Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Hepatocyte transplantation in a model of toxin-induced liver disease: variable therapeutic effect during replacement of damaged parenchyma by donor cells

Nature Medicine volume 6, pages 320–326 (2000)Cite this article

Abstract

To provide long-term therapy in patients with severe toxin-induced hepatic parenchymal damage, donor hepatocytes would need to replicate and replace a large portion of the damaged parenchyma. Using a mouse model developed to reproduce this type of hepatic injury, we found that hepatocyte transplantation only slightly improved survival after transplantation despite the fact that many non-survivors showed moderate liver repopulation by donor cells. Perhaps accounting for this outcome, donor parenchyma in non-survivors did not have typical lobular organization. These results indicate that the re-creation of functional parenchyma by transplanted hepatocytes requires time, during which donor cells proliferate and then establish normal parenchymal architecture.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Induction of lesions in AL–HSVtk-transgenic mice.
Figure 2: Clinical chemistry analysis of GCV-treated AL–HSVtk mice.
Figure 3: AL–HSVtk model validation.
Figure 4: Survival of mice treated with GCV.
Figure 5: Donor cell repopulation.
Figure 6: Characteristics of donor cell foci.

Similar content being viewed by others

References

  1. Fuller, B.J. Transplantation of isolated hepatocytes. A review of current ideas. J. Hepatol. 7, 368–376 (1988).

    Article  CAS  Google Scholar 

  2. Mito, M., Kusano, M. & Sawa, M. Hepatocyte transplantation for hepatic failure. Transplant. Rev. 7, 35–43 (1993).

    Article  Google Scholar 

  3. Gupta, S., Gorla, G.R. & Irani, A.N. Hepatocyte transplantation: emerging insights into mechanisms of liver repopulation and their relevance to potential therapies. J. Hepatol. 30, 162–170 (1999).

    Article  CAS  Google Scholar 

  4. Habibullah, C.M., Syed, I.H., Qamar, A. & Taher-Uz, Z. Human fetal hepatocyte transplantation in patients with fulminant hepatic failure. Transplantation 58, 951–952 (1994).

    Article  CAS  Google Scholar 

  5. Strom, S.C. et al. Hepatocyte transplantation as a bridge to orthotopic liver transplantation in terminal liver failure. Transplantation 63, 559–569 (1997).

    Article  CAS  Google Scholar 

  6. Wilson, J.M. et al. Temporary amelioration of hyperlipidemia in low density lipoprotein receptor-deficient rabbits transplanted with genetically modified hepatocytes. Proc. Natl. Acad. Sci. USA 87, 8437–8441 (1990).

    Article  CAS  Google Scholar 

  7. Chowdhury, J.R. et al. Long-term improvement of hypercholesterolemia after ex vivo gene therapy in LDLR-deficient rabbits. Science 254, 1802–1805 (1991).

    Article  CAS  Google Scholar 

  8. Gunsalus, J.R., Brady, D.A., Coulter, S.M., Gray, B.M. & Edge, A.S. Reduction of serum cholesterol in Watanabe rabbits by xenogeneic hepatocellular transplantation. Nature Med. 3, 48–53 (1997).

    Article  CAS  Google Scholar 

  9. Matas, A.J. et al. Hepatocellular transplantation for metabolic deficiencies: decrease of plasmsa bilirubin in Gunn rats. Science 192, 892–894 (1976).

    Article  CAS  Google Scholar 

  10. Moscioni, A.D. et al. Long-term correction of albumin levels in the Nagase analbuminemic rat: repopulation of the liver by transplanted normal hepatocytes under a regeneration response. Cell Transplant. 5, 499–503 (1996).

    Article  CAS  Google Scholar 

  11. Oren, R. et al. Restoration of serum albumin levels in nagase analbuminemic rats by hepatocyte transplantation. Hepatology 29, 75–81 (1999).

    Article  CAS  Google Scholar 

  12. Grossman, M. et al. Successful ex vivo gene therapy directed to liver in a patient with familial hypercholesterolaemia. Nature Genet. 6, 335–341 (1994).

    Article  CAS  Google Scholar 

  13. Fox, I.J. et al. Treatment of the Crigler-Najjar syndrome type I with hepatocyte transplantation. N. Engl. J. Med. 338, 1422–1426 (1998).

