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Molecular basis of transdifferentiation of pancreas to liver

Nature Cell Biology volume 2, pages 879–887 (2000)Cite this article

Abstract

The appearance of hepatic foci in the pancreas has been described in animal experiments and in human pathology. Here we show that pancreatic cells can be converted into hepatocytes by treatment with a synthetic glucocorticoid, dexamethasone. This occurs both in a pancreatic cell line, AR42J-B13, and in organ cultures of pancreatic buds from mouse embryos. We have established several features of the mechanism behind this transdifferentiation. We show that a proportion of the hepatocytes arises directly from differentiated exocrine-like cells, with no intervening cell division. This conversion is associated with induction of the transcription factor C/EBPβ and the activation of differentiated hepatic products. Transfection of C/EBPβ into the cells can provoke transdifferentiation; conversely, a dominant-negative form of C/EBPβ can inhibit the process. These results indicate that C/EBPβ is a key component that distinguishes the liver and pancreatic programmes of differentiation.

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Figure 1: Cell morphology in response to dexamethasone treatment.
Figure 2: Dexamethasone treatment results in the expression of liver markers.
Figure 3: Time courses of dexamethasone effects.
Figure 4: Do hepatocytes originate from differentiated exocrine cells or from stem cells?
Figure 5: Time course of C/EBPβ activation.
Figure 6: C/EBPβ induces transdifferentiation in AR42J-B13 cells.
Figure 7: Inhibition of transdifferentiation by LIP.
Figure 8: Hepatic transformation in pancreatic buds from mouse embryos.

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Acknowledgements

We thank the Wellcome Trust and Medical Research Council for financial support. We thank Itaru Kojima for the AR42J-B13 cells, Calvin Swift for the elastase promoter plasmid, Steve McKnight for the C/EBPβ plasmid and Ueli Schibler for the CMV-LIP plasmid. We also thank Birgit Lane, Ann Burchell and Mike Coughtrie for antibodies, and U. J. Potter for help with electron microscopy.

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Authors and Affiliations

  1. Department of Biology and Biochemistry, Developmental Biology Programme, University of Bath, Bath, BA2 7AY, UK

    Chia-Ning Shen, Jonathan M. W. Slack & David Tosh

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Correspondence to David Tosh.

Supplementary information

Figure 1

Time course of HNF4a activation in cells treated with 1 μM dexamethasone. Figure 2Translocation of HNF4a in cells with activated C/EBPβ. (PDF 196 kb)

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Shen, CN., Slack, J. & Tosh, D. Molecular basis of transdifferentiation of pancreas to liver. Nat Cell Biol 2, 879–887 (2000). https://doi.org/10.1038/35046522

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