Investigating the role of Bmi-1 in liver growth and function
Bmi-1 is a member of the Polycomb group (PcG) family of transcriptional repressors, which are implicated in the maintenance of embryonic and adult stem cells. Previous reports indicate that Bmi-1 plays a key role in repressing the Ink4a/Arf tumour suppressor locus. Overexpression of Bmi-1 in putative liver stem/progenitor cells leads to increased self-renewal in vitro and tumourigenesis following transplantation into immunocompromised mice. However, the in vivo functional requirement for Bmi-1 in liver development, homeostasis and regeneration has not been investigated. For this thesis, the consequences of Bmi-1 deletion for the post-natal murine liver were assessed using a knockout mouse model. Immunohistochemical techniques were first used to examine Bmi-1 expression in normal murine and human liver, and in human liver pathologies. Bmi-1 was highly expressed in biliary cells of both mouse and human liver, and at lower levels in some murine hepatocytes. Strong expression of Bmi-1 was observed in cytokeratin 19-positive oval cells in regenerating murine liver. Bmi-1 knockout mice exhibited structural abnormalities in the liver parenchyma, most strikingly the abnormal development of polyploidy in hepatocytes. Bmi-1 deletion did not result in impaired proliferation in mice, despite increased expression levels of cell cycle inhibitors p16Ink4a, p19Arf and p21. In contrast, an increase in hepatocyte proliferation was observed in 8 week old Bmi-1 deficient mice, which was correlated with upregulation of cyclin D1. Mel-18, a structural homologue of Bmi-1, was also expressed in murine cholangiocytes and was upregulated in the livers of Bmi-1 deficient mice during ageing, suggesting it may have been exerting a compensatory effect. Adult Bmi-1 knockout mice also exhibited excessive iron loading and abnormalities in the expression of key regulators of hepatic iron homeostasis.
AuthorsElder, Alex Kenneth
- Theses