    Article  CAS  Google Scholar 

  14. Lake, J.R. Hepatocyte transplantation. N. Engl. J. Med. 338, 1463–1465 (1998).

    Article  CAS  Google Scholar 

  15. Chowdhury, J.R. et al. Human hepatocyte transplantation: gene therapy and more? Pediatrics 102, 647–648 (1998).

    Article  CAS  Google Scholar 

  16. Zimmerman, H.J. & Maddrey, W.C. in Diseases of the Liver Vol. 1 (eds. Schiff, L. & Schiff, E.R.) 707–783 (J. B. Lippincott, Philadelphia, 1993).

    Google Scholar 

  17. Lee, W.M. Acute liver failure. Am. J. Med. 96, 3S–9S (1994).

    Article  CAS  Google Scholar 

  18. Lee, W.M. Drug-induced hepatotoxicity. N. Engl. J. Med. 333, 1118–1127 (1995).

    Article  CAS  Google Scholar 

  19. Cameron, R.G., Feuer, G. & de la Iglesia, F.A. Drug-Induced Hepatotoxicity (Springer-Verlag, Berlin Heidelberg, 1996).

  20. Groth, C.G., Arborgh, B., Bjorken, C., Sundberg, B. & Lundgren, G. Correction of hyperbilirubinemia in the glucuronyltransferase-deficient rat by intraportal hepatocyte transplantation. Transplant. Proc. 9, 313–316 (1977).

    CAS  Google Scholar 

  21. Kay, M.A. . et al. Expression of human alpha 1-antitrypsin in dogs after autologous transplantation of retroviral transduced hepatocytes. Proc. Natl. Acad. Sci. USA 89, 89–93 (1992).

    Article  CAS  Google Scholar 

  22. Kocken, J.M. et al. Correction of an inborn error of metabolism by intraportal hepatocyte transplantation in a dog model. Transplantation 62, 358–364 (1996).

    Article  CAS  Google Scholar 

  23. Borrelli, E., Heyman, R., Hsi, M. & Evans, R.M. Targeting of an inducible toxic phenotype in animal cells. Proc. Natl. Acad. Sci. USA 85, 7572–7576 (1988).

    Article  CAS  Google Scholar 

  24. Heyman, R.A. et al. Thymidine kinase obliteration: creation of transgenic mice with controlled immune deficiency. Proc. Natl. Acad. Sci. USA 86, 2698–2702 (1989).

    Article  CAS  Google Scholar 

  25. Wallace, H., McLaren, K., al-Shawi, R. & Bishop, J.O. Consequences of thyroid hormone deficiency induced by the specific ablation of thyroid follicle cells in adult transgenic mice. J. Endocrinol. 143, 107–120 (1994).

    Article  CAS  Google Scholar 

  26. Brand, K. et al. Liver-associated toxicity of the HSV-tk/GCV approach and adenoviral vectors. Cancer Gene Ther. 4, 9–16 (1997).

    CAS  Google Scholar 

  27. Culver, K.W. et al. In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors. Science 256, 1550–1552 (1992).

    Article  CAS  Google Scholar 

  28. Freeman, S.M. et al. The “bystander effect”: tumor regression when a fraction of the tumor mass is genetically modified. Cancer Res. 53, 5274–5283 (1993).

    CAS  Google Scholar 

  29. Sandgren, E.P. et al. Complete hepatic regeneration after somatic deletion of an albumin-plasminogen activator transgene. Cell 66, 245–256 (1991).

    Article  CAS  Google Scholar 

  30. Kiuchi, T. et al. Impact of graft size mismatching on graft prognosis in liver transplantation from living donors. Transplantation 67, 321–327 (1999).

    Article  CAS  Google Scholar 

  31. Sutherland, D.E., Numata, M., Matas, A.J., Simmons, R.L. & Najarian, J.S. Hepatocellular transplantation in acute liver failure. Surgery 82, 124–132 (1977).

    CAS  Google Scholar 

  32. Sommer, B.G., Sutherland, D.E., Matas, A.J., Simmons, R.L. & Najarian, J.S. Hepatocellular transplantation for treatment of D-galactosamine-induced acute liver failure in rats. Transplant. Proc. 11, 578–584 (1979).

