Role of thyroid hormone in stimulating liver repopulation in the rat by transplanted hepatocytes

Authors

  • Ran Oren,

    1. The Marion Bessin Liver Research Center, University of Cagliari, Cagliari, Italy
    2. Division of Gastroenterology, Hepatology, and Nutrition, University of Cagliari, Cagliari, Italy
    3. Medicine, University of Cagliari, Cagliari, Italy
    Search for more papers by this author
  • Mariana D. Dabeva,

    1. The Marion Bessin Liver Research Center, University of Cagliari, Cagliari, Italy
    2. Division of Gastroenterology, Hepatology, and Nutrition, University of Cagliari, Cagliari, Italy
    3. Medicine, University of Cagliari, Cagliari, Italy
    Search for more papers by this author
  • Anthony N. Karnezis,

    1. The Marion Bessin Liver Research Center, University of Cagliari, Cagliari, Italy
    2. Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY University of Cagliari, Cagliari, Italy
    Search for more papers by this author
  • Petko M. Petkov,

    1. The Marion Bessin Liver Research Center, University of Cagliari, Cagliari, Italy
    2. Division of Gastroenterology, Hepatology, and Nutrition, University of Cagliari, Cagliari, Italy
    3. Medicine, University of Cagliari, Cagliari, Italy
    Search for more papers by this author
  • Richard Rosencrantz,

    1. The Marion Bessin Liver Research Center, University of Cagliari, Cagliari, Italy
    2. Division of Pediatric Gastroenterology and Department of Pediatrics, and the Departments of University of Cagliari, Cagliari, Italy
    Search for more papers by this author
  • Jaswinder P. Sandhu,

    1. The Marion Bessin Liver Research Center, University of Cagliari, Cagliari, Italy
    2. Division of Gastroenterology, Hepatology, and Nutrition, University of Cagliari, Cagliari, Italy
    3. Medicine, University of Cagliari, Cagliari, Italy
    Search for more papers by this author
  • Steven F. Moss,

    1. Division of Gastroenterology, St. Luke's/Roosevelt Hospital Center University of Cagliari, Cagliari, Italy
    Search for more papers by this author
  • Shaobai Wang,

    1. Division of Gastroenterology, St. Luke's/Roosevelt Hospital Center University of Cagliari, Cagliari, Italy
    Search for more papers by this author
  • Ethel Hurston,

    1. The Marion Bessin Liver Research Center, University of Cagliari, Cagliari, Italy
    2. Division of Gastroenterology, Hepatology, and Nutrition, University of Cagliari, Cagliari, Italy
    3. Medicine, University of Cagliari, Cagliari, Italy
    Search for more papers by this author
  • Ezio Laconi,

    1. Istituto di Patologia Sperimentale, Ospedale Oncologico “A Businco,” University of Cagliari, Cagliari, Italy
    Search for more papers by this author
  • Peter R. Holt,

    1. Division of Gastroenterology, St. Luke's/Roosevelt Hospital Center University of Cagliari, Cagliari, Italy
    Search for more papers by this author
  • Swan N. Thung,

    1. Department of Pathology, Mount Sinai Medical Center, New York, NY
    Search for more papers by this author
  • Liang Zhu,

    1. The Marion Bessin Liver Research Center, University of Cagliari, Cagliari, Italy
    2. Medicine, University of Cagliari, Cagliari, Italy
    3. Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY University of Cagliari, Cagliari, Italy
    Search for more papers by this author
  • David A. Shafritz M.D.

    Corresponding author
    1. The Marion Bessin Liver Research Center, University of Cagliari, Cagliari, Italy
    2. Division of Gastroenterology, Hepatology, and Nutrition, University of Cagliari, Cagliari, Italy
    3. Medicine, University of Cagliari, Cagliari, Italy
    4. Cell Biology, University of Cagliari, Cagliari, Italy
    5. Pathology, and University of Cagliari, Cagliari, Italy
    • Marion Bessin Liver Research Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461fax: (718) 430-8975
    Search for more papers by this author

Abstract

Recently, we reported near-complete repopulation of the rat liver by transplanted hepatocytes using retrorsine (RS), a pyrrolizidine alkaloid that alkylates cellular DNA and blocks proliferation of resident hepatocytes, followed by transplantation of normal hepatocytes in conjunction with two-thirds partial hepatectomy (PH). Because two-thirds PH is not feasible for use in humans, in the present study, we evaluated the ability of thyroid hormone (triiodothyronine [T3 ]), a known hepatic mitogen, to stimulate liver repopulation in the retrorsine model. Because T3 initiates morphogenesis in amphibians through a process involving both cell proliferation and apoptosis, we also determined whether apoptosis might play a role in the mechanism of hepatocyte proliferation induced by T3 . Following hepatocyte transplantation and repeated injections of T3 , the number of transplanted hepatocytes in the liver of RS-pretreated animals increased progressively to repopulate 60% to 80% of parenchymal cell mass in 60 days. We show further that T3 treatment augments proliferation of normal hepatocytes, as evidenced by increased histone 3 mRNA and cyclin-dependent kinase 2 (cdk2) expression, and this is followed by apoptosis. These combined effects of T3 lead to selective proliferation of transplanted hepatocytes in RS-pretreated rats, while endogenous hepatocytes, which are blocked in their proliferative capacity by RS, mainly undergo apoptosis. Thus, T3 can replace PH in the RS-based rat liver repopulation model and therefore represents a significant advance in developing methods for hepatocyte transplantation.

Ancillary