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

Mami Uemura,Takashi Yao,Masami Kanai-Azuma,Yoshiakira Kanai,Hiroki Higashiyama,Shohei Takami,Yuki Fukumura,Mayumi Higashi,Naoki Ichikawa,Montri Pattarapanawan,Tatsuro Tajiri,Taizo Furukawa,Jun Fujishiro

doi:10.1242/dmm.042119

Abstract

ABSTRACTBiliary 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.

Highlights

Biliary atresia (BA) occurs in one out of every 10,000–15,000 live births, and causes bile duct inflammation owing to the blockage of bile flow during the perinatal period (Hartley et al, 2009; Mieli-Vergani and Vergani, 2009)
We conducted the phenotypic analysis with the SRY-related HMG box factor-17 (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)

Summary

Introduction

Biliary atresia (BA) occurs in one out of every 10,000–15,000 live births, and causes bile duct inflammation owing to the blockage of bile flow during the perinatal period (Hartley et al, 2009; Mieli-Vergani and Vergani, 2009). The “perinatal” form mainly consists of the “isolated” BA, the largest group with neither clear etiology nor any appreciable defects in other tissues/organs except for the bile ducts (Kelay and Davenport, 2017). Despite these potential heterogeneous causes, one of the most reliable characters of BA is the presence of gallbladder abnormality, such as echogenic non-identical, atrophic, non-contractile and/or irregularly shaped gallbladder without a definable luminal wall (Tan Kendrick et al, 2003; Kanegawa et al, 2003; Zhou et al, 2016; Aziz et al, 2016; Hwang et al, 2018). The pathological phenotypes and their causes in human BA gallbladders are unclear

Methods

Results

Discussion

Conclusion