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

摘要

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 fetal EHBD 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 BA-like symptoms during the perinatal period. However, the similarities with human BA gallbladders are still unclear. In the present study, we conducted phenotypic analysis of 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 13 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 that PBG/PPG formation is 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 of human BA gallbladders. This article has an associated First Person interview with the joint first authors of the paper. RESULTS Increased density of PBG/PPG-like glands in the gallbladder wall of Sox17 /? neonates In the Sox17 /? mouse BA model, the ectopic appearance of cystic duct-like epithelia in the gallbladder domain occurs during the fetal stages before the first secretion of bile fluid from the fetal liver [by 15.5?days post-coitum (dpc); Uemura et al., 2013 ; Higashiyama et al., 2017 ]. One prominent histological character of the cystic duct walls is the PBGs, which are formed in EHBDs but not the gallbladder (see review by de Jong et al., 2018 ). First, we observed the normal development patterns of PBGs in the gallbladder and cystic duct regions of wild-type mouse neonates ( Fig.?1 ). Whole-mount Dolichos biflorus agglutinin (DBA) staining visualized the epithelial architecture of the gallbladder and cystic duct of the EHBDs isolated from 18.5 dpc to 7?days post-partum (dpp) ( Fig.?1 A-C). In the cystic duct region, as well as in the gallbladder, PBG structures were not identified in the wild-type embryos before birth. PBG-like bud structures first arose in the cystic duct region at 0?dpp (arrowheads in lower plates of Fig.?1 A). Subsequently, the complete PBGs were rapidly formed in the cystic duct region from 1 to 7?dpp ( Fig.?1 A; right plates in Fig.?1 B). In contrast, long and narrow epithelial folds were formed along the proximal-to-distal axis of the developing gallbladder (upper plates in Fig.?1 A; right plates in Fig.?1 C), and PBG-like structures could be rarely found in the wild-type gallbladder at 1-7 dpp.