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(American Journal of Pathology. 1998;153:319-329.)
© 1998 American Society for Investigative Pathology

Animal Model

Long-Term, Near-Total Liver Replacement by Transplantation of Isolated Hepatocytes in Rats Treated with Retrorsine

Ezio Laconi* , Ran Oren , Deb K. Mukhopadhyay , Ethel Hurston , Sergio Laconi* , Paolo Pani* , Mariana D. Dabeva and David A. Shafritz§¶||

From the Istituto di Patologia Sperimentale,* Ospedale Oncologico "A Businco," University of Cagliari, Cagliari, Italy, and The Marion Bessin Liver Research Center, Division of Gastroenterology, Hepatology and Nutrition and the Departments of Medicine,§ Cell Biology,¶ and Pathology,^|| Albert Einstein College of Medicine of Yeshiva University, Bronx, New York

Genetically marked hepatocytes from dipeptidyl peptidase (DPP) IV⁺ Fischer 344 rats were transplanted into the liver of DPPIV^- mutant Fischer 344 rats after a combined treatment with retrorsine, a pyrrolizidine alkaloid that blocks the hepatocyte cell cycle, and two-thirds partial hepatectomy. In female rats, clusters of proliferated DPPIV⁺ hepatocytes containing 20 to 50 cells/cluster, mostly derived from single transplanted cells, were evident at 2 weeks, increasing in size to hundreds of cells per cluster at 1 month and 1000 to several thousand cells per cluster at 2 months, representing 40 to 60% of total hepatocyte mass. This level of hepatocyte replacement remained constant for up to 1 year, the duration of experiments conducted. In male rats, liver replacement occurred more rapidly and was more extensive, with transplanted hepatocytes representing 10 to 15% of hepatocyte mass at 2 weeks, 40 to 50% at 1 month, 90 to 95% at 2 months, 98% at 4 months, and 99% at 9 months. Transplanted hepatocytes were integrated into the parenchymal plates, exhibited unique hepatic biochemical functions, and fully reconstituted a normal hepatic lobular structure. The extensive proliferation of transplanted cells in this setting of persistent inhibition of resident hepatocytes represents a new general model to study basic aspects of liver repopulation with potential applications in chronic liver disease and ex vivo gene therapy.

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