{
  "abstract": "Background Injured or reactive biliary epithelial cells participate in most chronic liver injuries in a process referred to as ductular reaction, which involves multicellular interactions with marked local infiltration of macrophages and fibrogenic cell activation. The direct roles of biliary epithelial cells in shaping their cellular niche remain unknown.Objective We aimed at investigating the effects of biliary epithelial cell-derived acute phase response protein orosomucoid 2 (ORM2) in shaping monocyte/macrophage response to liver injury.Design Transcriptome data sets from human and mouse livers were used, results were confirmed with multiplex immunofluorescence. A multicellular biliary-niche-on-a-chip derived from primary liver and blood cells (wild-type, Mdr2 −/− mice) was established to model ductular reaction. Human blood cells collected from healthy donors and intrahepatic cholangiocyte organoids derived from normal and cirrhotic liver patients were used.Results Our transcriptome data set and multiplex immunofluorescence analyses indicated a previously unrecognised involvement of the acute phase response protein ORM2 in ductular reactions in both human and mouse livers. ORM2 gene expression was increased in biliatresone-challenged, bile acid-challenged and acetaminophen-challenged cholangiocytes. Cholangiocyte-derived ORM2 induced unique transcriptome changes and functional adaptation of liver macrophages. ORM2-activated macrophages exacerbated cholangiocyte cell stress and Orm2 expression, but also tended to promote fibrogenic activation of hepatic stellate cells. Mechanistically, ORM2 effects were mediated by an inositol 1,4,5-trisphosphate receptor type 2-dependent calcium pathway.Conclusion This study reveals a paracrine communication circuit during ductular reaction, in which reactive cholangiocyte-derived ORM2 reprogrammes liver macrophages, participating in a pathogenic remodelling of the immune biliary niche.",
  "authors": [
    {
      "affiliations": [
        "Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, BE, Germany",
        "Cell Biology and Imaging Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"
      ],
      "name": "Hanyang Liu"
    },
    {
      "affiliations": [
        "Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, BE, Germany"
      ],
      "name": "Guo Yin"
    },
    {
      "affiliations": [
        "Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, BE, Germany",
        "Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil"
      ],
      "name": "Bianca Franco Leonardi"
    },
    {
      "affiliations": [
        "Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, BE, Germany",
        "Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China"
      ],
      "name": "Tian Lan"
    },
    {
      "affiliations": [
        "Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, BE, Germany"
      ],
      "name": "Yeni Ait Ahmed"
    },
    {
      "affiliations": [
        "Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, BE, Germany"
      ],
      "name": "Hilmar Berger"
    },
    {
      "affiliations": [
        "Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, BE, Germany"
      ],
      "name": "Marlene Sophia Kohlhepp"
    },
    {
      "affiliations": [
        "Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, BE, Germany"
      ],
      "name": "Natalja Amiridze"
    },
    {
      "affiliations": [
        "Department of Pediatric Gastroenterology, Nephrology and Metabolic Medicine, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany"
      ],
      "name": "Natalia Martagón Calderón"
    },
    {
      "affiliations": [
        "BIH Center for Regenerative Therapies (BCRT), Berlin, Germany, Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, Berlin, Germany"
      ],
      "name": "Carla Frau"
    },
    {
      "affiliations": [
        "BIH Center for Regenerative Therapies (BCRT), Berlin, Germany, Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, Berlin, Germany",
        "Max-Planck-Institute for Molecular Genetics, Berlin, Germany"
      ],
      "name": "Ludovic Vallier"
    },
    {
      "affiliations": [
        "Department of Pediatric Gastroenterology, Nephrology and Metabolic Medicine, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany",
        "BIH Center for Regenerative Therapies (BCRT), Berlin, Germany, Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, Berlin, Germany"
      ],
      "name": "Milad Rezvani"
    },
    {
      "affiliations": [
        "Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, BE, Germany"
      ],
      "name": "Frank Tacke"
    },
    {
      "affiliations": [
        "Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, BE, Germany"
      ],
      "name": "Adrien Guillot"
    }
  ],
  "title": "Reactive cholangiocyte-derived ORM2 drives a pathogenic modulation of the injured biliary niche through macrophage reprogramming",
  "uid": "d589b5cf-b4ae-5544-ac4a-2bb4b2169dcf"
}