Hepatocytes Exhibit Superior Transgene Expression after Transplantation into Liver and Spleen Compared with Peritoneal Cavity or Dorsal Fat Pad: Implications for Hepatic Gene Therapy

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Abstract
For hepatic gene therapy or applications of hepatocyte transplantation in liver failure, survival and function of transplanted cells is critical. Insights into site-specific gene regulation will significantly facilitate development of appropriate strategies for transplanting hepatocytes. To assess the function of transplanted cells, we used a transgenic hepatitis B virus (HBV) hepatocyte system, which allowed analysis of cellular gene expression with HBV surface antigen (HBsAg) mRNA expression, as well as secretion of HBsAg into peripheral circulation. When congeneic HBV hepatocytes were transplanted into the liver (via spleen), serum HBsAg promptly appeared in circulation and persisted for the entire duration of the studies. In contrast, transplantation of hepatocytes into the peritoneal cavity or dorsal fat pad resulted in serum 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 cavity or dorsal fat pad. Despite persistence of transplanted hepatocytes in peritoneal cavity or dorsal fat pad, serum HBsAg was cleared by antibody to HBsAg (anti-HBs) but this was not observed after hepatocyte transplantation into spleen. As the function of transplanted hepatocytes is optimally regulated in the liver, hepatic reconstitution with cell transplantation will be most appropriate for gene therapy.

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