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Title: Studies on cellular engraftment and hepatocytic differentiation in liver injury and repair
Author: Newsome, Philip N.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2004
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Aim: In this thesis the factors which regulate the adhesion and survival of hepatocytes in the face of acute liver injury environment are examined. Also factors which regulate the differentiation of human stem cells towards hepatocytes are examined in vitro and in vivo. Materials and Methods: Human hepatoblastoma (HepG2) cells were used as a model of human hepatocytes to study the effect of serum from patients with acute liver failure. Various laboratory assays were used to determine effects on adhesion, cell necrosis/apoptosis, integrin expression (flow cytometry) and integrin activation. Human cord blood was used as a source of human stem cells for both in vitro experiments and the in vivo work with the NOD-SCID mice. Results: Paracetamol-induced liver injury results in the marked up regulation of collagen IV on hepatic sinusoids. Adhesion of HepG2 cells to Collagen IV after exposure to fulminant serum was reduced within only a few hours. Apoptosis occurred approximately 24-48 hours after incubation and is associated with caspase3 activation. Furthermore, fulminant serum reduces the adhesive capabilities of HepG2 cells by a rapid down-regulation of their β1-integrin activity. Loss of cellular adhesion and subsequent apoptosis can be reversed by treatment of HepG2 cells with the stimulatory mAb TS2/16. Human cord blood could not be directed in vitro down the hepatocytic lineage under any of the different combinations of cytokines/matrix. In vivo however infused human cord blood cells are capable of engrafting into NOD-SCID mouse liver and differentiating down the hepatocytic lineage without fusion to host hepatocytes. Conclusion: In this thesis mechanisms regulating the engraftment and survival of HepG2 cells during exposure to fulminant serum were identified. Human stem cells were also demonstrated in vivo (but not in vitro) to differentiate into hepatocytes within the NOD-SCID mouse liver with no evidence of cellular fusion.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available