Modulation of transforming growth factorβ response and signaling during transdifferentiation of rat hepatic stellate cells to myofibroblasts

Dooley, Steven; Delvoux, Bert; Lahme, Birgit; Mangasser-Stephan, Kerstin; Gressner, A. M.

doi:10.1053/he.2000.6126

Cited by 231 publications

(202 citation statements)

References 65 publications

(70 reference statements)

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“…23 Among HSC-related genes expressed after cell transplantation, VEGF activates HSC and induces HSC proliferation. 24,25 Our observation of VEGF mRNA expression here was in agreement with that of previous immunostaining studies showing VEGF expression within a few hours after cell transplantation. 1 TGF-␤, which was upregulated early after cell transplantation, plays roles in activating HSC during liver fibrosis.…”

Section: Discussionsupporting

confidence: 92%

“…1 TGF-␤, which was upregulated early after cell transplantation, plays roles in activating HSC during liver fibrosis. Quiescent HSC are more responsive to TGF-␤ than fully activated ones, 25 although the role of TGF-␤ in regulating HSC proliferation is less clear. 6,26,27 Furthermore, platelet-derived growth factor and bFGF can induce proliferation or mediate the mitogenic effects of TGF-␤ in HSC.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Hepatocyte transplantation activates hepatic stellate cells with beneficial modulation of cell engraftment in the rat

Benten¹,

Kumaran²,

Joseph³

et al. 2005

Hepatology

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Hepatocyte transplantation activates hepatic stellate cells with beneficial modulation of cell engraftment in the rat

Benten¹,

Kumaran²,

Joseph³

et al. 2005

Hepatology

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“…In addition, de novo synthesis of GSH was a prerequisite for EGCG to Accumulating evidence has shown the important roles of TGF-b and its signaling in the development of hepatic fibrosis and activation of HSC. 30,31 It is intriguing to remove the causative agent and to evaluate its impact on HSC by blocking TGF-b signaling. Soluble TGF-b receptors and soluble Tb-RII antibodies block hepatic fibrosis in animal models.…”

Section: Discussionmentioning

confidence: 99%

The antifibrogenic effect of (−)-epigallocatechin gallate results from the induction of de novo synthesis of glutathione in passaged rat hepatic stellate cells

Zhou

Zheng

et al. 2006

Laboratory Investigation

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Hepatic stellate cells (HSC) are the major players during hepatic fibrogenesis. Overproduction of extracellular matrix (ECM) is a characteristic of activated HSC. Transforming growth factor-beta (TGF-b) is the most potent fibrogenic cytokine while connective tissue growth factor (CTGF) mediates the production of TGF-b-induced ECM in activated HSC. HSC activation and hepatic fibrogenesis are stimulated by oxidative stress. Glutathione (GSH) is the most important intracellular antioxidant. The aim of this study is to explore the mechanisms of (À)-epigallocatechin-3-gallate (EGCG), the major and most active component in green tea extracts, in the inhibition of ECM gene expression in activated HSC. It is hypothesized that EGCG inhibits ECM gene expression in activated HSC by interrupting TGF-b signaling through attenuating oxidative stress. It is found that EGCG interrupts TGF-b signaling in activated HSC by suppressing gene expression of type I and II TGF-b receptors. EGCG inhibits CTGF gene expression, leading to the reduction in the abundance of ECM, including aI(I) procollagen. Exogenous CTGF dose dependently eliminates the antifibrogenic effect. EGCG attenuates oxidative stress in passaged HSC by scavenging reactive oxygen species and reducing lipid peroxidation. De novo synthesis of GSH is a prerequisite for EGCG to interrupt TGF-b signaling and to reduce the abundance of aI(I) procollagen in activated HSC in vitro. Taken together, our results demonstrate that the interruption of TGF-b signaling by EGCG results in the suppression of gene expression of CTGF and ECM in activated HSC in vitro. In addition, our results, for the first time, demonstrate that the antioxidant property of EGCG derived from de novo synthesis of intracellular GSH plays a critical role in its antifibrogenic effect. These results provide novel insights into the mechanisms of EGCG as an antifibrogenic candidate in the prevention and treatment of liver fibrosis.

