Factors influencing hepatocyte trafficking during allogeneic hepatocyte transplantation: Improved liver sequestration with isolated perfusion
Transplantation of normal or ex vivo modified hepatocytes holds promise in therapy of a variety of diseases. In order to investigate hepatocyte trafficking, and specifically to determine whether the route, method of delivery, or other host factors may affect hepatocyte sequestration in the liver, 51chromium- and 111indium-labeled hepatocytes were transplanted into allogeneic hosts. Systemic injection of hepatocytes into the femoral vein resulted in sequestration mainly in the lungs (30 +/- 4%) whereas sequestration in the liver amounted to only 5 +/- 1%. Portal injection resulted in a dramatic increase in the liver sequestration (52 +/- 4%) and a reduction in the lung (2 +/- 1%, P < 0.05 vs systemic injection). Nevertheless, nearly half of portally injected hepatocytes came to rest in other organ sites. Partial hepatectomy prior to transplantation did not change the total hepatocyte sequestration in the liver or the organ specific activity. A remote site of inflammation, in the form of a turpentine abscess, also did not alter the pattern of hepatocyte trafficking. Isolated perfusion of the liver with labeled hepatocyte, however, significantly increased the sequestration of hepatocytes at this organ (control, 52 +/- 4%; isolated perfusion, 71 +/- 9%; P < 0.05). In the delivery of potentially toxic gene products for therapy, isolated perfusion of the target organ appears to provide the greatest likelihood of restricting expression of potentially toxic gene products to the target organ.