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Cell. 2015 Jan 15;160(1-2):299-312. doi: 10.1016/j.cell.2014.11.050. Epub 2014 Dec 18.

Long-term culture of genome-stable bipotent stem cells from adult human liver.

Author information

1
Hubrecht Institute-KNAW, University Medical Centre Utrecht, CancerGenomics.nl, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands. Electronic address: m.huch@gurdon.cam.ac.uk.
2
Hubrecht Institute-KNAW, University Medical Centre Utrecht, CancerGenomics.nl, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
3
Department of Surgery, Erasmus MC-University Medical Center, Postbus 2040, 3000 CA Rotterdam, the Netherlands.
4
Unit for Transplantation Surgery, Department of CLINTEC, Karolinska Institute, Karolinska University Hospital Huddinge, Hälsovägen, Flemingsberg, SE-141 86 Stockholm, Sweden.
5
Surgical Laboratory, Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
6
Division of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, the Netherlands.
7
Hubrecht Institute-KNAW, University Medical Centre Utrecht, CancerGenomics.nl, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands; Hubrecht Organoid Technology (HUB), Uppsalalaan 8, 3584CT, Utrecht, the Netherlands.
8
Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, the Netherlands.
9
Division of Pathology, Department of Laboratory Medicine, Karolinska Institute, Alfred Nobels Alle 8, F 56 141-86 Stockholm, Sweden.
10
Hubrecht Institute-KNAW, University Medical Centre Utrecht, CancerGenomics.nl, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands. Electronic address: h.clevers@hubrecht.eu.

Abstract

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.

PMID:
25533785
PMCID:
PMC4313365
DOI:
10.1016/j.cell.2014.11.050
[Indexed for MEDLINE]
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