Remarkable heterogeneity displayed by oval cells in rat and mouse models of stem cell–mediated liver regeneration

Authors

  • Peter Jelnes,

    1. Danish Stem Cell Research Centre, Department of Cellular and Molecular Medicine, The Panum Institute, University of Copenhagen, Copenhagen, Denmark
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  • Eric Santoni-Rugiu,

    1. Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
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  • Morten Rasmussen,

    1. Danish Stem Cell Research Centre, Department of Cellular and Molecular Medicine, The Panum Institute, University of Copenhagen, Copenhagen, Denmark
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  • Susanne Lunøe Friis,

    1. Danish Stem Cell Research Centre, Department of Cellular and Molecular Medicine, The Panum Institute, University of Copenhagen, Copenhagen, Denmark
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  • Jens Høiriis Nielsen,

    1. Danish Stem Cell Research Centre, Department of Cellular and Molecular Medicine, The Panum Institute, University of Copenhagen, Copenhagen, Denmark
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  • Niels Tygstrup,

    1. Department of Hepatology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
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  • Hanne Cathrine Bisgaard

    Corresponding author
    1. Danish Stem Cell Research Centre, Department of Cellular and Molecular Medicine, The Panum Institute, University of Copenhagen, Copenhagen, Denmark
    • Department of Medical Biochemistry and Genetics, The Panum Institute, Building 6.5.40, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark
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    • fax: (45) 35327701


  • Potential conflict of interest: Nothing to report.

Abstract

The experimental protocols used in the investigation of stem cell–mediated liver regeneration in rodents are characterized by activation of the hepatic stem cell compartment in the canals of Hering followed by transit amplification of oval cells and their subsequent differentiation along hepatic lineages. Although the protocols are numerous and often used interchangeably across species, a thorough comparative phenotypic analysis of oval cells in rats and mice using well-established and generally acknowledged molecular markers has not been provided. In the present study, we evaluated and compared the molecular phenotypes of oval cells in several of the most commonly used protocols of stem cell–mediated liver regeneration—namely, treatment with 2-acetylaminofluorene and partial (70%) hepatectomy (AAF/PHx); a choline-deficient, ethionine-supplemented (CDE) diet; a 3,5-diethoxycarbonyl-1,4-dihydro-collidin (DDC) diet; and N-acetyl-paraaminophen (APAP). Reproducibly, oval cells showing reactivity for cytokeratins (CKs), muscle pyruvate kinase (MPK), the adenosine triphosphate–binding cassette transporter ABCG2/BCRP1 (ABCG2), alpha-fetoprotein (AFP), and delta-like protein 1/preadipocyte factor 1 (Dlk/Pref-1) were induced in rat liver treated according to the AAF/PHx and CDE but not the DDC protocol. In mouse liver, the CDE, DDC, and APAP protocols all induced CKs and ABCG2-positive oval cells. However, AFP and Dlk/Pref-1 expression was rarely detected in oval cells. Conclusion: Our results delineate remarkable phenotypic discrepancies exhibited by oval cells in stem cell–mediated liver regeneration between rats and mice and underline the importance of careful extrapolation between individual species. (HEPATOLOGY 2007;45:1462–1470.)

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