Human myofibroblastlike cells obtained by outgrowth are representative of the fibrogenic cells in the liver

Abstract

During human fibrogenesis, myofibroblastlike cells proliferate and are the main source of fibrosis components. We have used cultured myofibroblastlike cells obtained by outgrowth from explants of human liver to study the expression of extracellular matrix (ECM) components and matrix-metalloproteinase-2 (MMP-2). These cells contained types I, III, IV, and V procollagen messenger RNAs (mRNAs). They also expressed mRNAs for laminin B1 chain and for cellular and plasma fibronectin. The corresponding proteins were detected by immunocytochemistry. MMP-2 expression was shown by Northern blot and gelatin zymography. Because transforming growth factor β1 (TGFβ1) is considered an important mediator in liver fibrogenesis, we examined its effect on expression of ECM components by cultured human myofibroblastlike cells. TGFβ1 increased collagen mRNAs steady-state levels and total collagen secretion in the culture medium. It also increased fibronectin mRNA levels but had no effect on laminin mRNA or MMP-2 expression. In summary, cultured human myofibroblastlike cells express those ECM components that accumulate during hepatic fibrogenesis, indicating the usefulness of this model to study mechanisms of human liver fibrogenesis. In addition to the mitogenic effect of TGFβ1 on human myofibroblastlike cells, we now demonstrate its stimulation of ECM accumulation in these cells, thus emphasizing the central role of TGFβ1 and myofibroblastlike cells in the pathophysiology of human hepatic fibrosis.