ORIGIN AND ISOLATION OF LIVER PROGENITOR CELLS

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DESCRIPTION (Provided by Applicant): Recent research has recognized the existence of stem cells in adult organs. However, liver stem cells have not yet been identified and isolated. Under certain conditions, when hepatocyte proliferation is impaired, liver progenitor cells, also termed oval cells, emerge in the liver, proliferate and commence differentiationalong hepatocyticor bile duct lineages. Recent studies have also shown that bone marrow cells or purified hematopoietic stem cells are capable of differentiating in the liver into hepatocytes and bile epithelial cells. Our working hypothesis is that liver progenitor/oval cells are progeny of both liver and hematopoietic stem cells. Because of the great biomedical significance of these cells, our long-term objectives are to isolate these cells, expand them in vitro under appropriate conditions and use them for repopulation and treatment of the diseased liver in animal models. To achieve this goal, it is of great importance to identify their site of origin, whether they originate from the liver, from bone marrow or both of these organs. To determine whether progenitor/oval cells originate from bone marrow, genetically marked bone marrow cells will be transplanted into lethally irradiated recipients and their appearance and distribution in D-galactosamine and retrorsine/partial hepatectomy injury models will be monitored. Using known oval cell markers, we will be able to determine whether some of the transplanted cells behave like liver progenitor cells and commence differentiation along hepatocytic/bile duct lineages. If liver progenitor cells are progeny of bone marrow cells, it will be extremely important to identify their precursors by designing a combination of appropriate cell markers uniquely expressed in a subset of hematopoietic progenitor cells and the oval cells and use this panel of markers to isolate them from bone marrow. Following the same strategy, we will design a combination of markers for the identification of progenitor cells in the liver. The panel of markers will represent cell surface markers expressed in hematopoietic progenitor cells, hepatoblasts, biliary epithelial cells and hepatocytes. A combination of these markers will be designed that is expressed only in liver progenitor/oval cells. This panel of markers will be then used for isolation of liver progenitor cells from the liver.