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The anti-fibrotic effects of CCN1/CYR61 in primary portal myofibroblasts are mediated through induction of reactive oxygen species resulting in cellular senescence, apoptosis and attenuated TGF-β signaling
Open accessAbstract
Unlabelled Cysteine-rich protein 61 (CCN1/CYR61) is a CCN (CYR61, CTGF (connective tissue growth factor), and NOV (Nephroblastoma overexpressed gene)) family matricellular protein comprising six secreted CCN proteins in mammals. CCN1/CYR61 expression is associated with inflammation and injury repair. Recent studies show that CCN1/CYR61 limits fibrosis in models of cutaneous wound healing by inducing cellular senescence in myofibroblasts of the granulation tissue which thereby transforms into an extracellular matrix-degrading phenotype. We here investigate CCN1/CYR61 expression in primary profibrogenic liver cells (i.e., hepatic stellate cells and periportal myofibroblasts) and found an increase of CCN1/CYR61 expression during early activation of hepatic stellate cells that declines in fully transdifferentiated myofibroblasts. By contrast, CCN1/CYR61 levels found in primary parenchymal liver cells (i.e., hepatocytes) were relatively low compared to the levels exhibited in hepatic stellate cells and portal myofibroblasts. In models of ongoing liver fibrogenesis, elevated levels of CCN1/CYR61 were particularly noticed during early periods of insult, while expression declined during prolonged phases of fibrogenesis. We generated an adenovirus type 5 encoding CCN1/CYR61 (i.e., Ad5-CMV-CCN1/CYR61) and overexpressed CCN1/CYR61 in primary portal myofibroblasts. Interestingly, overexpressed CCN1/CYR61 significantly inhibited production of collagen type I at both mRNA and protein levels as evidenced by quantitative real-time polymerase chain reaction, Western blot and immunocytochemistry. CCN1/CYR61 further induces production of reactive oxygen species (ROS) leading to dose-dependent cellular senescence and apoptosis. Additionally, we demonstrate that CCN1/CYR61 attenuates TGF-β signaling by scavenging TGF-β thereby mitigating in vivo liver fibrogenesis in a bile duct ligation model. Conclusion In line with dermal fibrosis and scar formation, CCN1/CYR61 is involved in liver injury repair and tissue remodeling. CCN1/CYR61 gene transfer into extracellular matrix-producing liver cells is therefore potentially beneficial in liver fibrotic therapy.
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“There is evidence of a beneficial effect of both pro-senescent and anti-senescent approaches, depending on context.”
From Ageing, Cellular Senescence and Neurodegenerative Disease (2018) · cites this paper as [301]
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“A pro-senescent effect may be desirable in treating cancer [295,296,297], renal, liver and cutaneous fibrosis [298,299,300,301].”
From Ageing, Cellular Senescence and Neurodegenerative Disease (2018) · cites this paper as [301]
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Metadata
- Authors
- Borkham-Kamphorst, E., Schaffrath, C., Van de Leur, E., Haas, U., Tihaa, L., Meurer, S. K., Nevzorova, Y. A., Liedtke, C., & Weiskirchen, R.
- Affiliations
- Universitätsklinikum Aachen (DE)
- Corresponding author
- Weiskirchen, Ralf
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
- Publisher
- Elsevier BV
- Published
- 2014-05
- Volume
- 1843
- Issue
- 5
- Pages
- 902-914
- ISSN
- 0167-4889 (ISSN-L)
- OpenAlex
- W2001252458
- Cited by
- 105
- References
- 41
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 6 · 2023: 5 · 2022: 7 · 2021: 3 · 2020: 9 · 2019: 7 · 2018: 13 · 2017: 14 · 2016: 13 · 2015: 12 · 2014: 4
- FWCI
- 5.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (publishedVersion)
- PubMed (publishedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion, other-oa)
- Funders
- Faculty of Medicine, RWTH-Aachen University
- Deutsche Forschungsgemeinschaft (SFB/TRR57 P13)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Keywords
- CYR61, liver fibrosis, hepatic stellate cells, reactive oxygen species, cellular senescence, apoptosis, TGF-beta signaling, type I collagen, bile duct ligation, antifibrotic therapy, adenoviral gene transfer, extracellular matrix
- MeSH terms
- Animals, Male, Signal Transduction, Transforming Growth Factor beta, Cellular Senescence, Rats, Sprague-Dawley, Apoptosis, Reactive Oxygen Species, Rats, Cysteine-Rich Protein 61, Myofibroblasts
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