M.Sc Thesis

M.Sc StudentGruber Rita
SubjectHeparanase Expression and Role during Normal Liver
Development and Following Partial Hepatectomy in
Normal and Cirrhotic Animals
DepartmentDepartment of Medicine
Supervisor ASSOCIATE PROF. Gad Spira


Heparan sulphate proteoglycans (HSPGs) are major components of the extracellular matrix (ECM), playing an essential role in maintaining the integrity and functional state of tissues and organs. Cleavage of HSPGs may thus influence normal and pathological processes including structural changes in tissue architecture, cell migration, and response to heparin binding growth factors sequestered by the ECM. Heparanase is a mammalian endoglycosidase capable of specific cleavage of heparan sulphate (HS) chains. Liver regeneration involves cell migration and remodeling of ECM constituents, both mediated by up-regulation of heparanase in the regenerating cells. Moreover, the ability of heparanase to release HS-bound growth factors may equally contribute to tissue regeneration through an effect on cell migration, proliferation, and neovascularization.

Heparanase mRNA and protein were expressed during liver development but not in the mature healthy liver. A biphasic gain of heparanase expression, detected by immunostaining, western blotting, and real-time RT-PCR, was clearly noted following partial hepatectomy, peaking at 12 and 96-168 h and subsiding 2 weeks post-surgery. Expression of heparan sulphate gradually increased throughout the regeneration process. Unlike heparanase, baseline levels of matrix metalloproteinase-2 (MMP-2) were detected in the intact liver, increasing up to 4 days following partial hepatectomy and subsiding at day 10. Bands matching MMP-9 were absent prior to hepatectomy, but visible 2 h post-hepatectomy. Thioacetamide-induced liver fibrosis was associated with increased levels of MMP-9 and MMP-2, correlating with the severity of the disease. Elevated heparanase levels were noted in the early stages of fibrosis, with no further increase evident in rats exhibiting higher fibrotic grades. Taken together, these data suggest a role for heparanase during liver development and remodelling.