TGF beta1 and PDGF AA override collagen type I inhibition of proliferation in human liver connective tissue cells.
BACKGROUND
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. 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-beta 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.


METHODS
In 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-beta, PDGF AA and combinations of collagen type I and TGF-beta or PDGF AA.


RESULTS
Our 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.


CONCLUSIONS
The synergistic interaction of growth factors and extracellular matrix proteins may underlie the development of chronic liver fibrosis.
Geremias
Alvaro T
AT
Departamento de Bioquímica, Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21949, Brazil. atgeremias@uol.com.br <atgeremias@uol.com.br>
Carvalho
Marcelo A
MA
Borojevic
Radovan
R
Monteiro
Alvaro N A
AN
D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D002908:Chronic Disease; D024042:Collagen Type I / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
D024042:Collagen Type I; D010982:Platelet-Derived Growth Factor; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C075278:platelet-derived growth factor A