ArticleCellular and molecular life sciences : CMLS2024
Delineating the heterogeneity of senescence-induced-functional alterations in hepatocytes.
Article in Cellular and molecular life sciences : CMLS, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 18 citations in OpenAlex.
- MnOMaterials today. Bio · 2026Article
- Senescent hepatic stellate cells drive inflammation and disease progression in MASH (Review).Experimental and therapeutic medicine · 2026Review
- Mitochondria-endoplasmic reticulum contact sites in hepatocytic senescence.Cellular & molecular biology letters · 2026Review
- Insulin-stimulated glucose uptake is impaired in senescent human adipocytes.Frontiers in endocrinology · 2026Article
- Organoid: a promising solution to current challenges in cancer immunotherapy.npj biomedical innovations · 2025Review
- Immunosenescence and organoids: pathophysiology and therapeutic opportunities.Immunity & ageing : I & A · 2025Review
- The Passive Immunoprotective Activity Using Egg Yolk IgY Antibodies of Live or InactivatedVeterinary sciences · 2025Article
- Article
- Influence of a Zombie-like State of the Liver on Drugs and Its Medico-Legal Implications: A Scoping Review.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Hyperammonemia induces programmed liver cell death.Science advances · 2025Article
- The Common Hallmarks and Interconnected Pathways of Aging, Circadian Rhythms, and Cancer: Implications for Therapeutic Strategies.Research (Washington, D.C.) · 2025Review
- Senescence in the bone marrow microenvironment: A driver in development of therapy-related myeloid neoplasms.Journal of bone oncology · 2024Article
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4 authors at 2 institutions in 1 country.
Funding
Abstract
BACKGROUND AND
aimCellular senescence of hepatocytes involves permanent cell cycle arrest, disrupted cellular bioenergetics, resistance to cell death, and the release of pro-inflammatory cytokines. This 'zombie-like' state perpetuates harmful effects on tissues and holds potential implications for liver disease progression. Remarkably, senescence exhibits heterogeneity, stemming from two crucial factors: the inducing stressor and the cell type. As such, our present study endeavors to characterize stressor-specific changes in senescence phenotype, its related molecular patterns, and cellular bioenergetics in primary mouse hepatocytes (PMH) and hepatocyte-derived liver organoids (HepOrgs).
methodsPMH, isolated by collagenase-perfused mouse liver (C57B6/J; 18-23 weeks), were cultured overnight in William's E-medium supplemented with 2% FBS, L-glutamine, and hepatocyte growth supplements. HepOrgs were developed by culturing cells in a 3D matrix for two weeks. The senescence was induced by DNA damage (doxorubicin, cisplatin, and etoposide), oxidative stress (H
resultsEach senescence inducer triggers a unique combination of senescence markers in hepatocytes. All senescence inducers, except hydroxyurea and ethanol, increased SA-β galactosidase activity, the most commonly used marker for cellular senescence. Among the SASP factors, CCL2 and IL-10 were consistently upregulated, while Plasminogen activator inhibitor-1 exhibited global downregulation across all modes of senescence. Notably, DNA damage response was activated by DNA damage inducers. Cell cycle markers were most significantly reduced by doxorubicin, cisplatin, and galactosamine. Additionally, DNA damage-induced senescence shifted cellular bioenergetics capacity from glycolysis to oxidative phosphorylation. In HepOrgs exposed to senescence inducers, there was a notable increase in γH2A.X, p53, and p21 levels. Interestingly, while showing a similar trend, SASP gene expression in HepOrgs was significantly higher compared to PMH, demonstrating a several-fold increase.
conclusionIn our study, we demonstrated that each senescence inducer activates a unique combination of senescence markers in PMH. Doxorubicin demonstrated the highest efficacy in inducing senescence, followed by cisplatin and H
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