Department of Veterinary Anatomy, the University of Tokyo, Tokyo 113-8657, Japan.
Department of Experimental Animal Model for Human Disease, Center for Experimental Animals, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
Dis Model Mech. 2020 Apr 3;13(4):dmm042119. doi: 10.1242/dmm.042119.
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 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 BA neonate mice, in order to compare with the gallbladder wall phenotype of human BA infants. The most characteristic phenotype of the 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 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.
先天性胆道闭锁（BA）的特征是新生儿肝外胆管（EHBD）的炎症和阻塞。SOX17 是胎儿 EHBD 形成的主要调节因子。在小鼠 BA 模型中，SOX17 的减少导致细胞自主上皮脱落，同时胆囊壁出现异位 SOX9 阳性的胆管样上皮，导致围产期出现类似 BA 的症状。然而，与人类 BA 胆囊的相似之处仍不清楚。在本研究中，我们对 BA 新生小鼠进行了表型分析，以便与人类 BA 婴儿的胆囊壁表型进行比较。BA 胆囊最典型的表型是异位出现 SOX9 阳性的胆管旁腺（PBG），即所谓的假幽门腺（PPG）。接下来，我们检查了 13 名 BA 婴儿的人类胆囊的 SOX17/SOX9 表达谱。其中，5 例 BA 病例在整个胆囊上皮区域均出现 SOX17 阳性信号的缺失或明显减少（SOX17-低组）。即使在其余 8 个胆囊（SOX17-高组）中，靠近蜕膜部位的上皮细胞的 SOX17 阳性信号强度也经常减少。最有趣的是，人类 BA 胆囊的最典型表型是胆囊体中 PBG/PPG 样腺的密度增加，尤其是在靠近上皮蜕膜部位，表明 PBG/PPG 的形成是人类 BA 和小鼠 BA 胆囊的共同表型。这些发现为 SOX17 减少和 PBG/PPG 形成对人类 BA 胆囊早期发病机制的潜在贡献提供了首个证据。本文有与论文共同第一作者的第一人称采访。
