The future of hepatocyte transplantation

Although the clinical potential of liver cell transplantation has been increasingly acknowledged in recent years, several important issues remain to be addressed before this method is effectively applied in the treatment of human diseases. The application of liver cell transplantation has been envisioned for (a) temporary metabolic support during acute liver failure, (b) long-term metabolic supplementation in chronic liver failure, (c) provision of specific liver functions in inherited metabolic diseases of the liver and (d) as a vehicle for hepatocyte-directed ex vivo gene therapy. In addition to being a simpler procedure, the advantages of hepatocyte transplantation over orthotopic liver transplantation are that hepatocytes can be cryopreserved, cells from a single donor can be transplanted in several recipients, conditionally immortalized hepatocytes may be expanded by culturing in vitro and abrogation of allograft rejection may be easier with hepatocytes than with the whole organ. The optimum route and method of liver cell transplantation are still being investigated. Presently, seeding of the hepatic parenchyma by injection into the splenic pulp appears to be the most efficient method, although the peritoneal cavity may also provide a suitable site. In rodents, up to 10% of the liver cell mass may be replaced by intrasplenic injection. However, in the cirrhotic liver, intrasplenic injection of hepatocytes produces severe and prolonged portal hypertension. The problem of liver shortage may be partly alleviated by the use of conditionally immortalized hepatocytes, fetal hepatocytes or hepatocyte progenitors. For ex vivo gene therapy, the problem of allograft rejection has been circumvented by harvesting liver cells from the mutant subject and retransplanting these cells after introduction of a normal therapeutic gene. Ultraviolet radiation or encapsulation of hepatocytes inhibits allograft rejection. Recently, injection of donor type splenocytes into the thymus of recipient rodents, along with ablation of the peripheral lymphocytes with antilymphocytic serum, was shown to tolerize the recipient to allogeneic hepatocytes transplanted at extrathymic sites.