Ayabe Hiroaki, DePasquale Erica A K, Amarachintha Surya P, Mourya Reena, Li Wenqi, Nalluri Shreya, Fox Sejal R, Konishi Kenichiro, Shivakumar Pranavkumar, Bezerra Jorge A
Department of Pediatrics, University of Texas Southwestern Medical Center and Children's Medical Center, Dallas, TX, USA.
Division of Gastroenterology, Hepatology & Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Nat Commun. 2025 Jul 17;16(1):6575. doi: 10.1038/s41467-025-61442-5.
Deficiencies in the development of epithelial structures and delays in cellular maturation can increase the susceptibility of neonates to disease early in life. To investigate human biliary development and its vulnerability to biliary atresia, a severe pediatric cholangiopathy, we engineered multi-compartment biliary organoids (MBOs) from co-cultures of human liver-derived epithelial organoid cells with human endothelial and mesenchymal cells. MBOs derived from normal livers effectively replicated the epithelial structure of the bile duct epithelium and peribiliary glands (PBGs). Conversely, MBOs from diseased livers exhibited defective epithelial layers, a significant epithelial-mesenchymal transition (EMT), and an activation of the TGF-β/Activin-SMAD2/3 signaling, primarily due to intermediary cell sub-populations. Inhibition of TGF-β signaling suppressed EMT and promoted biliary epithelial development in human MBOs and suppressed the phenotype of experimental biliary atresia in neonatal mice. Thus, the modulation of TGF-β-dependent EMT regulates bile duct epithelial development and influences the susceptibility of neonates to biliary injuries.
上皮结构发育缺陷和细胞成熟延迟会增加新生儿在生命早期对疾病的易感性。为了研究人类胆管发育及其对胆道闭锁（一种严重的儿科胆管病）的易感性，我们用人肝脏来源的上皮类器官细胞与人内皮细胞和间充质细胞共培养构建了多室胆管类器官（MBOs）。源自正常肝脏的MBOs有效地复制了胆管上皮和胆管周围腺体（PBGs）的上皮结构。相反，来自患病肝脏的MBOs表现出上皮层缺陷、显著的上皮-间质转化（EMT）以及TGF-β/激活素-SMAD2/3信号通路的激活，主要是由于中间细胞亚群所致。抑制TGF-β信号通路可抑制人MBOs中的EMT并促进胆管上皮发育，并抑制新生小鼠实验性胆道闭锁的表型。因此，TGF-β依赖性EMT的调节可调控胆管上皮发育并影响新生儿对胆管损伤的易感性。
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