LONG-TERM, NEAR-TOTAL LIVER REPLACEMENT BY TRANSPLANTATION OF ISOLATED HEPATOCYTES IN RATS TREATED WITH RETRORSINE

Genetically marked hepatocytes from dipeptidyl peptidase (DPP) IV+ Fis cher 344 rats were transplanted into the liver of DPPIV- mutant Fische r 344 rats after a combined treatment with retrorsine, a pyrrolizidine alkaloid that blocks the hepatocyte cell cycle, and two-thirds partia l hepatectomy. In female rats, clusters of proliferated DPPIV+ hepatoc ytes containing 20 to 50 cells/cluster, mostly derived from single tra nsplanted cells, were evident at 2 weeks, increasing in size to hundre ds 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 ma ss. This level of hepatocyte replacement remained constant for up to 1 year, the duration of experiments conducted. In male rats, Liver repl acement occurred more rapidly and was more extensive, with transplante d 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 parenchym al plates, exhibited unique hepatic biochemical functions, and fully r econstituted a normal hepatic lobular structure, The extensive prolife ration 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 l iver disease and ex vivo gene therapy.