Embryonic development of intrahepatic and extrahepatic bile ducts: Molecular mechanisms, morphogenesis, and developmental disorders

Background Embryonic development of the biliary system is a complex and tightly regulated process, and disruption of this process may contribute to congenital biliary diseases such as biliary atresia (BA). Despite advances in surgical techniques, the prognosis of these diseases remains suboptimal, possibly due to an incomplete understanding of the underlying developmental biological mechanisms. In recent years, significant progress has been made in the study of bile duct development, particularly in understanding molecular pathways, morphogenesis, and the establishment of in vitro models. An integrated and comprehensive narrative review of these advances is urgently needed. Objective This review summarizes the spatiotemporal atlas of intrahepatic and extrahepatic bile duct development during embryogenesis. It also reviews the key cellular and molecular mechanisms involved. In addition, we discuss their relevance to congenital diseases such as BA and consider possible clinical translation. Methods We performed a narrative literature review. The review integrates classical morphological studies with modern approaches, including genetics, organoid models, and single-cell technologies. Based on these data, we constructed a framework linking morphogenesis with disease mechanisms. Conclusions The development of intrahepatic and extrahepatic bile ducts follows a highly regulated spatiotemporal program. The intrahepatic bile ducts originate from ductal plate remodeling, whereas the extrahepatic bile ducts arise from the hepatic diverticulum. Their connection at the hepatic hilum is essential for an integrated biliary system. This process is controlled by signaling pathways such as Notch and Hedgehog, as well as transcription networks such as SOX17 (SRY-box transcription factor 17) and HNF6 (hepatocyte nuclear factor 6). Disruption of this program may contribute to disorders such as BA and ductal plate malformation. Organoid models and single-cell technologies may help clarify disease mechanisms and support future clinical translation. Prospects Integrating insights from developmental biology with advanced technologies may facilitate more precise disease stratification and the development of personalized therapeutic strategies, ultimately improving clinical outcomes in children with biliary disorders.