Optimal Technique

Although significant progress has been achieved in isolated hepatocyte transplantation, the optimal site of implantation has not been determined. Many investigators have transplanted hepatocytes at sites away from the liver, including spleen, kidney, abdominal cavity, thymus, testis, brain, pancreas, lungs, subcutaneous tissue, muscle, fat pads and other locations.1-8,24-26 Although the spleen and peritoneal cavity have been most frequently used, there are reasons to believe that transplanted hepatocytes, similarly to auxiliary liver (auto) grafts, undergo atrophy when implanted ectopically outside the portal stream. In addition, the intrasplenic route is limited by the small number of cells transplanted. In 1986, Vroemen et al observed that, during intrasplenic injection, the cell suspension was flowing via the splenic vein into the portal system. 6 Similar findings were reported by Gupta et al.25 We therefore examined direct intraportal hepatocyte transplantation. We were hoping to obtain better cell engraftment, survival and function, because:

1. Transplanting hepatocytes into the unique liver architecture allows interaction with other hepatocytes and nonparenchymal cells;

2. Proximity to hepatocyte-specific growth and differentiation factors creates an environment particularly conducive to hepatocyte engraftment and function;

3. Locally released mitogens and portal-borne hepatotrophic factors can increase transplanted cell numbers;

4. The liver may be an immunologically privileged site;

5. In the liver, hepatocytes are able to secrete bile directly into the biliary tree.

In the past, intraportal infusion of isolated hepatocytes produced severe liver damage, due to the occlusion of the portal blood supply by transplanted cells.4 In addition, early mortality resulted from cell aggregates passing to the cardiopulmonary circulation, portal vein thrombosis and portal hypertension. We have overcome these complications by developing a method of intraportal injection of isolated hepatocytes in a single cell suspension selectively into specific liver lobes, but not others, which allows portal decompression following transplantation.9 Use of this technique has resulted in improved cell engraftment, absence of thrombosis in the portal venules and minimal to no injury to the liver. We have subsequently transplanted hepatocytes repeatedly by means of an indwelling catheter system connected to the portal venous branch and designed a method of stimulating transplanted hepatocytes to proliferate by means of portal blood occlusion of the nontransplanted liver lobes. 12,19 The latter strategy resulted in near-complete correction of analbuminemia in NAR rats13 and in profound and sustained lowering of blood cholesterol levels in Watanabe hyperlipidemic (WHHL) rabbits.14

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