Liver fibrogenesis due to cholestasis is associated with increased Smad7 expression and Smad3 signaling

Seyhan, Harun; Hamzavi, Jafar; Wiercinska, Eliza; Gressner, A. M.; Mertens, Peter R.; Kopp, Jürgen; Horch, Raymund E.; Breitkopf, Katja; Dooley, Steven

doi:10.1111/j.1582-4934.2006.tb00535.x

Cited by 29 publications

(26 citation statements)

References 35 publications

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“…Dooley et al (2003) found that the overexpression of Smad7 could inhibit the activation of HSCs, the expression of a-SMA, and the progression of liver fibrosis. Seyhan et al (2006) found that the Smad3 mRNA content in HSCs in the liver fibrosis model group was significantly higher than that of the normal liver group. Moreover, the expression of Smad7 mRNA decreased with the development of hepatic fibrosis.…”

Section: Discussionmentioning

confidence: 91%

Effect of bone marrow mesenchymal stem cells on the TGF-β1/Smad signaling pathway of hepatic stellate

Xe¹,

Xq²,

Liu³

2015

Genet. Mol. Res.

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ABSTRACT. This study investigated the effect of bone marrow mesenchymal stem cells (BMCs) on the transforming growth factor-β1 (TGF-b1)-induced activation of the Smad signaling pathway in rat hepatic stellate cells (HSCs). There were four experimental groups: 1) a blank control group, 2) a TGF-b1 treatment group, 3) an MSCcombined group, and 4) an induced MSC-combined group. Isolation and culture of rat liver HSCs in vitro and the proliferation of HSCs in each group were detected by MTT method. The expression of a-SMA and the TGF receptors (TbRI and II) were determined by immunohistochemical staining of HSCs in all groups, while Smad2/3, Smad4, and Smad7 mRNA expressions were detected by RT-PCR for HSCs in each group. TGF-b1 treatment significantly promoted the 8744-8754 (2015) proliferation of HSCs (P < 0.01); it has different inhibition effects on the proliferation of HSCs in the MSC-combined group and in the induced MSC-combined group (P < 0.05). TGF-β1 treatment also enhanced the expression of α-SMA as compared to the control group (P < 0.01). Alternatively, when compared with the pure TGF-β1 group, the MSCcombined group and the induced MSC-combined group showed lower α-SMA expression (P < 0.05). Activation of HSCs induced by TGF-b1, TβRI and TβRII fluorescence was (+ + +); the fluorescences of TbRI and TbRII in MSC-combined group and in induced MSC-combined group were (+ +) and (± ~ +), respectively. The expressions of TβRI and TβRII in activated HSCs induced by TGF-β1 were significantly decreased in the MSC-combined group (P < 0.05) and in the induced MSC-combined group (P < 0.01). The expression of HSC Smad2/3 and Smad4 was reduced in the MSC-combined group (P < 0.05) and in the induced MSC-combined group (P < 0.01), as compared to the TGF-b1 group. However, the expression of Smad7 in HSCs was upregulated in the MSC-combined group (P < 0.05) and in the induced MSCcombined group (P < 0.01). These results indicate that BMCs can inhibit the activation and proliferation of HSCs by downregulating the expression of TbRI and TbRII in the cell membrane of HSCs. Moreover, BMCs can upregulate the expression of Smad7 and downregulate the expression of Smad2/3 and Smad4 in the HSCs induced by TGF-b1, which resulted in an inhibition of HSC activation.

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Section: Discussionmentioning

confidence: 91%

Effect of bone marrow mesenchymal stem cells on the TGF-β1/Smad signaling pathway of hepatic stellate

Xe¹,

Xq²,

Liu³

2015

Genet. Mol. Res.

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“…An interesting point, although beyond the scope of the current study, is whether portal fibroblasts, which may be important effectors in biliary fibrogenesis, 45,46 could also exhibit differential Smad3 activation. 43 We have shown there to be apparent divergent signaling repertoires in stellate cells after BDL compared to other forms of activation. On one hand, this is surprising because many investigators believe that activation is a common response to injury, with a common phenotype.…”

Section: Functional Effects On Ece-1 Regulation 723mentioning

confidence: 82%

“…43,44 One question raised by our study is whether differential signaling may lead to differential functional effects in these two forms of liver injury and if so, what are the functional effects? Also, is it possible that there could be different cellular mechanisms in different forms of liver injury-a reflection of the apparent different Smad3 signaling pathways?…”

