Monocrotaline promotes transplanted cell engraftment and advances liver repopulation in rats via liver conditioning

Authors

  • Brigid Joseph,

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

    1. Departments of Medicine and Pathology, Marion Bessin Liver Research Center, Cancer Research Center, Diabetes Center, and General Clinical Research Center, Jack and Pearl Resnick Campus, Albert Einstein College of Medicine, Bronx, NY
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  • Ekaterine Berishvili,

    1. Departments of Medicine and Pathology, Marion Bessin Liver Research Center, Cancer Research Center, Diabetes Center, and General Clinical Research Center, Jack and Pearl Resnick Campus, Albert Einstein College of Medicine, Bronx, NY
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  • Kuldeep K. Bhargava,

    1. Division of Nuclear Medicine, Long Island Jewish Medical Center Campus, Albert Einstein College of Medicine, Bronx, NY
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  • Christopher J. Palestro,

    1. Division of Nuclear Medicine, Long Island Jewish Medical Center Campus, Albert Einstein College of Medicine, Bronx, NY
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  • Sanjeev Gupta

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


  • Potential conflict of interest: Nothing to report.

Abstract

Disruption of the hepatic endothelial barrier or Kupffer cell function facilitates transplanted cell engraftment in the liver. To determine whether these mechanisms could be activated simultaneously, we studied the effects of monocrotaline, a pyrollizidine alkaloid, with reported toxicity in liver sinusoidal endothelial cells and Kupffer cells. The effects of monocrotaline in Fischer 344 rats were examined by tissue morphology, serum hyaluronic acid levels, and liver tests (endothelial and hepatocyte injury) or incorporation of carbon and 99mTc-sulfur colloid (Kupffer cell damage). To study changes in cell engraftment and liver repopulation, Fischer 344 rat hepatocytes were transplanted into syngeneic dipeptidyl peptidase IV–deficient rats followed by histological assays. We observed extensive endothelial injury without Kupffer cell or hepatocyte damage in monocrotaline-treated rats. Monocrotaline enhanced transplanted cell engraftment without changes in transplanted cell numbers or induction of proliferation in native hepatocytes over 3 months. In monocrotaline-treated rats, transplanted cells integrated into the liver parenchyma and survived in vascular spaces. To determine whether native hepatocytes suffered inapparent damage after monocrotaline, we introduced further liver injury with carbon tetrachloride subsequent to cell transplantation. Monocrotaline sensitized the liver to carbon tetrachloride–induced necrosis, which advanced transplanted cell proliferation, leading to significant liver repopulation. During this process, we observed proliferation of bile duct cells and small epithelial cells, although transplanted hepatocytes did not appear to reconstitute bile ducts. The studies showed that perturbation of multiple liver cell compartments by monocrotaline promoted transplanted cell engraftment and proliferation. In conclusion, development of drugs with monocrotaline-like effects will help advance liver cell therapy. (HEPATOLOGY 2006;44:1411–1420.)

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