Format

Send to

Choose Destination
Nat Biotechnol. 2015 Aug;33(8):845-852. doi: 10.1038/nbt.3275. Epub 2015 Jul 13.

Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation.

Author information

1
Wellcome Trust-Medical Research Council Stem Cell Institute, Anne McLaren Laboratory for Regenerative Medicine, Department of Surgery, University of Cambridge, Cambridge, UK.
2
Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
3
Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK.
4
Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
5
K.G. Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
6
Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
7
Department of Hepatology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
8
Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
9
Child Health Clinical Academic Grouping, King's Health Partners, Denmark Hill Campus, London, United Kingdom.
10
Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, United Kingdom.
11
Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom.
#
Contributed equally

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.

Comment in

PMID:
26167629
PMCID:
PMC4768345
DOI:
10.1038/nbt.3275
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center