Section: Functional Effects On Ece-1 Regulation 723mentioning

confidence: 98%

Divergent Transforming Growth Factor-β Signaling in Hepatic Stellate Cells after Liver Injury

Khimji

Shao

Rockey

2008

The American Journal of Pathology

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In liver wound healing, transforming growth factor-␤ (TGF-␤) plays a critical role in stellate cell activation as well as signaling cascades in the fibrogenic response to injury. We postulate that the TGF-␤-dependent downstream signaling pathway may vary according to the mechanism of stellate cell activation; this study was undertaken to ascertain whether the downstream signaling pathways mediated by TGF-␤ vary in different liver injury models. We measured Smad3 and MAP kinase activation after isolating stellate cells from rat livers injured by either bile duct ligation (BDL) or repeated carbon tetrachloride (CCl 4 ) administration. Phospho-Smad3 was dramatically up-regulated in stellate cells after CCl 4 injury, but not after BDL-induced injury. TGF-␤ signaling in stellate cells activated after BDL was mediated prominently through ERK activation, whereas activation induced by CCl 4 injury or culture led to a cross-signaling mechanism involving both Smad3 and p38. The divergent Smad signaling pathways observed appeared to be attributable to the differential regulation of the early growth response gene-1 (Egr-1), an apparent negative transcriptional factor for Smad3 in our system. In addition, inhibition of ERK activation in stellate cells from BDL-injured liver led to a decrease in expression of endothelin-converting enzyme-1, a critical regulator of endothelin-1. We speculate that TGF-␤ signaling proceeds through differential signaling pathways depending on the mechanism of liver injury that leads to stellate cell activation. (Am J

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“…Smad6/7 represents the inhibition mechanism of this pathway, being able to divide Smad2/3 from the receptor [149]. Activated HSCs express TGF 1 and Smad 2, 3, 4 and 7, but Smad7 appears to be silenciated [149]. The TGF /Smad pathway may play a pivotal role in liver fibrogenesis mediated by activation of HSCs.…”

Section: Ppar In Hepatic Stellate Cellsmentioning

confidence: 99%

“…Following activation due to liver damage, TGF 1 binds its receptors (T R1 and T R2), allows the phosphorylation of Smad2 and Smad3 and permits Smad2/3 to associate with Smad4; the signaling pathway traslocates to the nucleus and initiates the transcription of several genes, including collagen I and III [144]. Smad6/7 represents the inhibition mechanism of this pathway, being able to divide Smad2/3 from the receptor [149]. Activated HSCs express TGF 1 and Smad 2, 3, 4 and 7, but Smad7 appears to be silenciated [149].…”

Section: Ppar In Hepatic Stellate Cellsmentioning

confidence: 99%

Hepatic PPARs: Their Role in Liver Physiology, Fibrosis and Treatment

Zardi¹,

Navarini²,

Sambataro³

et al. 2013

CMC

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Abstr act: Complex molecular and cellular mechanisms are involved in the pathway of liver fibrosis. Activation and transformation of hepatic stellate cells (HSCs) are considered the two main reasons for the cause and development of liver fibrosis. The peroxisome proliferator-activated receptors (PPARs) belonging to the family of ligand-activated transcription factors play a key role in liver homeostasis, regulating adipogenesis and inhibiting fibrogenesis in HSCs. Normal transcriptional function of PPARs contributes to maintain HSCs in quiescent phase. A reduced expression of PPARs in HSCs greatly induces a progression of liver fibrosis and an increased production of collagen. Here, we discuss role and function of PPARs and we take into consideration molecular factors able to reduce PPARs activity in HSCs. Finally, although further validations are needed, we illustrate novel strategies available from in vitro and animal studies on how some PPARs-agonists have been proved effective as antifibrotic substances in liver disease.

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Liver fibrogenesis due to cholestasis is associated with increased Smad7 expression and Smad3 signaling

Cited by 29 publications

References 35 publications

Effect of bone marrow mesenchymal stem cells on the TGF-β1/Smad signaling pathway of hepatic stellate

Effect of bone marrow mesenchymal stem cells on the TGF-β1/Smad signaling pathway of hepatic stellate

Divergent Transforming Growth Factor-β Signaling in Hepatic Stellate Cells after Liver Injury

Hepatic PPARs: Their Role in Liver Physiology, Fibrosis and Treatment

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