title: Kupffer cells induce Notch-mediated hepatocyte conversion in a common mouse model of intrahepatic cholangiocarcinoma.
abstract: 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.
authors.affiliation: Division of Organogenesis and Regeneration, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Maiko
authors.initials: M
authors.lastname: Terada
authors.affiliation: Division of Organogenesis and Regeneration, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Horisawa
authors.affiliation: Division of Organogenesis and Regeneration, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Shizuka
authors.initials: S
authors.lastname: Miura
authors.affiliation: Division of Organogenesis and Regeneration, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Takashima
authors.affiliation: Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.|Core Research for Evolutional Science and Technology, The Japan Agency for Medical Research and Development, 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Ohkawa
authors.affiliation: Division of Organogenesis and Regeneration, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Sekiya
authors.affiliation: Division of Organogenesis and Regeneration, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Kanae
authors.initials: K
authors.lastname: Matsuda-Ito
authors.affiliation: Division of Organogenesis and Regeneration, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.|Core Research for Evolutional Science and Technology, The Japan Agency for Medical Research and Development, 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D001650:Bile Duct Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002273:Carcinogens / Q000633:toxicity; D002450:Cell Communication; D054337:Cell Dedifferentiation / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000139:chemically induced / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D004002:Clodronic Acid / Q000494:pharmacology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D000072100:Jagged-1 Protein / Q000235:genetics* / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011725:Pyridines / Q000633:toxicity; D051881:Receptor, Notch1 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D013853:Thioacetamide / Q000633:toxicity
chemical_list: C530773:3,5-diethoxycarbonyl-1,4-dihydrocollidine; D002273:Carcinogens; D000072100:Jagged-1 Protein; C497762:Notch1 protein, mouse; D011725:Pyridines; D051881:Receptor, Notch1; D013853:Thioacetamide; D004002:Clodronic Acid