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Nat Biotechnol. 2015 Aug;33(8):853-61. doi: 10.1038/nbt.3294. Epub 2015 Jul 13.

Directed differentiation of cholangiocytes from human pluripotent stem cells.

Author information

1
1] McEwen Centre for Regenerative Medicine, University Health Network, Toronto, Ontario, Canada. [2] Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
2
McEwen Centre for Regenerative Medicine, University Health Network, Toronto, Ontario, Canada.
3
Program in Molecular Structure &Function, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.
4
Department of Pediatrics, Oregon Health and Science University, Portland, Oregon, USA.
5
1] McEwen Centre for Regenerative Medicine, University Health Network, Toronto, Ontario, Canada. [2] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. [3] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
6
1] Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada.
7
1] Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada. [2] Division of General Surgery, University Health Network, Toronto, Ontario, Canada. [3] Department of Surgery, University of Toronto, Toronto, Ontario, Canada.

Abstract

Although bile duct disorders are well-recognized causes of liver disease, the molecular and cellular events leading to biliary dysfunction are poorly understood. To enable modeling and drug discovery for biliary disease, we describe a protocol that achieves efficient differentiation of biliary epithelial cells (cholangiocytes) from human pluripotent stem cells (hPSCs) through delivery of developmentally relevant cues, including NOTCH signaling. Using three-dimensional culture, the protocol yields cystic and/or ductal structures that express mature biliary markers, including apical sodium-dependent bile acid transporter, secretin receptor, cilia and cystic fibrosis transmembrane conductance regulator (CFTR). We demonstrate that hPSC-derived cholangiocytes possess epithelial functions, including rhodamine efflux and CFTR-mediated fluid secretion. Furthermore, we show that functionally impaired hPSC-derived cholangiocytes from cystic fibrosis patients are rescued by CFTR correctors. These findings demonstrate that mature cholangiocytes can be differentiated from hPSCs and used for studies of biliary development and disease.

Comment in

PMID:
26167630
DOI:
10.1038/nbt.3294
[Indexed for MEDLINE]

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