX17-positive signal intensity. Most interestingly, the most characteristic phenotype of human BA gallbladders is the increased density of PBG/PPG-like glands in the gallbladder body, especially near the epithelial decidual site, indicating the PBG/PPG formation as a common phenotype between human BA and mouse Sox17+/- BA gallbladders. These findings provide the first evidence of the potential contribution of SOX17 reduction and PBG/PPG formation to the early pathogenesis in human BA gallbladders.