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“…For example, tumor necrosis factor ␣-induced abrogation of TGF␤-dependent profibrotic responses was linked to the induction of endogenous SMAD7 (48). On the other hand, defective SMAD7 induction is implicated in the exaggerated TGF␤ responsiveness characteristic of hepatic cells and myofibroblasts from chronically injured livers (49,50). While the highest level of SMAD7 expression is normally found in the kidneys (23), in spontaneous renal fibrosis in TGF␤1-transgenic mice, and in renal fibrosis induced by anti-Thy-1 antibody, excessive matrix accumulation occurs in the setting of reduced SMAD7, resulting in exaggerated or sustained local TGF␤ response (51,52).…”

Section: Discussionmentioning

confidence: 99%

Expression and regulation of intracellular SMAD signaling in scleroderma skin fibroblasts

Mori

Chen

Varga

2003

Arthritis & Rheumatism

172

115

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Objective. Scleroderma is characterized by excessive synthesis and accumulation of matrix proteins in lesional tissues. Transforming growth factor ␤ (TGF␤) plays a central role in the pathogenesis of fibrosis by inducing and sustaining activation of fibroblasts; however, the underlying mechanisms are poorly understood. We undertook this study to examine the expression and function of SMADs, recently characterized intracellular effectors of TGF␤ signaling, in scleroderma fibroblasts.Methods. Primary dermal fibroblasts obtained from 14 patients with scleroderma and from 4 healthy adult volunteers were studied. Northern analysis was used to determine the expression of endogenous SMAD messenger RNA (mRNA), and Western analysis was used to determine SMAD protein expression. Intracellular compartmentalization of cellular SMAD proteins in the presence and absence of TGF␤ was studied by antibody-mediated immunofluorescence confocal microscopy. The effect of TGF␤ blockade on SMAD subcellular distribution was determined using anti-TGF␤ antibodies as well as a dominant-negative TGF␤ receptor type II (TGF␤RII) vector to disrupt TGF␤ responses. SMAD-regulated luciferase reporter expression was examined to investigate the potential functional significance of activation and nuclear accumulation of endogenous SMADs in scleroderma fibroblasts.Results. Protein and mRNA levels of SMAD3, but not of SMAD4 or SMAD7, were variably elevated in scleroderma fibroblasts compared with those from healthy controls. In sharp contrast to control fibroblasts, which displayed predominantly cytoplasmic localization of SMAD3/4 in the absence of exogenous TGF␤, in scleroderma fibroblasts SMAD3 and SMAD4 consistently showed elevated nuclear localization. Furthermore, phosphorylated SMAD2/3 levels were elevated and nuclear localization of phosphorylated SMAD2/3 was increased, suggesting activation of the SMAD pathway in scleroderma fibroblasts. Blockade of autocrine TGF␤ signaling with antibodies or by expression of dominant-negative TGF␤RII failed to normalize SMAD subcellular distribution, suggesting that elevated nuclear SMAD import was due to alterations downstream of the TGF␤ receptors. The activity of a SMADresponsive minimal promoter-reporter construct was enhanced in transiently transfected scleroderma fibroblasts.Conclusion. This study is the first to demonstrate apparently ligand-independent constitutive activation of the intracellular TGF␤/SMAD signaling axis in scleroderma fibroblasts. SMAD signaling may be a mechanism contributing to the characteristic phenotype of scleroderma fibroblasts and playing a role in the pathogenesis of fibrosis.Scleroderma is associated with fibrosis of affected tissues due to excessive synthesis and progressive accumulation of connective tissue macromolecules (1). Scleroderma fibroblasts display features of sustained activation in vitro and in vivo. In culture, these cells show elevated synthesis of collagens, fibronectin, proteoglycans, and tissue inhibitors of metalloproteinases, constitutive secretion of i...

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Modulation of transforming growth factorβ response and signaling during transdifferentiation of rat hepatic stellate cells to myofibroblasts

Abstract: Activation and transdifferentiation of liver-specific pericytes, i.e., the hepatic stellate cell (HSC), is the main step in the process of liver fibrogenesis.

Cited by 231 publications

References 65 publications

Hepatocyte transplantation activates hepatic stellate cells with beneficial modulation of cell engraftment in the rat

Hepatocyte transplantation activates hepatic stellate cells with beneficial modulation of cell engraftment in the rat

The antifibrogenic effect of (−)-epigallocatechin gallate results from the induction of de novo synthesis of glutathione in passaged rat hepatic stellate cells

Expression and regulation of intracellular SMAD signaling in scleroderma skin fibroblasts

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