PDF(Pubmed)
Abstract：
Hepatocytes form bile canaliculi that dynamically respond to the signalling activity of bile acids and bile flow. Little is known about their responses to intraluminal pressure. During embryonic development, hepatocytes assemble apical bulkheads that increase the canalicular resistance to intraluminal pressure. Here, we investigate whether they also protect bile canaliculi against elevated pressure upon impaired bile flow in adult liver. Apical bulkheads accumulate upon bile flow obstruction in mouse models and patients with primary sclerosing cholangitis (PSC). Their loss under these conditions leads to abnormally dilated canaliculi, resembling liver cell rosettes described in other hepatic diseases. 3D reconstruction reveals that these structures are sections of cysts and tubes formed by hepatocytes. Mathematical modelling establishes that they positively correlate with canalicular pressure and occur in early PSC stages. Using primary hepatocytes and 3D organoids, we demonstrate that excessive canalicular pressure causes the loss of apical bulkheads and formation of rosettes. Our results suggest that apical bulkheads are a protective mechanism of hepatocytes against impaired bile flow, highlighting the role of canalicular pressure in liver diseases.
摘要：
肝细胞形成动态响应胆汁酸和胆汁流的信号传导活性的胆小管。关于它们对腔内压力的反应知之甚少。在胚胎发育过程中,肝细胞组装顶端舱壁，增加小管对管腔内压力的抵抗力。这里,我们研究了它们是否也能在成人肝脏胆汁流量受损时保护胆管免受压力升高的影响。在小鼠模型和患有原发性硬化性胆管炎（PSC）的患者中，胆汁流阻塞会积聚根尖舱壁。在这些条件下它们的损失导致异常扩张的小管，类似于其他肝病中描述的肝细胞玫瑰花结。三维重建显示，这些结构是由肝细胞形成的囊肿和管的部分。数学模型确定它们与小管压力呈正相关，并发生在PSC早期阶段。使用原代肝细胞和3D类器官，我们证明，过高的小管压力会导致根尖舱壁的丢失和玫瑰花结的形成。我们的结果表明，顶端舱壁是肝细胞对抗胆汁流动受损的保护机制，强调泪小管压力在肝脏疾病中的作用。
