title: Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation.
abstract: The study of biliary disease has been constrained by a lack of primary human cholangiocytes. Here we present an efficient, serum-free protocol for directed differentiation of human induced pluripotent stem cells into cholangiocyte-like cells (CLCs). CLCs show functional characteristics of cholangiocytes, including bile acids transfer, alkaline phosphatase activity, γ-glutamyl-transpeptidase activity and physiological responses to secretin, somatostatin and vascular endothelial growth factor. We use CLCs to model in vitro key features of Alagille syndrome, polycystic liver disease and cystic fibrosis (CF)-associated cholangiopathy. Furthermore, we use CLCs generated from healthy individuals and patients with polycystic liver disease to reproduce the effects of the drugs verapamil and octreotide, and we show that the experimental CF drug VX809 rescues the disease phenotype of CF cholangiopathy in vitro. Our differentiation protocol will facilitate the study of biological mechanisms controlling biliary development, as well as disease modeling and drug screening.
authors.affiliation: Wellcome Trust-Medical Research Council Stem Cell Institute, Anne McLaren Laboratory for Regenerative Medicine, Department of Surgery, University of Cambridge, Cambridge, UK.|Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Fotios
authors.initials: F
authors.lastname: Sampaziotis
authors.affiliation: Wellcome Trust-Medical Research Council Stem Cell Institute, Anne McLaren Laboratory for Regenerative Medicine, Department of Surgery, University of Cambridge, Cambridge, UK.
authors.forename: Miguel Cardoso
authors.initials: MC
authors.lastname: de Brito
authors.affiliation: Wellcome Trust-Medical Research Council Stem Cell Institute, Anne McLaren Laboratory for Regenerative Medicine, Department of Surgery, University of Cambridge, Cambridge, UK.|Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Pedro
authors.initials: P
authors.lastname: Madrigal
authors.affiliation: Wellcome Trust-Medical Research Council Stem Cell Institute, Anne McLaren Laboratory for Regenerative Medicine, Department of Surgery, University of Cambridge, Cambridge, UK.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bertero
authors.affiliation: Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK.
authors.forename: Kourosh
authors.initials: K
authors.lastname: Saeb-Parsy
authors.affiliation: Wellcome Trust-Medical Research Council Stem Cell Institute, Anne McLaren Laboratory for Regenerative Medicine, Department of Surgery, University of Cambridge, Cambridge, UK.
authors.forename: Filipa A C
authors.initials: FAC
authors.lastname: Soares
authors.affiliation: Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.|K.G. Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.|Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Schrumpf
authors.affiliation: Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.|K.G. Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: Espen
authors.initials: E
authors.lastname: Melum
authors.affiliation: Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.|K.G. Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.|Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Tom H
authors.initials: TH
authors.lastname: Karlsen
authors.affiliation: Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK.
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Bradley
authors.affiliation: Department of Hepatology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
authors.forename: William Th
authors.initials: WT
authors.lastname: Gelson
authors.affiliation: Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Davies
authors.affiliation: Child Health Clinical Academic Grouping, King's Health Partners, Denmark Hill Campus, London, United Kingdom.
authors.forename: Alastair
authors.initials: A
authors.lastname: Baker
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, United Kingdom.
authors.forename: Arthur
authors.initials: A
authors.lastname: Kaser
authors.affiliation: Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Alexander
authors.affiliation: Wellcome Trust-Medical Research Council Stem Cell Institute, Anne McLaren Laboratory for Regenerative Medicine, Department of Surgery, University of Cambridge, Cambridge, UK.
authors.forename: Nicholas R F
authors.initials: NRF
authors.lastname: Hannan
authors.affiliation: Wellcome Trust-Medical Research Council Stem Cell Institute, Anne McLaren Laboratory for Regenerative Medicine, Department of Surgery, University of Cambridge, Cambridge, UK.|Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Vallier
mesh_terms: D001659:Biliary Tract / Q000166:cytology*; D035843:Biomedical Research; D002478:Cells, Cultured; D055808:Drug Discovery; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008107:Liver Diseases; D008954:Models, Biological