Versican Expression And Turnover In Hepatic Stellate Cell Activation

The pathophysiologic processes of extracellular matrix deposition and turnover in liver injury are central to our understanding of liver fibrosis and the development of antifibrotic therapies. Here we report expression of versican and the proteoglycan degrading enzymes ADAMTS1 and 4 by hepatic stellate cells (HSCs) activated to a myofibroblastic phenotype in tissue culture. HSCs were isolated from C57B/6 mice by pronase/collagenase digestion and density gradient centrifugation and activated by culture on plastic. Versican expression was detected in HSCs at all stages of activation in culture. Expression increased gradually from days 1 through to 7, then more dramatically, up to 5 fold, by days 10 and 14. Immunofluorescence microscopy confirmed versican production by activated HSCs. Western blotting of activated HSC media demonstrated secretion of both intact versican and versican proteolytic products. Expression of the known versican processing enzymes, ADAMTS1 and 4, was detected at all time points but was suppressed during early stages of HSC activation (days 2 through 7) relative to day 1 levels. Versican synthesis and turnover appear to be important components of HSC activation. Its regulated turnover may play a role in modulating normal and fibrotic remodeling in the liver. The reduction in ADAMTS expression could contribute to the deposition of a versican rich matrix in which tissue remodeling occurs. Grant Funding Source : Northern Medical Program