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dc.contributor.authorCurrie, Ian Stewarten
dc.date.accessioned2018-01-31T11:42:06Z
dc.date.available2018-01-31T11:42:06Z
dc.date.issued2006en
dc.identifier.urihttp://hdl.handle.net/1842/27856
dc.description.abstracten
dc.description.abstractIn the United Kingdom, the number of patients with liver failure awaiting transplantation now exceeds the capacity of the nation's donor pool, with the result that 20% of patients now die on the waiting list. The future for the treatment of liver failure lies in part with cell-based therapies, in which liver support may be provided on a short-term basis by biological liver-assist devices, or in which sufficient mass of liver tissue may be transplanted into patients to reverse liver failure as a graft. However, cell therapies are at a preliminary stage, due to a lack of basic understanding as to how human liver cells can be made to divide and to undergo functional maturation in vitro.en
dc.description.abstractIn 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, experiments were carried out to determine which circulating endocrine stimuli might initiate morphologic and functional maturation in the developing hepatocytes. Cells were then incubated with growth factors and cytokines and subject to two-colour flow cytometry to assess which cell fraction might proliferate in vitro. Finally, urea metabolism and protein secretion were assessed in the presence and absence of glucocorticoid and different growth factors, to assess the interactions of these various stimuli at a functional level.en
dc.description.abstractThe results showed that glucocorticoid alone brought about functional maturation in terms of increased protein secretion, with significant increases observed in a-fetoprotein, fibrinogen and a-i-antichymotrypsin secretion. This represented increased secretion per cell, as there was no effect of glucocorticoid on cell number. However, incubation with growth factors and cytokines showed that EGF stimulated cellular proliferation. This proliferation occurred within a primitive epithelial fraction, positive for cytokeratin 18, but negative for fibrinogen. 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 oc-i-antichymotrypsin secretion, whereas, tumour necrosis factor inhibited fibrinogen alone. All of these observations were made only in the presence of dexamethasone.en
dc.description.abstractThese data show that a satisfactory method for fetal liver cell culture was developed. This model demonstrated that proliferation of liver epithelial cells was stimulated by EGF, whereas functional maturation of fetal liver cells could be brought about by exposure to glucocorticoid. Various growth factors and cytokines had modest effects on urea and protein secretion, but only in the presence of glucocorticoid. These experiments have provided new insights into the maturational and proliferative signals in developing human liver. These data provide a frame of reference from which to develop cell-based therapies for the treatment of liver failure in clinical practice.en
dc.publisherThe University of Edinburghen
dc.relation.isreferencedbyAlready catalogueden
dc.subjectAnnexe Thesis Digitisation Project 2017 Block 16en
dc.titleProliferation and maturation in developing human liveren
dc.typeThesis or Dissertationen
dc.type.qualificationlevelen
dc.type.qualificationnameMD Doctor of Medicineen


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