Transplantation of conditionally immortalized hepatocytes to treat hepatic encephalopathy
Authors: I Schumacher
Journal: Hepatology (1996)

form cell preparations makes it unlikely that primary human Transplantation of hepatocytes has been shown to hepatocytes would be available in sufficient quantity and adprovide metabolic support during liver failure in experiequate quality to treat more than a fraction of the patients mental models.The potential clinical application of hewho would need them.The alternative approach of using patocyte transplantation, however, is limited by the animal cells would raise additional concerns regarding the need for readily available, well-characterized cells, and transmission of infectious agents and immunological and posa worldwide shortage of donor organs.A clonal hepatosible physiological incompatibilities with human hosts. 3cyte cell line that could be grown economically in vitro An attractive alternative to the transplantation of primary and would exhibit a differentiated, nontransformed phehepatocytes would be to use a clonal hepatocyte cell line that notype following transplantation would be an attractive could be grown economically in tissue culture and would exsolution to this problem.To test this alternative, primary hibit the characteristics of differentiated, nontransformed he-Lewis rat hepatocytes were conditionally immortalized patocytes following transplantation.Such cell lines would ofby retroviral transduction with a thermolabile mutant fer the advantages of unlimited availability, uniformity, Simian virus 40 (SV40) large T antigen.The cloned imsterility and freedom from infectious pathogens, and could mortalized cells proliferate in culture at 33ЊC and stop be used clinically to improve the lives of a large number of growing at 37ЊC to 39ЊC.Transplanted into normal livers, patients with liver insufficiency.Investigators have prethese hepatocytes integrate normally into liver cords.viously shown that following transplantation into the brain, When transplanted into the spleens of portacavalimmortalized neuronal cells integrate into the brain and difshunted rats, they protect recipients from hyperammoferentiate normally in the nervous system, but have not nemia-induced hepatic encephalopathy.The cells enshown the functional capacity of transplanted cells. 4-7grafted in the spleen exhibit normal morphology, secreteTo test the feasibility of creating a hepatocyte cell line that bile, and express albumin messenger RNA.The proteccould be used for transplantation, we conditionally immortaltion from hyperammonemia is reversed by splenectomy.ized rat hepatocytes using a thermolabile mutant Simian vi-These studies show that hepatocytes can be conditionrus 40 (SV40) T antigen. [8][][10][11] The resulting hepatocytes prolifally immortalized, expanded in culture, and are capable erate at the transforming gene permissive temperature of providing metabolic support in chronic liver insuffi-(33ЊC).At 37ЊC to 39ЊC, the mutant T antigen is degraded, ciency.Safeguards that could make these cells clinically cell growth stops, and the cells express relatively high levels useful can be accomplished using currently available of liver-specific functions.The conditionally immortalized hetechnology.(HEPATOLOGY 1996;24:337-343.)patocytes are not tumorigenic after transplantation into syngeneic rats or severe combined immunodeficiency mice.We Currently, whole-organ liver transplantation is the only now report that transplantation of cloned hepatocytes, conditherapeutic modality that significantly improves the prognotionally immortalized with a temperature-sensitive SV40 T sis of patients with hepatic failure.Studies in experimental antigen, can ameliorate ammonium acetate-induced hypermodels indicate that hepatocyte transplantation (HTx) could ammonemia and prevent coma in portacaval shunted rats be used to treat hepatic failure and liver-based metabolic with chronic liver insufficiency.To our knowledge, this is the diseases, and would, in some cases, obviate the need for surgifirst report of successful treatment of hepatic insufficiency by cal intervention with its associated risks. 1,2However, the transplantation of conditionally immortalized hepatocytes.shortage of human livers available for whole organ or hepato-These studies represent the first step of a potential novel cyte transplantation severely limits the use of these modalstrategy for dealing with the problem of organ shortage that ities for the treatment of liver failure.In addition, the need currently limits the use of liver or hepatocyte transplantation for immediate availability of consistent and functionally uniin the treatment of liver failure.