Transforming growth factor‐β1 regulates platelet‐derived growth factor receptor β subunit in human liver fat‐storing cells
Hepatology (Impact Factor: 11.06). 01/1995; 21(1):232 - 239. DOI: 10.1002/hep.1840210136
Activated liver fat-storing cells (FSC) are known to play a key role in the development of liver fibrosis. An important element in FSC activation process is the increased expression of receptors for platelet-derived growth factor (PDGF), a potent mitogen for FSC. The aim of the present study was to evaluate the expression PDGF-receptor alpha and beta subunits in cultured human FSC and their regulation induced by transforming growth factor-β1 (TGF-β), a cytokine potentially involved in an autocrine loop. TGF-β induced a significant increase of the mitogenic effect of PDGF-BB and did not affect the mitogenicity of PDGF-AA and PDGF-AB, suggesting a selective action of the PDGF-receptor-β subunit. This hypothesis was confirmed by regulation experiments showing selective and time-dependent upregulation of the messenger (m)RNA encoding for the PDGF-receptor-β subunit and the relative protein induced by TGF-β. In addition, binding studies showed a parallel increase of PDGF-BB binding sites after incubation of human FSC with TGF-β. These studies provide evidence for an additional mechanism leading to the perpetuation of FSC activation and proliferation and contribute to a better understanding of the role of TGF-β and PDGF in the development of liver fibrosis. (Hepatology 1995;21:232–239).
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ABSTRACT: Excess matrix in hepatic fibrosis results from both fibrogenic stimulation of stellate cells by TGFβ1 and cell proliferation due to induction of β-platelet derived growth factor receptor (β-PDGFR). In this paper, treatment of culture-activated rat stellate cells with anti-TGFβ inhibited collagen and fibronectin mRNA expression by 82 and 58%, respectively, versus control cells. In vivo, anti-TGFβ inhibited collagen I gene expression by 86% in stellate cells isolated from rats treated with CC14 compared with control antibody. In contrast to stellate cells, anti-TGFβ had no effect on collagen I gene expression in isolated sinusoidal endothelial cells. Anti-TGFβ administered in vivo to rats with liver injury also reduced expression of stellate cell β-PDGFR mRNA to that of control animals. Anti-TGFβ antibody had no effect on the histologic appearance of the tissue. These data support a role for TGFβ in stellate cell matrix expression and provide evidence for transmodulation of PDGF receptor by TGFβ in vivo. However, inhibition of TGFβ alone may not be adequate to attenuate severe hepatic injury and fibrosis.International Hepatology Communications 01/1997; 6(3-4-6):144-152. DOI:10.1016/S0928-4346(96)00341-6
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ABSTRACT: Among early-passage, near-diploid gliomas in vitro, transforming growth factor type beta (TGF beta) has been previously shown to be an autocrine growth inhibitor. In contrast, hyperdiploid (> or = 57 chromosomes/metaphase) glioblastoma multiforme (HD-GM) cultures were autocrinely stimulated by the TGF beta. The mechanism of this 'conversion' from autocrine inhibitor to mitogen is not understood; previous studies have suggested that platelet-derived growth factor (PDGF) might be modulated by TGF beta. The similar expression of TGF beta types 1-3, PDGF-AA; -BB, as well as the PDGF receptor alpha and beta subunits (a/beta PDGFR) between biopsies of the HD-GM and near-diploid, TGF beta-inhibited glioblastomas (GM) by immunohistochemistry did not explain the discrepancy in their regulatory responses. Flow cytometry demonstrated that TGF beta's mitogenic effect was selective for the aneuploid subpopulations of two of three selected HD-GM cultures, while the diploid cells were inhibited. Among the HD-GM, TGF beta 1 induced the RNA of PDGF-A, c-sis and TGF beta 1. The amount of PDGF-AA secreted following TGF beta treatment was sufficient to stimulate the proliferation of a HD-GM culture. Antibodies against PDGF-AA, -BB, -AB, alpha PDGFR and/or beta PDGFR subunits effectively neutralized TGF beta's induction of DNA synthesis among the HD-GM cell lines, indicating that PDGF served as the principal mediator of TGF beta's growth stimulatory effect. By comparison, TGF beta induced only the RNA of PDGF-A and TGF beta 1 among the near-diploid GM, c-sis was not expressed at all. However, the amount of PDGF-A which was secreted in response to TGF beta 1 was insufficient to prevent TGF beta's arrest of the near-diploid cultures in G1 phase. Thus, the emergence of hyperdiploidy was associated with qualitative and quantitative differences in TGF beta's modulation of PDGF-A and c-sis, which provided a mechanism by which the aneuploid glioma cells might achieve 'clonal dominance'. We hypothesize that TGF beta may serve as an autocrine promoter of GM progression by providing a selective advantage to the hyperdiploid subpopulation through the loss of a tumor suppressor gene which mediates TGF beta's inhibitory effect.Journal of Neuro-Oncology 02/1997; 31(3):233-54. DOI:10.1023/A:1005767616500 · 3.07 Impact Factor
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ABSTRACT: The hepatic stellate (Ito) cell lies within the space of Disse and has a variety of functions. Stellate cells store vitamin A in characteristic lipid droplets. In the normal human liver, the cells can be identified by the presence of these lipid droplets; in addition, many stellate cells in the normal liver express alpha-smooth muscle actin. In acute liver injury, there is an expansion of the stellate cell population with increased alpha-smooth muscle actin expression; stellate cells appear to play a role in extracellular matrix remodelling after recovery from injury. In chronic liver injury, the stellate cell differentiates into a myofibroblast-like cell with marked expression of alpha-smooth muscle actin and occasional expression of desmin. Myofibroblast-like cells have a high fibrogenic capacity in the chronically diseased liver and are also involved in matrix degradation. In vitamin A intoxication, hypertrophy and proliferation of the stellate and myofibroblast-like cells may lead to non-cirrhotic portal hypertension, fibrosis and cirrhosis. In liver tumours, myofibroblast-like cells are involved in the capsule formation around the tumour and in the production of extracellular matrix within it. The transition of stellate cells into myofibroblast-like cells is regulated by an intricate network of intercellular communication between stellate cells and activated Kupffer cells, damaged hepatocytes, platelets, endothelial and inflammatory cells, involving cytokines and nonpeptide mediators such as reactive oxygen species, eicosanoids and acetaldehyde. The findings suggest that the stellate cell plays an active role in a number of human liver diseases, with a particular reactivity pattern in fibrotic liver disorders.Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 04/1997; 430(3):195-207. DOI:10.1007/BF01324802 · 2.65 Impact Factor
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