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

Meritxell Huch, Helmuth Gehart, Ruben van Boxtel, Karien Hamer, Francis Blokzijl, Monique M A Verstegen, Ewa Ellis, Martien van Wenum, Sabine A Fuchs, Joep de Ligt, Marc van de Wetering, Nobuo Sasaki, Susanne J Boers, Hans Kemperman, Jeroen de Jonge, Jan N M Ijzermans, Edward E S Nieuwenhuis, Ruurdtje Hoekstra, Stephen Strom, Robert R G VriesLuc J W van der Laan, Edwin Cuppen, Hans Clevers

Research output: Contribution to journal/periodicalArticleScientificpeer-review

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.

Original languageEnglish
Pages (from-to)299-312
Number of pages14
JournalCell
Volume160
Issue number1-2
DOIs
Publication statusPublished - 15 Jan 2015

Keywords

  • Animals
  • Genomic Instability
  • Hepatocytes
  • Humans
  • Liver
  • Mice
  • Organ Culture Techniques
  • Organoids

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