Modulation of perisinusoidal cell cytoskeletal features during experimental hepatic fibrosis

Abstract

Hepatic perisinusoidal cells (PSCs) proliferate and are thought to be the principal source of extracellular matrix proteins during the development of liver fibrosis. We have studied the classical model of carbon tetrachloride induced liver fibrosis in order to evaluate the possible modulation of PSCs into a synthetically active and contractile cell: the myofibroblast (MF). At the ultrastructural level, this modulation was characterized by reduction of lipid vacuoles and appearance of a developed rough endoplasmic reticulum as well as of microfilament bundles. On investigating the cytoskeletal equipment of PSCs and MFs using light and electron microscopic immunohistochemistry, we found a heterogeneity of phenotypic features. While typical PSCs in normal and fibrotic livers always contained desmin, MFs expressed alpha-smooth muscle (SM) actin in areas of tissue injury and active fibrogenesis. Cells co-expressing alpha-SM actin and desmin were most prominent in the prevenular zone of the lobule (known to be vulnerable to carbon tetrachloride toxicity) and in developing fibrous septa. As demonstrated by immunogold electron microscopy, labelling of microfilament bundles by alpha-SM actin antibody was noted in PSCs containing lipid droplets in early stages of fibrosis; here MFs gradually accumulated and showed alpha-SM actin containing microfilament bundles. In scar tissue, alpha-SM actin expression decreased in both PSCs and myofibroblasts. Our observations support the concept of phenotypic plasticity of PSCs and confirm, at the ultrastructural level, previous suggestions of modulation of these cells into MFs in the course of liver fibrosis.