Extracellular matrix regulates hepatic stellate cell phenotype and survival

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During liver fibrosis, hepatic stellate cells (HSC) phenotypically alter from quiescent compact, vitamin A rich non-fibrogenic cells into proliferative myofibroblasts (activated HSC) with reduced vitamin A and expressing abundant extracellular matrix components (ECM). Modifications to the ECM during liver injury may initiate and support HSC activation. Integrins may play a role in transducing these ECM signals and their expression on HSC alters dunng cell activation. In this study we have examined if ECM can influence HSC transformation and survival in vitro. HSC were isolated from normal rat liver and activated by culturing for 14 days on plastic. Cells were recovered by trypsinisation and transferred back onto plastic or 0.5 mm layers of Matrigel. Dunng culture over the next 7 days, HSC on plastic maintained a myofibroblastic appearance, expressing abundant ~-smooth muscle actin (SMA) and collagen I by a Northern and Western blotting. They continued to proliferate by H thymidine incorporation, but also underwent a high rate of apoptosis assessed by nuclear acridine orange staining when subjected to serum deprivation for 6 hours. In contrast, HSC raplated on Matrigel over the same period adopted a quiescent phenotypa, with minimal proliferation, reacquired vitamin A droplets and stopped expressing SMA. These cells also showed enhanced bcl-2 expression and a 3-fold reduction in rate of apoptosis dunng serum deprivation compared to plastic cultures. The disintegdn echistatin increased HSC apoptosis on plastic or Matrigel. Our studies show that ECM profoundly influences HSC phenotypa, proliferation and apoptosis. We suggest that, dunng liver fibrosis, remodelling of the non~al basement membrane-like ECM underlying HSC might sustain the activated fibrogenic phenotype of these cells. Molecular and cell biology (gene expression, signalling, fibrosis)