Cell
Volume 160, Issues 1–2, 15 January 2015, Pages 299-312
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Article
Long-Term Culture of Genome-Stable Bipotent Stem Cells from Adult Human Liver

https://doi.org/10.1016/j.cell.2014.11.050Get rights and content
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open access

Highlights

  • Establishment of a long-term human liver organoid culture

  • Human liver stem cells retain genetic stability after long-term expansion

  • Liver organoid cultures differentiate to functional hepatocytes in vitro and in vivo

  • Organoids derived from patients with genetic disorders model liver disease in vitro

Summary

Despite the enormous replication potential of the human liver, there are currently no culture systems available that sustain hepatocyte replication and/or function in vitro. We have shown previously that single mouse Lgr5+ liver stem cells can be expanded as epithelial organoids in vitro and can be differentiated into functional hepatocytes in vitro and in vivo. We now describe conditions allowing long-term expansion of adult bile duct-derived bipotent progenitor cells from human liver. The expanded cells are highly stable at the chromosome and structural level, while single base changes occur at very low rates. The cells can readily be converted into functional hepatocytes in vitro and upon transplantation in vivo. Organoids from α1-antitrypsin deficiency and Alagille syndrome patients mirror the in vivo pathology. Clonal long-term expansion of primary adult liver stem cells opens up experimental avenues for disease modeling, toxicology studies, regenerative medicine, and gene therapy.

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This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).

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Co-first author

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Present address: Wellcome Trust/Cancer Research UK Gurdon Institute, Wellcome Trust/MRC Stem Cell Institute and Department of Physiology, Development and Neuroscience, University of Cambridge, Tennis Court Road, CB2 1QN Cambridge, UK