Correction of liver disease by hepatocyte transplantation in a mouse modelof progressive familial intrahepatic cholestasis

Background & Aims: Patients with progressive familiar intrahepatic cholesta sis (PFIC) type 3 have a mutation in the MDR3 gene, encoding the hepatocana licular phospholipid translocator. In general, liver failure develops withi n the first decade of life in these patients. Previous studies have shown t hat in the mdr2-knockout mouse, the animal model for this disease, the abse nce of phospholipids in bile causes chronic bile salt-induced damage to hep atocytes. We aimed to test the efficacy of hepatocyte transplantation and l iver repopulation in this disease model. Methods: Transgenic MDR3-expressin g hepatocytes as well as normal mdr2(+/+) hepatocytes were transplanted in mdr2(-/-) mice, and liver repopulation was assessed by immunohistochemistry and measurement of biliary lipid secretion. Results: Transplanted hepatocy tes partially repopulated the liver, restored phospholipid secretion, and d iminished liver pathology. Repopulation was stronger when hepatocellular da mage was enhanced by a bile salt-supplemented diet. After 1 year, however, these animals developed multiple hepatic tumors, and biliary phospholipid s ecretion decreased. In transplanted animals receiving a control diet, repop ulation was slower but eventually remained stable at 21%, while liver patho logy was completely abrogated and tumor formation was prevented. Conclusion s: These results suggest that moderate liver pathology is a safe condition for the induction of effective hepatocyte repopulation and that this therap y is potentially applicable to patients with PFIC type 3.