HEPATOCYTES EXHIBIT SUPERIOR TRANSGENE EXPRESSION AFTER TRANSPLANTATION INTO LIVER AND SPLEEN COMPARED WITH PERITONEAL-CAVITY OR DORSAL FATPAD - IMPLICATIONS FOR HEPATIC GENE-THERAPY

For hepatic gene therapy or applications of hepatocyte transplantation in liver failure, survival and function of transplanted cells is crit ical. Insights into site-specific gene regulation will significantly f acilitate development of appropriate strategies for transplanting hepa tocytes. To assess the function of transplanted cells, we used a trans genic hepatitis B virus (HBV) hepatocyte system, which allowed analysi s of cellular gene expression with HBV surface antigen (HBsAg) mRNA ex pression, as well as secretion of HBsAg into peripheral circulation. W hen congeneic HBV hepatocytes were transplanted into the liver (via sp leen), serum HBsAg promptly appeared in circulation and persisted for the entire duration of the studies. In contrast, transplantation of he patocytes into the peritoneal cavity or dorsal fat pad resulted in ser um HBsAg levels that were either significantly lower or gradually rose after a lag period. HBsAg mRNA expression was several-fold greater in transplanted hepatocytes in liver or spleen versus in peritoneal cavi ty or dorsal fat pad. Despite persistence of transplanted hepatocytes in peritoneal cavity or dorsal fat pad, serum HBsAg was cleared by ant ibody to HBsAg (anti-HBs) but this was not observed after hepatocyte t ransplantation into spleen, As the function of transplanted hepatocyte s is optimally regulated in the liver, hepatic reconstitution with cel l transplantation will be most appropriate for gene therapy.