Study of the role of hepatic stellate cells in liver fibrosis

Abstract

In chronic liver injury, activated hepatic stellate cells (HSC) are the major source of collagens that facilitate liver fibrosis. Drugs and stem cells targeting patho-physiology of HSC can be potential therapeutic strategies against liver fibrosis. In the present thesis work, we took three different approaches to modulate the pathophysiological characteristic of HSC and also further studied the role of HSC, a liver specific pericyte in controlling endothelial functions and angiogenesis. In the present study, we demonstrated that HSC attenuated nitric oxide (NO) production by endothelial cells (EC) and thereby inhibiting endothelial functions in vitro and angiogenesis ex vivo. The study demonstrated that HSC interferes with endothelial functions and angiogenesis by attenuating NO-cGMP pathway in endothelial cells. Out study also elaborated that stem cells reverse HSC dampened endothelial NO production and further recovered HSC driven faulty endothelial functions. In the last part of the thesis work, we used sunitinib, a receptor tyrosine kinase inhibitor and everolimus, a mTOR inhibitor in modulating activated HSC frunctions. Our study demonstrated that sunitinib, everolimus (RAD001) and their combination treatment blocked trans differentiation of HSC to it s activated form and also attenuated the pathological characteristic of activated HSC with out affecting primary HSC functions. This part of the thesis work elaborated that sunitinib, RAD001 and their combination treatment attenuated HSC functions and reversed HSC associated endothelial dysfunctions and faulty angiogenesis. In conclusion, the study from the present thesis work demonstrated that inactivation of activated HSC can be a logical approach to curb liver fibrosis. Further we concluded that pharmacological agents and stem cell can be effective therapeutic strategies against liver fibrosis. newline newline newline