    CAS  Google Scholar 

  33. Makowka, L. et al. Reversal of experimental acute hepatic failure in the rat. J. Surg. Res. 29, 479–487 (1980).

    Article  CAS  Google Scholar 

  34. Makowka, L. et al. Studies into the mechanism of reversal of experimental acute hepatic failure by hepatocyte transplantation. Can. J. Surg. 24, 39–44 (1981).

    CAS  Google Scholar 

  35. Baumgartner, D., LaPlante-O'Neill, P.M., Sutherland, D.E. & Najarian, J.S. Effects of intrasplenic injection of hepatocytes, hepatocyte fragments and hepatocyte culture supernatants on D-galactosamine-induced liver failure in rats. Eur. Surg. Res. 15, 129–135 (1983).

    Article  CAS  Google Scholar 

  36. Birraux, J. et al. Does hepatocyte transplantation in a chemically induced acute hepatic failure make sense? Eur. J. Pediatr. Surg. 8, 224–229 (1998).

    Article  CAS  Google Scholar 

  37. Overturf, K. et al. Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tyrosinaemia type I. Nature Genet. 12, 266–273 (1996).

    Article  CAS  Google Scholar 

  38. Heckel, J.L., Sandgren, E.P., Degen, J.L., Palmiter, R.D. & Brinster, R.L. Neonatal bleeding in transgenic mice expressing urokinase-type plasminogen activator. Cell 62, 447–456 (1990).

    Article  CAS  Google Scholar 

  39. Brinster, R.L., Chen, H.Y., Trumbauer, M.E., Yagle, M.K. & Palmiter, R.D. Factors affecting the efficiency of introducing foreign DNA into mice by microinjecting eggs. Proc. Natl. Acad. Sci. USA 82, 4438–4442 (1985).

    Article  CAS  Google Scholar 

  40. Rhim, J.A., Sandgren, E.P., Degen, J.L., Palmiter, R.D. & Brinster, R.L. Replacement of diseased mouse liver by hepatic cell transplantation. Science 263, 1149–1152 (1994).

    Article  CAS  Google Scholar 

  41. Kisseberth, W.C., Brettingen, N.T., Lohse, J.K. & Sandgren, E.P. Ubiquitous expression of marker transgenes in mice and rats. Dev. Biol. 214, 128–138 (1999).

    Article  CAS  Google Scholar 

  42. Klaunig, J.E. et al. Mouse liver cell culture. I. Hepatocyte isolation. In Vitro 17, 913–925 (1981).

    Article  CAS  Google Scholar 

  43. Smith, D.D., Jr. & Campbell, J.W. Distribution of glutamine synthetase and carbamoyl-phosphate synthetase I in vertebrate liver. Proc. Natl. Acad. Sci. USA 85, 160–164 (1988).

    Article  CAS  Google Scholar 

  44. Overturf, K., al-Dhalimy, M., Ou, C.N., Finegold, M. & Grompe, M. Serial transplantation reveals the stem-cell-like regenerative potential of adult mouse hepatocytes. Am. J. Pathol. 151, 1273–1280 (1997).

    CAS  Google Scholar 

Download references

Acknowledgements

We thank P. MacWilliams for assistance and discussions regarding blood chemistry analysis, M. Bowden for assistance with surgeries and computer image analysis, and R. Szakaly for assistance with figures. This work has been supported by National Institutes of Health grant R01-DK49787 to E.P.S., and by a National Science Foundation predoctoral fellowship to K.M.B.

Author information

Authors and Affiliations

  1. Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, 53706, Wisconsin, USA

    Kristin M. Braun & Eric P. Sandgren

  2. Division of Developmental Biology, Children's Hospital Research Foundation, Cincinnati, 45229, Ohio, USA

    Jay L. Degen

Authors
  1. Kristin M. Braun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jay L. Degen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eric P. Sandgren
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eric P. Sandgren.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Braun, K., Degen, J. & Sandgren, E. Hepatocyte transplantation in a model of toxin-induced liver disease: variable therapeutic effect during replacement of damaged parenchyma by donor cells. Nat Med 6, 320–326 (2000). https://doi.org/10.1038/73179

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/73179

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing