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

Disease models & mechanisms 2020 Apr 03

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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. © 2020. Published by The Company of Biologists Ltd.

Citation

Mami Uemura, Mayumi Higashi, Montri Pattarapanawan, Shohei Takami, Naoki Ichikawa, Hiroki Higashiyama, Taizo Furukawa, Jun Fujishiro, Yuki Fukumura, Takashi Yao, Tatsuro Tajiri, Masami Kanai-Azuma, Yoshiakira Kanai. Gallbladder wall abnormality in biliary atresia of mouse Sox17+/- neonates and human infants. Disease models & mechanisms. 2020 Apr 03;13(4)