Src Inhibition Attenuates Liver Fibrosis by Preventing Hepatic Stellate Cell Activation and Decreasing Connective Tissue Growth Factor

Seo, Hye‐Young; Lee, So Hee; Lee, Ji Ha; Kang, Yu Na; Park, Keun Gyu; Kim, Mi Kyung; Jang, Byoung Kuk

doi:10.3390/cells9030558

Cited by 46 publications

(27 citation statements)

References 30 publications

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“…Ma et al reported that ampelopsin, a natural flavonoid, attenuated CCl 4 -induced mouse liver fibrosis and HSC activation by inducing autophagy (Ma et al 2019). Seo et al found that Src inhibition increased autophagy flux and alleviated liver fibrosis and HSC activation (Seo et al 2020). The protective effect of autophagy was contradictory to our results.…”

Section: Discussioncontrasting

confidence: 96%

Exosomal miR-223 derived from natural killer cells inhibits hepatic stellate cell activation by suppressing autophagy

Wang

Quan

2020

Mol Med

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Background: Activation of hepatic stellate cells (HSCs) is a prominent driver of liver fibrosis. We previously demonstrated that exosomes derived from natural killer (NK) cells (NK-Exo) attenuated TGF-β1-induced HSC activation. Herein, this study was designed to investigate the mechanism underlying the action of NK-Exo. Methods: NK-Exo was isolated from NK-92MI cells and then administered into TGF-β1-treated LX-2 (human HSC line) cells. MiR-223 expression in NK-Exo was downregulated by transfecting NK-92MI cells with miR-223 inhibitor followed by exosome isolation. The HSC activation was evaluated by determining cell proliferation using CCK-8 assay and measuring the protein levels of α-SMA and CoL1A1 using western blot in LX-2 cells. The expression of miR-223 was detected by qRT-PCR. The interaction between miR-223 and ATG7 was analyzed by a dual-luciferase activity assay. The autophagy was evaluated by measuring the autophagy-related proteins using western blot. Results: miR-223 was highly expressed in NK-Exo and inhibition of miR-223 expression in NK-Exo abrogated the inhibitory effect of NK-Exo on TGF-β-induced HSC activation. ATG7 was confirmed as a direct target of miR-223. Furthermore, treatment with the autophagy activator rapamycin and ATG7 overexpression in LX-2 cells abolished the HSC activation-suppressive effect of NK-Exo. Conclusion: NK-Exo attenuated TGF-β-induced HSC activation by transferring miR-223 that inhibited autophagy via targeting ATG7.

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Section: Discussioncontrasting

confidence: 96%

Exosomal miR-223 derived from natural killer cells inhibits hepatic stellate cell activation by suppressing autophagy

Wang

Quan

2020

Mol Med

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“…The interaction of Src with integrin αV is required for integrin αV-mediated Src activation and subsequent fibroblast migration [ 58 ]. The interaction of SFKs and integrins plays critical roles in the development of lung fibrosis [ 59 , 60 , 61 ], liver fibrosis [ 62 , 63 ], and chronic kidney disease [ 64 ]. SFKs seem to play critical roles in the development of lung fibrosis, and the signaling involved may represent a novel opportunity to target fibrotic diseases [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

Regulation of Fibroblast Cell Polarity by Src Tyrosine Kinase

Katoh

2021

Biomedicines

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Src protein tyrosine kinases (SFKs) are a family of nonreceptor tyrosine kinases that are localized beneath the plasma membrane and are activated during cell adhesion, migration, and elongation. Due to their involvement in the activation of signal transduction cascades, SFKs have been suggested to play important roles in the determination of cell polarity during cell extension and elongation. However, the mechanism underlying Src-mediated polarity formation remains unclear. The present study was performed to investigate the mechanisms underlying Src-induced cell polarity formation and cell elongation using Src knockout fibroblasts (SYFs) together with an inhibitor of Src. Normal and Src knockout fibroblasts were also transfected with a wild-type c-Src, dominant negative c-Src, or constitutively active c-Src gene to analyze the changes in cell morphology. SYF cells cultured on a glass substrate elongated symmetrically into spindle-shaped cells, with the formation of focal adhesions at both ends of the cells. When normal fibroblasts were treated with Src Inhibitor No. 5, a selective inhibitor of Src tyrosine kinases, they elongated into symmetrical spindle-shaped cells, similar to SYF cells. These results suggest that cell polarity during extension and elongation may be regulated by SFKs and that the expression and regulation of Src are important for the formation of polarity during cell elongation.

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“…In the wild type (WT) mice, Src inhibitors (saracatinib and PP2) markedly suppressed the expression of α-SMA in HSCs and decreased the TGF-β-induced CTGF expression by increasing autophagy flux in hepatocytes. However, in primary hepatocytes of hepatocyte-specific Atg7 KO mice (Atg7 f/f Alb-Cre + ), Src inhibitors-induced autophagy and increased CTGF levels did not occur 45 . Thus, there is still a substantial gap between the current understanding of the potential roles of autophagy deficiency in the progression of liver fibrosis and whether Atg5 and Atg7 can be used as effective targets for the treatment of liver diseases.…”

Section: Liver Fibrosis and Autophagymentioning

confidence: 98%

Self-eating: friend or foe? The emerging role of autophagy in fibrotic diseases

Liu¹,

Wu²,

Li³

2020

Theranostics

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Fibrosis occurs in most human organs including the liver, lung, heart and kidney, and is crucial for the progression of most chronic diseases. As an indispensable catabolic process for intracellular quality control and homeostasis, autophagy occurs in most mammalian cells and is implicated in many biological processes including fibrogenesis. Although advances have been made in understanding autophagy process, the potential role of autophagy in fibrotic diseases remains controversial and has recently attracted a great deal of attention. In the current review, we summarize the commonalities of autophagy affecting different types of fibrosis in different organs, including the liver, lung, heart, and kidney as well as in cystic fibrosis, systematically outline the contradictory results and highlight the distinct role of autophagy during the various stages of fibrosis. In summary, the exact role autophagy plays in fibrogenesis depends on specific cell types and different stimuli, and identifying and evaluating the pathogenic contribution of autophagy in fibrogenesis will promote the discovery of novel therapeutic strategies for the clinical management of these fibrotic diseases.

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Src Inhibition Attenuates Liver Fibrosis by Preventing Hepatic Stellate Cell Activation and Decreasing Connective Tissue Growth Factor

Cited by 46 publications

References 30 publications

Exosomal miR-223 derived from natural killer cells inhibits hepatic stellate cell activation by suppressing autophagy

Exosomal miR-223 derived from natural killer cells inhibits hepatic stellate cell activation by suppressing autophagy

Regulation of Fibroblast Cell Polarity by Src Tyrosine Kinase

Self-eating: friend or foe? The emerging role of autophagy in fibrotic diseases

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