Therapeutic liver repopulation (TLP) is a process similar in which transplanted donor cells selectively expand and reconstitute > 90 percent of the hepatocytes in the recipient. Although TLP has been achieved only in animal models to date, the procedure holds great promise for the treatment of human liver diseases, particularly hepatic enzyme deficiencies. Several cell types can be used for liver repopulation including the hepatocytes themselves, hepatic oval cells, pancreatic liver stem cells and hematopoietic stem cells. Selective replacement of host hepatocytes with donor cells occurs whenever the division of endogenous cells, but not transplanted cells, is impaired. These conditions are present in some genetic liver diseases including hereditary tyrosinemia type I, the model used by our laboratory. In this application we propose experiments to find a set of general conditions that will permit safe and efficient liver repopulation in any animal. In addition, we will explore the properties of liver repopulation by transplanted hematopoietic stem cells (HSCs).
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