Hepatic targeting of transplanted liver sinusoidal endothelial cells in intact mice

Authors

  • Daniel Benten,

    1. Departments of Medicine and Pathology, Marion Bessin Liver Research Center, Cancer Research Center, Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY
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    • Daniel Benten and Antonia Follenzi contributed equally to the study.

  • Antonia Follenzi,

    1. Departments of Medicine and Pathology, Marion Bessin Liver Research Center, Cancer Research Center, Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY
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    • Daniel Benten and Antonia Follenzi contributed equally to the study.

  • Kuldeep K. Bhargava,

    1. Division of Nuclear Medicine, Long Island Jewish Medical Center, New Hyde Park, NY
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  • Vinay Kumaran,

    1. Departments of Medicine and Pathology, Marion Bessin Liver Research Center, Cancer Research Center, Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY
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  • Christopher J. Palestro,

    1. Division of Nuclear Medicine, Long Island Jewish Medical Center, New Hyde Park, NY
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  • Sanjeev Gupta

    Corresponding author
    1. Departments of Medicine and Pathology, Marion Bessin Liver Research Center, Cancer Research Center, Diabetes Research Center, 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

Targeting of cells to specific tissues is critical for cell therapy. To study endothelial cell targeting, we isolated mouse liver sinusoidal endothelial cells (LSEC) and examined cell biodistributions in animals. To identify transplanted LSEC in tissues, we labeled cells metabolically with DiI-conjugated acetylated low density lipoprotein particles (DiI-Ac-LDL) or 111Indium-oxine, used LSEC from Rosa26 donors expressing β-galactosidase or Tie-2-GFP donors with green fluorescent protein (GFP) expression, and tranduced LSEC with a GFP-lentiviral vector. LSEC efficiently incorporated 111Indium and DiI-Ac-LDL and expressed GFP introduced by the lentiviral vector. Use of radiolabeled LSEC showed differences in cell biodistributions in relation to the cell transplantation route. After intraportal injection, LSEC were largely in the liver (60 ± 13%) and, after systemic intravenous injection, in lungs (67 ± 9%); however, after intrasplenic injection, only some LSEC remained in the spleen (29 ± 10%; P < .01), whereas most LSEC migrated to the liver or lungs. Transplanted LSEC were found in the liver, lungs, and spleen shortly after transplantation, whereas longer-term cell survival was observed only in the liver. Transplanted LSEC were distinct from Kupffer cells with expression of Tie-2 promoter-driven GFP and of CD31, without F4/80 reactivity. In further studies using radiolabeled LSEC, we established that the manipulation of receptor-mediated cell adhesion in liver sinusoids or the manipulation of blood flow–dependent cell exit from sinusoids improved intrahepatic retention of LSEC to 89 ± 7% and 89 ± 5%, respectively (P < .01). In conclusion, the targeting of LSEC to the liver and other organs is directed by vascular bed–specific mechanisms, including blood flow–related processes, and cell-specific factors. These findings may facilitate analysis of LSEC for cell and gene therapy applications. (HEPATOLOGY 2005.)

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