Cytoglobin expression in the hepatic stellate cell line HSC-T6 is regulated by extracellular matrix proteins dependent on FAK-signalling

Abstract

BackgroundFibrosis is a physiological response to cellular injury in the liver and is mediated by the activation of hepatic stellate cells resulting in the replacement of hepatocytes with extracellular matrix comprised principally of collagen 1 to form a hepatic scar. Although the novel hexaco-ordinated globin cytoglobin was identified in activated hepatic stellate cells more than 10 years ago, its role in stellate cell biology and liver fibrosis remains enigmatic.ResultsIn the current study, we investigated the role of different extracellular matrix proteins in stellate cell proliferation, activation (alpha smooth muscle actin expression and retinoic acid uptake) and cytoglobin expression. Our results demonstrate that cytoglobin expression is correlated with a more quiescent phenotype of stellate cells in culture and that cytoglobin is regulated by the extracellular matrix through integrin signalling dependent on activation of focal adhesion kinase.ConclusionsAlthough further studies are required, we provide evidence that cytoglobin is a negative regulator of stellate cell activation and therefore may represent a novel target for anti-fibrotic treatments in the future.Electronic supplementary materialThe online version of this article (doi:10.1186/s13069-015-0032-y) contains supplementary material, which is available to authorized users.

Human hepatic stellate cell isolation and characterization

“…Co-staining of Thy-1 and CD248 was detected in isolated human hepatic stellate cells [87]. It has been reported that cytoglobin expression is correlated with a more quiescent phenotype of HSCs and is regulated by extracellular matrix proteins dependent on FAK signaling in rat HSC-T6 cell line [88].…”

Alpha-1 antitrypsin deficient individuals have circulating extracellular vesicles with profibrogenic cargo 

“…In contrast, the iPSc-derived HSCs incubated without EVs or with MM plasma-derived EVs exhibited a more rounded morphology suggestive of a more quiescent state ( Figure 4B). The activation status of HSCs was determined by quantifying α-SMA and Col1A1 mRNA expression, markers of stellate cell activation (27). They were found to be signi cantly increased by incubation with ZZ plasma-derived EVs after 24 hours compared to control and MM plasma-derived EV treatment ( Figure 4C).…”

Role of cytoglobin, a novel radical scavenger, in stellate cell activation and hepatic fibrosis

“…In Xu et al [ 103 ], overexpression of Cygb protected primary rat HSCs against oxidative stress, as assessed by reduced production of malondialdehyde and 4-hydroxynonenal, biomarkers of lipid peroxidation. In Stone et al [ 154 ], Cygb expression was correlated with a more quiescent phenotype of stellate cells in culture and Cygb was regulated by the extracellular matrix through integrin signaling in a manner dependent on activation of focal adhesion kinase. Consistently, in human liver tissues damaged by HCV infection at various fibrosis stages, the number of Cygb-positive cells decreases with fibrosis progression [ 37 ].…”