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Title: Proliferation and maturation in developing human liver
Author: Currie, Ian Stewart
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2006
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In order to understand how human liver cells can proliferate and differentiate in vitro, a culture system was developed to support second trimester fetal liver cells. Having characterised the culture system, and demonstrated viable hepatocytes after seven days in vitro, cells were incubated with growth factors and cytokines and subject to two-colour flow cytometry to assess which cell fraction might proliferate in vitro. Experiments were then carried out to determine which circulating endocrine stimuli might initiate morphologic and functional maturation in the developing hepatocytes. Finally, urea metabolism and protein secretion were assessed in the presence and absence of glucocorticoid and different growth factors, to assess the interaction of these various stimuli at a functional level. Incubation with growth factors and cytokines showed that EGF alone caused cellular proliferation. This proliferation occurred within a primitive epithelial fraction, positive for cytokeratin 18, but negative for fibrinogen. The results showed that glucocorticoid alone brought about functional maturation in terms of increased protein secretion, with significant increases observed in α-fetoprotein, fibrinogen and α-1-antichymotrypsin secretion. This represented increased secretion per cell, as there was no effect of glucocorticoid on cell proliferation. Final experiments showed that EGF and HGF had modest stimulatory effects on urea synthesis. By contrast, KGF reduced urea synthesis by channelling ammonia into anabolic pathways. With regard to protein secretion, EGF inhibited fibrinogen and α-1-antichymotrypsin secretion, whereas, tumour necrosis factor inhibited fibrinogen alone. All of these observations were made only in the presence of dexamethasone. These data provide a frame of reference from which to develop cell-based therapies for the treatment of liver failure in clinical practice.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available