Entry and integration of transplanted hepatocytes in rat liver plates occur by disruption of hepatic sinusoidal endothelium

Authors

  • Sanjeev Gupta,

    Corresponding author
    1. Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY
    2. Cancer Research Center, Albert Einstein College of Medicine, Bronx, NY
    3. Medicine, Albert Einstein College of Medicine, Bronx, NY
    • Address reprint requests to: Sanjeev Gupta, M.D., Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Ullmann 625, 1300 Morris Park Avenue, Bronx, NY 10461. fax: (718) 430-8975
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  • Pankaj Rajvanshi,

    1. Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY
    2. Medicine, Albert Einstein College of Medicine, Bronx, NY
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  • Rana Sokhi,

    1. Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY
    2. Medicine, Albert Einstein College of Medicine, Bronx, NY
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  • Sanjeev Slehria,

    1. Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY
    2. Medicine, Albert Einstein College of Medicine, Bronx, NY
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  • Ana Yam,

    1. Pathology, Pathology, Albert Einstein College of Medicine, Bronx, NY
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  • Andrew Kerr,

    1. Radiology, Albert Einstein College of Medicine, Bronx, NY
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  • Phyllis M. Novikoff

    1. Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY
    2. Pathology, Pathology, Albert Einstein College of Medicine, Bronx, NY
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Abstract

To establish the process by which transplanted cells integrate into the liver parenchyma, we used dipeptidyl peptidase IV-deficient F344 rats as hosts. On intrasplenic injection, transplanted hepatocytes immediately entered liver sinusoids, along with attenuation of portal vein radicles on angiography. However, a large fraction of transplanted cells (>70%) was rapidly cleared from portal spaces by phagocyte/macrophage responses. On the other hand, transplanted hepatocytes entering the hepatic sinusoids showed superior survival. These cells translocated from sinusoids into liver plates between 16 and 20 hours after transplantation, during which electron microscopy showed disruption of the sinusoidal endothelium. Interestingly, production of vascular endothelial growth factor was observed in hepatocytes before endothelial disruptions. Portal hypertension and angiographic changes resulting from cell transplantation resolved promptly. Integration of transplanted hepatocytes in the liver parenchyma required cell membrane regenesis, with hybrid gap junctions and bile canaliculi forming over 3 to 7 days after cell transplantation. We propose that strategies to deposit cells into distal hepatic sinusoids, to disrupt sinusoidal endothelium for facilitating cell entry into liver plates, and to accelerate cell integrations into liver parenchyma will advance applications of hepatocyte transplantation

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