Regulation of Hepatocyte Engraftment and Proliferation after Cytotoxic Drug-Induced Perturbation of the Rat Liver

Abstract

Perturbations in specific liver cell compartments benefit transplanted cell engraftment and/or proliferation. We analyzed whether cytotoxic drugs interfering with the integrity of genomic DNA or cell division could be useful for liver cell transplantation. We used dipeptidyl peptidase IV deficient (DPPIV-) rats as recipients of syngeneic F344 rat hepatocytes. Rats were pretreated with doxorubicin, irinotecan, or vincristine prior to cell transplantation and synergistic liver perturbations were induced by drug administration followed by partial hepatectomy or carbon tetrachloride treatments. Transplanted cells were identified by DPPIV histochemistry and cell engraftment and proliferation were analyzed morphometrically. Perturbations in endothelial, Kupffer cell, and hepatocyte compartments were analyzed by electron microscopy, carbon incorporation, and blood tests, respectively. Cell engraftment was improved in rats treated with doxorubicin but not with irinotecan or vincristine. Doxorubicin disrupted endothelial cells for up to seven days without causing Kupffer cell or hepatocellular toxicity. Neither doxorubicin nor vincristine induced liver repopulation in animals up to three months, including after partial hepatectomy or carbon tetrachloride-induced additional liver injury. Doxorubicin-induced hepatic endothelial damage enhanced cell engraftment, which should be useful in cell therapy strategies.