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Prof George Yeoh
Molecular mechanisms underlying liver development is our area of
interest. This is investigated using in vivo and in vitro models. In
vivo models comprise transgenic mice bearing reporter genes regulated
by promoters which are associated with developmentally regulated
liver-specific genes. Knockout mice, lacking cytokines or their
receptors are also utilised to identify factors which are important for
the growth and differentiation of liver stem cells. In vitro models
include isolated fetal hepatocytes and liver stem cells maintained in
culture. Changing patterns of gene expression are used to document the
differentiation of these cells into either hepatocytes or bile duct
cells. We are defining the cytokines which play an important role in
the processes of cell proliferation and differentiation with the aim of
establishing a method which allows hepatocytes to be generated from
stem cells and maintained for extended periods in culture. Such cells
can be frozen, stored and thawed as required. Recently, we generated
liver progenitor cells from a mouse (the “blue” mouse) bearing a
transgene which allows us to identify and quantify their
differentiation into hepatocytes. When they differentiate, they
activate a reporter gene which permits their detection using a blue
stain (see figure below). The ability of these cells to relieve the
symptoms of liver dysfunction will be evaluated by transplanting them
into mouse models of liver disease. Our long term aim is to utilise
these cells for liver cell therapy to treat patients with liver
disease. Ultimately, they may serve as an alternative to liver
transplantation which is proving to be increasingly difficult due to
the shortage of donated organs and increasing incidence of end-stage
liver disease. With this in mind, we have recently turned our attention
to establishing cultures of human liver stem cells by applying
techniques we have developed for mouse cells.
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| The digital images above show liver progenitor cells from the "blue" mouse. They grow rapidly (figure A) and they do not differentiate into hepatocytes (figure B where cells are unstained). If you look carefully you will see one blue cell in figure B. If we induce differentiation of these liver progenitor cells in culture, they form spheres comprising functional heptaocytes (figure C, observe spheres). It is clear that these spheres stain blue (figure D) showing the progenitor cells have differentiated. Figures A and C are viewed by phase contrast microscopy (to show detail) and figures B and D are viewed under bright field conditions (to show stained cells). | | |
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