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Hepatic sinusoidal vasodilators improve transplanted cell engraftment and ameliorate microcirculatory perturbations in the liver

Authors

  • Sanjeev Slehria Ullmann 625, 1300 Morris Park Ave.,

    Corresponding author
    1. Marion Bessin Liver Research Center, College of Medicine, University of Arizona, Tucson, AZ
    2. Department of Medicine, College of Medicine, University of Arizona, Tucson, AZ
    • Bronx, NY 10461. fax: 718-430-8975.
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  • Pankaj Rajvanshi,

    1. Marion Bessin Liver Research Center, College of Medicine, University of Arizona, Tucson, AZ
    2. Department of Medicine, College of Medicine, University of Arizona, Tucson, AZ
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  • Yoshiya Ito,

    1. Department of Cell Biology and Anatomy, College of Medicine, University of Arizona, Tucson, AZ
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  • Rana P. Sokhi,

    1. Marion Bessin Liver Research Center, College of Medicine, University of Arizona, Tucson, AZ
    2. Department of Medicine, College of Medicine, University of Arizona, Tucson, AZ
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  • Kuldeep K. Bhargava,

    1. Division of Nuclear Medicine at Long Island Jewish Hospital Campus, University of Arizona, Tucson, AZ
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  • Christopher J. Palestro,

    1. Division of Nuclear Medicine at Long Island Jewish Hospital Campus, University of Arizona, Tucson, AZ
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  • Robert S. McCuskey,

    1. Department of Cell Biology and Anatomy, College of Medicine, University of Arizona, Tucson, AZ
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  • Sanjeev Gupta

    1. Marion Bessin Liver Research Center, College of Medicine, University of Arizona, Tucson, AZ
    2. Department of Medicine, College of Medicine, University of Arizona, Tucson, AZ
    3. Department of Pathology, Albert Einstein College of Medicine, Bronx, NY
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Abstract

After transplantation, hepatocytes entering liver sinusoids are engrafted, whereas cells entrapped in portal spaces are cleared. We studied whether hepatic sinusoidal dilatation will increase the entry of transplanted cells in the liver lobule, improve cell engraftment, and decrease microcirculatory perturbations. F344 rat hepatocytes were transplanted intrasplenically into syngeneic dipeptidyl peptidase IV (DPPIV)-deficient rats. Animals were treated with adrenergic receptor blockers (phentolamine, labetalol), a calcium channel blocker (nifedipine), and splanchnic vasodilators (nitroglycerine, calcitonin gene-related peptide [CGRP], glucagon). Transplanted cells were localized by histochemistry. The hepatic microcirculation was studied with in vivo videomicroscopy. Changes in cell translocations were analyzed by injection of 99mTc-labeled hepatocytes. Pretreatment with phentolamine and nitroglycerine increased transplanted cell entry in liver sinusoids, whereas labetalol, nifedipine, CGRP, and glucagon were ineffective. Increased deposition of transplanted cells in sinusoids resulted in greater cell engraftment. In vivo microscopy showed disruption of sinusoidal blood flow immediately after cell transplantation with circulatory restoration requiring more than 12 to 24 hours after cell transplantation. However, in nitroglycerine-treated animals, sinusoidal blood flow was perturbed less. Nitroglycerine did not meaningfully increase intrapulmonary cell translocations. In conclusion, these findings indicate that hepatic sinusoidal capacitance is regulated by α-adrenergic– and nitroglycerine-responsive elements. Sinusoidal vasodilatation benefited intrahepatic distribution of transplanted cells and restored hepatic microcirculation after cell transplantation. This shall facilitate optimization of clinical cell transplantation and offers novel ways to investigate vascular mechanisms regulating hepatic sinusoidal reactivity.

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