Inside-out construction of the biliary system

项目摘要 肝内胆管的功能是将胆汁从肝小管排出。先天或 后天性的肝内胆管形成和开放异常有严重的，通常是致命的 后果。在发育中的肝脏中，胆管的形态发生是一个自组织的过程，因此双潜能 肝母细胞同时采用胆道命运，并组织成无细胞的连续管状网络 组织。越来越多的证据表明，成熟肝细胞的转分化也可以产生正常的 成人肝脏再生胆管形态发生和与疾病相关的异常胆管反应。 胆道结构和命运协调的机制，以实现这种戏剧性的形态发生 编程和构建功能胆道树在很大程度上是未知的。认识胆道疾病的机制基础 形态发生是必要的，以利用肝脏的再生潜力，同时避免致命的 慢性和恶性肝病的后果。我们最近发现新的管腔形成 扩张启动胆管形态发生，对胆管结构和命运的协调至关重要。 我们已发表的和初步的研究提出了一种模型，在该模型中，管腔形成创建了一个物理信号 利基，反馈以加强胆道架构和命运，从而创建胆道系统 从里到外。这个项目的长期目标是了解管腔的形成和延伸如何引导 胆小管网络的形成。这项工作的成功完成将填补我们在 了解如何安全地建造这个关键器官，并在疾病中限制或修复它。

Project Summary The intrahepatic biliary tree functions to drain bile from hepatocytic canaliculi away from the liver. Congenital or acquired abnormalities in the formation and patency of intrahepatic bile ducts have severe, often fatal consequences. In the developing liver, biliary morphogenesis is a self-organizing process whereby bipotential hepatoblasts simultaneously adopt a biliary fate and organize into a continuous tubular network without cell division. Mounting evidence suggests that transdifferentiation of mature hepatocytes can also yield both normal regenerative biliary morphogenesis and abnormal disease-associated biliary `ductal reactions' in the adult liver. The mechanisms by which biliary architecture and fate are coordinated to enact this dramatic morphogenetic program and build a functional biliary tree are largely unknown. Understanding the mechanistic basis of biliary morphogenesis is necessary to harness the regenerative potential of the liver while avoiding the lethal consequences of chronic and malignant liver disease. We recently discovered that de novo lumen formation and expansion initiates biliary morphogenesis and is central to the coordination of biliary architecture and fate. Our published and preliminary studies suggest a model wherein lumen formation creates a physical signaling niche that feeds back to reinforce both biliary architecture and fate, thereby creating the biliary system from the inside out. The long-term goal of this project is to understand how lumen formation and extension guides the formation of the biliary tubular network. The successful completion of this work will address a key gap in our understanding of how to safely build this critical organ, and limit or repair it in disease.