Liver Directed Cell Therapy for Acute and Chronic Liver Failure

Results of hepatocytes transplantation in animal models of acute liver failure and chronic liver disease have been mixed. These animal models often pose difficulties because of variable susceptibilities of individual animals to disease and the possibility of improved outcomes unrelated to hepatocyte regeneration (89). Nonetheless, more recent studies in better defined genetic animals models have begun to demonstrate that cell therapy could have therapeutic potential in acute liver failure (81,82). Clinical studies of hepatocyte transplantation in acute liver failure are limited (86,90,91). It is difficult to conduct controlled cell transplantation studies in acute liver failure because of emergency settings, the need to perform orthotopic liver transplantation whenever a donor liver becomes available, and a lack of unequivocal markers to assess metabolic and synthetic contributions of transplanted cells.

End-stage liver disease with complications, such as hepatic encephalopathy and coagulopathy, represents another challenging condition for cell therapy. Many patients with chronic liver failure are candidates for orthotopic liver transplantation. However, the current organ supply is insufficient and fourfold or greater disproportionality exists in the United States between people on waiting lists versus recipients of liver transplants. Many liver recipients develop recurrent disease in the transplanted organ (e.g., hepatitis C). These individuals often show rapid advancement toward liver failure and have no further therapeutic prospects. Moreover, in many parts of the world, liver transplantation is not available either because of prohibitive costs or lack of donor organs. Therefore, cell transplantation could have a potential role to play in this situation, especially if transplanted cells could be made to resist viral hepatitis or other ongoing disease processes in the recipient. Hepatocyte transplantation in rats with hepatic encephalopathy has been shown to improve encephalopathy scores and partially correct changes in serum amino acid levels (83,92,93). Studies in animals with cirrhosis showed that transplanted hepatocytes could integrate in the liver parenchyma despite extensive fibrosis (94). Moreover, intrasplenic cell transplantation in extremely sick cirrhotic rats improved liver tests, coagulation abnormality, and mortality (83). These findings suggest that creation of additional reservoirs of hepatocytes could prolong survival in end-stage liver disease. The clinical experience of cell transplantation in chronic liver disease is limited. In an early study of 10 patients with cirrhosis, transplantation of autologous hepatocytes in spleen may have improved the condition of 1 patient (95). In several patients with chronic liver disease, it was unclear whether transplantation of allogeneic hepatocytes via the splenic artery (86) was responsible for improving liver function. Therefore, further studies of cell transplantation are necessary in such situations.

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