Division of Organogenesis and Regeneration, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Sci Rep. 2016 Oct 4;6:34691. doi: 10.1038/srep34691.
Intrahepatic cholangiocarcinoma (ICC) is a malignant epithelial neoplasm composed of cells resembling cholangiocytes that line the intrahepatic bile ducts in portal areas of the hepatic lobule. Although ICC has been defined as a tumor arising from cholangiocyte transformation, recent evidence from genetic lineage-tracing experiments has indicated that hepatocytes can be a cellular origin of ICC by directly changing their fate to that of biliary lineage cells. Notch signaling has been identified as an essential factor for hepatocyte conversion into biliary lineage cells at the onset of ICC. However, the mechanisms underlying Notch signal activation in hepatocytes remain unclear. Here, using a mouse model of ICC, we found that hepatic macrophages called Kupffer cells transiently congregate around the central veins in the liver and express the Notch ligand Jagged-1 coincident with Notch activation in pericentral hepatocytes. Depletion of Kupffer cells prevents the Notch-mediated cell-fate conversion of hepatocytes to biliary lineage cells, inducing hepatocyte apoptosis and increasing mortality in mice. These findings will be useful for uncovering the pathogenic mechanism of ICC and developing prevenient and therapeutic strategies for this refractory disease.
肝内胆管癌 (ICC) 是一种恶性上皮性肿瘤，由类似于肝小叶门脉区胆管内的胆管细胞的细胞组成。虽然 ICC 已被定义为源自胆管细胞转化的肿瘤，但最近的遗传谱系追踪实验证据表明，肝细胞可以通过直接改变其命运为胆管谱系细胞而成为 ICC 的细胞起源。 Notch 信号已被确定为 ICC 起始时肝细胞向胆管谱系细胞转化的必需因素。然而，Notch 信号在肝细胞中激活的机制尚不清楚。在这里，我们使用 ICC 的小鼠模型发现，称为库普弗细胞的肝巨噬细胞在肝脏中央静脉周围短暂聚集，并表达 Notch 配体 Jagged-1，同时在中央周围肝细胞中激活 Notch。耗尽库普弗细胞可防止 Notch 介导的肝细胞向胆管谱系细胞的命运转化，诱导肝细胞凋亡并增加小鼠的死亡率。这些发现将有助于揭示 ICC 的发病机制，并为这种难治性疾病开发预防和治疗策略。
