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

Abstract

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 SOX17positive signals throughout the whole region of gallbladder epithelia (SOX17-low group). Even in the remaining eight gallbladders (SOX17high 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.

Anatomical and histological characteristics of the hepatobiliary system in adult Sox17 heterozygote mice

“…This toxin disturbs the bile duct epithelial polarity and reduces Sox17 expression, resulting in luminal obstruction in cultured EHBD spheroids (Lorent et al, 2015; Waisbourd‐Zinman et al, 2016). Recently, we also found reduced SOX17 expression in some of the “isolated” BA cases with well‐preserved gallbladder walls (Uemura et al, 2020), suggesting a potential contribution of reduced SOX17 expression to early pathogenesis in some human BA cases.…”

“…The bile duct injury may be repaired by EHBD progenitors in peribiliary glands (PBGs), that is, so-called pseudopyloric glands (PPGs) in pathology (Cardinale et al, 2012(Cardinale et al, , 2014DiPaola et al, 2013). This is because the PBG/PPG-like glands are ectopically formed in the Sox17 +/− gallbladder soon after birth (Uemura et al, 2020). Such ectopic PBG/PPG-like glands were also found in the gallbladder of surviving Sox17 +/− mice at the adult stage ( Figure S3), which supports the potential contribution of the PBGs to gallbladder wall repair, albeit of no appreciable alteration in epithelial PCNA (proliferative cell nuclear antigen) indices (Takami and Kanai, unpublished observation), at the neonatal stages.…”

Role of YAP1 Signaling in Biliary Development, Repair, and Disease

“…68 Haploinsufficiency of Sox17 leads to malformation or agenesis of the gallbladder with defective contractility and function, although other parts of the EHBD network are not as drastically affected. 69 Hes1 null mice showed major dysgenesis of the EHBDs along with expression of ectopic pancreatic cells, suggesting that Notch activity is involved in promoting and maintaining biliary differentiation while simultaneously blocking pancreatic acinar differentiation from common progenitors. 68 70 Activation of transcription factors including hematopoietically expressed homeobox protein (Hhex), Hnf6, and Hnf1β, along with BMP and FGF signals from the adjacent mesenchyme, has also been shown to play a critical role in EHBD formation.…”

Sry-related High Mobility Group Box 17 Functions as a Tumor Suppressor by Antagonizing the Wingless-related Integration Site Pathway

“…Sox17 heterozygous mutant female mice display a failure of embryo implantation [ 8 ]. Moreover, Sox17 heterozygous mutant embryos cause embryonic cholecystitis [ 9 ], defective gallbladder contraction [ 9 ], and gallbladder wall abnormality [ 10 ] in perinatal biliary atresia [ 11 ]. In the wild-type mice, a transient increase in the Sox17 expression in oligodendrocyte progenitors is required for the oligodendrocyte differentiation [ 12 , 13 ].…”