Establishing a relationship between bone marrow cells and liver progenitor cells by expression profiling and cell tracing studies

[Truncated abstract] There is great interest in the field of liver progenitor (oval) cells which are a bipotential compartment of cells responding to chronic liver damage. Oval cells have enormous potential to treat patients with liver disease by a cell therapy approach but their use is limited by their scarcity and number of donor livers from which they can be derived. Knowledge is lacking in the origin of oval cells as well as the mechanisms which drive their activation, proliferation and differentiation which is required for their therapeutic potential to be realised. Bone marrow may be a suitable source of liver progenitor cells which could circumvent both disadvantages of using liver-derived material. Derivation of oval cells from bone marrow has been examined in rodents using hepatotoxins and partial hepatectomy to create liver damage. These protocols induce oval cell proliferation however they do not mimic the disease conditions that occur in humans. The first aim of this thesis was therefore to evaluate the contribution of bone marrow cells to oval cells in conditions that more closely mimic human liver disease pathophysiology using a choline-deficient, ethionine-supplemented (CDE) diet which causes fatty liver and virus-induced hepatitis. To determine the contribution of bone marrow cells to CDE and viral-hepatitis injury, lacZ transgenic bone marrow cells were transplanted into congenic mice, liver injury was induced and the movement of bone marrow cells to the liver monitored. Cells originating from donor BM were identified by x-gal staining and their phenotype was determined by immunohistochemical staining with cell type specific markers. Bone marrow-derived oval cells were observed in response to the CDE diet and viral injury but represented a minor fraction (0-1.6%) of the oval cell compartment.