Hepatocyte transplantation activates hepatic stellate cells with beneficial modulation of cell engraftment in the rat

Authors

  • Daniel Benten,

    1. Departments of Medicine and Pathology, Marion Bessin Liver Research Center, Comprehensive Cancer Research Center and General Clinical Research Center, Albert Einstein College of Medicine, Bronx, NY
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  • Vinay Kumaran,

    1. Departments of Medicine and Pathology, Marion Bessin Liver Research Center, Comprehensive Cancer Research Center and General Clinical Research Center, Albert Einstein College of Medicine, Bronx, NY
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  • Brigid Joseph,

    1. Departments of Medicine and Pathology, Marion Bessin Liver Research Center, Comprehensive Cancer Research Center and General Clinical Research Center, Albert Einstein College of Medicine, Bronx, NY
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  • Jörn Schattenberg,

    1. Departments of Medicine and Pathology, Marion Bessin Liver Research Center, Comprehensive Cancer Research Center and General Clinical Research Center, Albert Einstein College of Medicine, Bronx, NY
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  • Yury Popov,

    1. Department of Medicine I, University of Erlangen-Nuernberg, Germany
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  • Detlef Schuppan,

    1. Department of Medicine I, University of Erlangen-Nuernberg, Germany
    2. Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
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  • Sanjeev Gupta

    Corresponding author
    1. Departments of Medicine and Pathology, Marion Bessin Liver Research Center, Comprehensive Cancer Research Center and General Clinical Research Center, Albert Einstein College of Medicine, Bronx, NY
    • Albert Einstein College of Medicine, Ullmann 625, 1300 Morris Park Avenue, Bronx, NY 10461
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    • fax: 718-430-8975


  • Potential conflict of interest: Nothing to report.

Abstract

We investigated whether transplanted hepatocytes interact with hepatic stellate cells, as cell–cell interactions could modulate their engraftment in the liver. We transplanted Fischer 344 rat hepatocytes into syngeneic dipeptidyl peptidase IV–deficient rats. Activation of hepatic stellate cells was analyzed by changes in gene expression, including desmin and α-smooth muscle actin, matrix proteases and their inhibitors, growth factors, and other stellate cell-associated genes with histological methods or polymerase chain reaction. Furthermore, the potential role of hepatic ischemia, Kupffer cells, and cytokine release in hepatic stellate cell activation was investigated. Hepatocyte transplantation activated desmin-positive hepatic stellate cells, as well as Kupffer cells, including in proximity with transplanted cells. Inhibition of Kupffer cells by gadolinium chloride, blockade of tumor necrosis factor alpha (TNF-α) activity with etanercept or attenuation of liver ischemia with nitroglycerin did not decrease this hepatic stellate cell perturbation. After cell transplantation, soluble signals capable of activating hepatic stellate cells were rapidly induced, along with early upregulated expression of matrix metalloproteinases-2, -3, -9, -13, -14, and their inhibitors. Moreover, prior depletion of activated hepatic stellate cells with gliotoxin decreased transplanted cell engraftment. In conclusion, cell transplantation activated hepatic stellate cells, which, in turn, contributed to transplanted cell engraftment in the liver. Manipulation of hepatic stellate cells might provide new strategies to improve liver repopulation after enhanced transplanted cell engraftment. Supplementary material for this article can be found on the HEPATOLOGYwebsite (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html). (HEPATOLOGY 2005;42:1072–1081.)

Ancillary