STUDIES ON THE SAFETY OF INTRASPLENIC HEPATOCYTE TRANSPLANTATION - RELEVANCE TO EXVIVO GENE-THERAPY AND LIVER REPOPULATION IN ACUTE HEPATIC-FAILURE

Hepatocytes transplanted into the host liver engraft promptly, retain normal function, and survive indefinitely. Although intrasplenic trans plantation is effective in delivering hepatocytes to the liver, to def ine potentially limiting complications, we studied its safety in norma l, cirrhotic, and partial portal vein-ligated rats. In normal rats, po rtal pressures increased severalfold after hepatocyte transplantation but returned to normal within 3 weeks. In contrast, in portal hyperten sive rats with partial portal vein ligation or cirrhosis, portal press ures were either unchanged or increased less after hepatocyte transpla ntation. However, more transplanted cells migrated to the lungs along with a rise in right atrial pressures in portal hypertensive rats. Fur ther quantitative studies using Indium-111-labeled hepatocytes showed that intrasplenic retention of transplanted hepatocytes was similar in all animal groups. Intrahepatic cell translocation was comparable in normal and cirrhotic rats, whereas fewer cells migrated to the liver i n partial portal vein-ligated rats. The most remarkable difference, ho wever, was significantly greater intrapulmonary translocation of hepat ocytes in portal hypertensive rats, which was presumably related to po rtosystemic shunting. These results indicate that because intrasplenic hepatocyte transplantation induces only temporary portal hypertension in normal subjects, potential strategies to augment liver repopulatio n could include repeated cell transplantation. This should be useful f or optimizing the results of ex vivo gene therapy, or other hepatocyte -based therapies. However, the hepatic and portal hemodynamic status r equires careful evaluation in portal hypertensive or cirrhotic subject s if serious complications are to be avoided.