Depletion of activated hepatic stellate cell correlates with severe liver damage and abnormal liver regeneration in acetaminophen-induced liver injury
Abstract
Hepatic stellate cells (HSCs) are important part of the local 'stem cell niche' for hepatic progenitor cells (HPCs) and hepatocytes. However, it is unclear as to whether the products of activated HSCs are required to attenuate hepatocyte injury, enhance liver regeneration, or both. In this study, we performed 'loss of function' studies by depleting activated HSCs with gliotoxin. It was demonstrated that a significantly severe liver damage and declined survival rate were correlated with depletion of activated HSCs. Furthermore, diminishing HSC activation resulted in a 3-fold increase in hepatocyte apoptosis and a 66% decrease in the number of proliferating hepatocytes. This was accompanied by a dramatic decrease in the expression levels of five genes known to be up-regulated during hepatocyte replication. In particular, it was found that depletion of activated HSCs inhibited oval cell reaction that was confirmed by decreased numbers of Pank-positive cells around the portal tracts and lowered gene expression level of cytokeratin 19 (CK19) in gliotoxin-treated liver. These data provide clear evidence that the activated HSCs are involved in both hepatocyte death and proliferation of hepatocytes and HPCs in acetaminophen (APAP)-induced acute liver injury.
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HSC depletion with lower potency and specificity, using gliotoxin or GFAP-TK, has yielded inconsistent effects on liver regeneration and injury.
“HSC depletion with lower potency and specificity, using gliotoxin or GFAP-TK, has yielded inconsistent effects on liver regeneration and injury15–18.”
From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [16]
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- Authors
- Shen, K., Chang, W., Gao, X., Wang, H., Niu, W., Song, L., & Qin, X.
- Affiliations
- Shanghai Medical College of Fudan University (CN)
- Venue
- Acta Biochimica et Biophysica Sinica
- Published
- 2011-04-01
- Volume
- 43
- Issue
- 4
- Pages
- 307-315
- ISSN
- 1672-9145 (ISSN-L)
- OpenAlex
- W2098452191
- Cited by
- 57
- References
- 30
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 5 · 2023: 2 · 2022: 5 · 2021: 5 · 2020: 5 · 2019: 3 · 2018: 2 · 2017: 3 · 2016: 3 · 2015: 6 · 2014: 4 · 2013: 4 · 2012: 3
- FWCI
- 2.23
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Acta Biochimica et Biophysica Sinica (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Keywords
- hepatic stellate cells, hepatic stellate cell activation, acetaminophen hepatotoxicity, liver regeneration, hepatocyte apoptosis, hepatocyte proliferation, hepatic progenitor cells, oval cells, gliotoxin, cytokeratin 19, liver injury
- MeSH terms
- Acetaminophen, Alanine Transaminase, Animals, Aspartate Aminotransferases, Gliotoxin, Humans, Immunohistochemistry, Immunosuppressive Agents, Kupffer Cells, Liver, Liver Regeneration, Mice, Inbred C57BL, Gene Expression, Survival Rate, Reverse Transcriptase Polymerase Chain Reaction, Hepatocytes, Mice, Kaplan-Meier Estimate, Keratin-19, Hepatic Stellate Cells, Chemical and Drug Induced Liver Injury
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