טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentShalev Lital
SubjectRole of Heparanase in Liver Fibrosis and Recovery
DepartmentDepartment of Medicine
Supervisor Professor Gad Spira
Full Thesis textFull thesis text - English Version


Abstract

Liver fibrosis represents a wound healing response caused by a variety of stimuli and constitutes a severe medical problem. Currently, the lack of robust markers of fibrosis represents the single greatest factor limiting both the validation of progression or regression of fibrosis and the testing of antifibrotic therapies in clinical trials. Therefore, the need to understand the molecular basis for the development, progression and regression of liver fibrosis is of immense importance. Heparanase, an endo-β-D-glucoronidase, capable of cleaving heparan sulfate chains, was shown to have a role in a wide range of normal and pathological processes, such as angiogenesis, tumor metastasis and wound healing responses. In a study conducted in our laboratory, a biphasic expression of heparanase was evident following partial hepatectomy. Based on the above we now postulate that heparanase might have a role in the development and regression of the fibrotic process. This research project had three main objectives. First, to follow the expression of heparanase in TAA-induced fibrotic rats. Second, to investigate the assumption that hepatic stellate cells (HSCs) are the main source of heparanase in the fibrotic and recovering liver. Finally, to determine the possible effects of heparanase over key extracellular matrix (ECM) remodeling enzymes, like the matrix metalloproteinase (MMP) family members. The results presented in this thesis show peak of heparanase expression with the initiation of the recovery process in fibrotic rats. Furthermore, heparanase over‑expression in HSC lines had greatly affect on the expression of the MMP family, tissue inhibitor metalloproteinase (TIMP) family, alpha smooth muscle actin (α‑SMA) and collagen type I. Surprisingly though, heparanase nuclear localization was evident in HSC lines tested. The results of this study may not conclusively support the initial assumption that HSCs are the main producers of heparanase in the recovering liver. However, they do reveal interesting new data regarding heparanase ability to regulate the production of ECM remodeling enzymes. Based on these results, it is reasonable to assume that heparanase might have an important regulatory role during spontaneous liver recovery.