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Replicative Senescence of Activated Human Hepatic Stellate Cells Is Accompanied by A Pronounced Inflammatory But Less Fibrogenic Phenotype
Open accessAbstract
Limited proliferative capacity is a characteristic of most normal human cells and results in a growth–arrested state, called replicative senescence . Functional expression of the telomerase catalytic subunit (human telomerase reverse transcriptase; hTERT) in human activated hepatic stellate cells (HSCs) rescues them from death with immortalization and maintains an activated HSC phenotype. The aim of this study was to evaluate alterations in gene and protein expression of in vitro aged human activated HSCs and to define the pathway by which senescent–activated HSCs are eliminated in culture. Altered patterns of gene expression in senescent human HSCs were assessed using DNA microarray analysis and compared with early passage HSCs or hTERT immortalized HSCs. Senescent HSCs showed higher expression of inflammation and stress–associated genes as compared with early passage HSCs. Senescent HSCs expressed reduced levels of extracellular matrix proteins, including collagens, tenascin, and fibronectin. TUNEL staining of senescent HSCs showed approximately 21% positive cells, indicating DNA fragmentation and apoptosis. Apoptosis involved the mitochondrial pathway with decreased levels of Bcl–2 and Bcl–x L protein, release of cytochrome c, and increased caspase–3 activity. In contrast, 4% to 5% of early activated HSCs or telomerase positive HSCs were TUNEL positive. In conclusion, cultured human HSCs undergo a switch from a fibrogenic to an inflammatory phenotype, suggesting that senescent human HSCs might modulate chronic wound healing processes. Maintenance of telomere length represents an important survival factor for activated human HSCs.
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“These results provide a causal explanation for earlier findings showing that the presence of senescent hepatic stellate cells correlates with increased inflammation but reduced fibrosis (148).”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [148]
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“In response to liver injury, hepatic stellate cells (HSC) began to proliferate and produce extracellular matrixes for tissue repair before undergoing cellular senescence to prevent fibrosis.38, 39”
From Cellular senescence and senescence-associated secretory phenotype via the cGAS-STING signaling pathway in cancer (2020) · cites this paper as [38]
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Metadata
- Authors
- Schnabl, B., Purbeck, C. A., Choi, Y. H., Hagedorn, C. H., & Brenner, D.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Emory University (US)
- Corresponding author
- Brenner, David
- Venue
- Hepatology
- Published
- 2003-03
- Volume
- 37
- Issue
- 3
- Pages
- 653-664
- ISSN
- 0270-9139 (ISSN-L)
- OpenAlex
- W2020573317
- Cited by
- 224
- References
- 53
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 13 · 2023: 11 · 2022: 13 · 2021: 12 · 2020: 14 · 2019: 8 · 2018: 10 · 2017: 10 · 2016: 8 · 2015: 10 · 2014: 6 · 2013: 12 · 2012: 12
- FWCI
- 5.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (DK-34987, AA-11605)
- National Institute on Alcohol Abuse and Alcoholism (AA 11605)
- National Institute of General Medical Sciences (GM41804, R01GM041804)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 34987, P30DK034987)
- Center for Gastrointestinal Biology and Disease, School of Medicine, University of North Carolina at Chapel Hill
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
- Keywords
- replicative senescence, hepatic stellate cells, telomerase reverse transcriptase, hTERT, apoptosis, mitochondrial apoptosis, Bcl-2, Bcl-xL, caspase-3, cytochrome c release, extracellular matrix proteins, inflammation, liver fibrosis, telomere length, gene expression profiling, chronic wound healing
- MeSH terms
- beta-Galactosidase, Cell Cycle, Cell Division, Cell Survival, Cytoskeletal Proteins, DNA-Binding Proteins, Hepatitis, Humans, Liver, Phenotype, RNA, Messenger, Gene Expression, Cytokines, Cellular Senescence, Reactive Oxygen Species, Intercellular Adhesion Molecule-1, Chemokines, Vascular Cell Adhesion Molecule-1, Telomerase, Caspases, In Situ Nick-End Labeling, Oligonucleotide Array Sequence Analysis, Caspase 3
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