Abstract
BackgroundA marked expansion of the connective tissue population and an abnormal deposition of extracellular matrix proteins are hallmarks of chronic and acute injuries to liver tissue. Liver connective tissue cells, also called stellate cells, derived from fibrotic liver have been thoroughly characterized and correspond phenotypically to myofibroblasts. They are thought to derive from fat-storing Ito cells in the perisinusoidal space and acquire a contractile phenotype when activated by tissue injury. In the last few years it has become evident that several peptide growth factors such as PDGF AA and TGF-β are involved in the development of fibrosis by modulating myofibroblast proliferation and collagen secretion. The fact that during the development of chronic fibrosis there is concomitant deposition of collagen, a known inhibitory factor, and sustained cell proliferation, raises the possibility that stellate cells from chronic liver fibrosis patients fail to respond to normal physiologic controls.MethodsIn this study we address whether cells from fibrotic liver patients respond to normal controls of proliferation. We compared cell proliferation of primary human liver connective tissue cells (LCTC) from patients with liver fibrosis and skin fibroblasts (SF) in the presence of collagens type I and IV; TGF-β, PDGF AA and combinations of collagen type I and TGF-β or PDGF AA.ResultsOur results indicate that despite displaying normal contact and collagen-induced inhibition of proliferation LCTC respond more vigorously to lower concentrations of PDGF AA. In addition, we show that collagen type I synergizes with growth factors to promote mitogenesis of LCTC but not SF.ConclusionsThe synergistic interaction of growth factors and extracellular matrix proteins may underlie the development of chronic liver fibrosis.
Highlights
A marked expansion of the connective tissue population and an abnormal deposition of extracellular matrix proteins are hallmarks of chronic and acute injuries to liver tissue
Extensive primary periportal fibrosis such as schistosomal fibrosis was related to expansion of myofibroblasts originating from the portal vein wall [8], while in cirrhosis resident periportal connective tissue cells, as well as lobular stellate cells and pericentrovenular cells were reported to convert into myofibroblasts [3,9,10]
By using a series of primary connective tissue cell lines from skin and from fibrotic livers, we investigated several parameters of cell growth in vitro in order to identify potential mechanisms to explain the excessive proliferation of liver connective tissue cells (LCTC) during fibrosis
Summary
A marked expansion of the connective tissue population and an abnormal deposition of extracellular matrix proteins are hallmarks of chronic and acute injuries to liver tissue. Extensive primary periportal fibrosis such as schistosomal fibrosis was related to expansion of myofibroblasts originating from the portal vein wall [8], while in cirrhosis resident periportal connective tissue cells, as well as lobular stellate cells and pericentrovenular cells were reported to convert into myofibroblasts [3,9,10]. Of their origin, connective tissue cells of human fibrotic and cirrhotic liver tissues were shown to have homogeneous morphologic characteristics, as well as a specific growth patterns [11,12,13,14,15]
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