Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation
de, Brito Miguel Cardoso
Karlsen, Tom H
Gelson, William TH
Alexander, Graeme J
Hanna, Nicholas RF
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Sampaziotis, F., de, B. M. C., Madrigal, P., Bertero, A., Saeb-Parsy, K., Soares, F., Schrumpf, E., et al. (2015). Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation. Nature Biotechnology, 33 845-852. https://doi.org/10.1038/nbt.3275
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, gamma-glutamyl-transpeptidase activity and physiological responses to secretin, somatostatin and VEGF. 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.
This work was funded by ERC starting grant Relieve IMDs (L.V., N.H.), the Cambridge Hospitals National Institute for Health Research Biomedical Research Center (L.V., N.H., F.S.), the Evelyn trust (N.H.) and the EU Fp7 grant TissuGEN (M.CDB.). FS has been supported by an Addenbrooke’s Charitable Trust Clinical Research Training Fellowship and a joint MRC-Sparks Clinical Research Training Fellowship.
European Research Council (281335)
External DOI: https://doi.org/10.1038/nbt.3275
This record's URL: https://www.repository.cam.ac.uk/handle/1810/248631