A Novel Murine Model to Deplete Hepatic Stellate Cells Uncovers Their Role in Amplifying Liver Damage in Mice
Open accessAbstract
We have developed a novel model for depleting mouse hepatic stellate cells (HSCs) that has allowed us to clarify their contributions to hepatic injury and fibrosis. Transgenic (Tg) mice expressing the herpes simplex virus thymidine kinase gene ( HSV-Tk ) driven by the mouse GFAP promoter were used to render proliferating HSCs susceptible to killing in response to ganciclovir (GCV). Effects of GCV were explored in primary HSCs and in vivo . Panlobular damage was provoked to maximize HSC depletion by combining CCl 4 (centrilobular injury) with allyl alcohol (AA) (periportal injury), as well as in a bile duct ligation (BDL) model. Cell depletion in situ was quantified using dual immunofluorescence (IF) for desmin and GFAP. In primary HSCs isolated from both untreated wild-type (WT) and Tg mice, GCV induced cell death in ˜50% of HSCs from Tg, but not WT, mice. In TG mice treated with CCl 4 +AA+GCV, there was a significant decrease in GFAP and desmin-positive cells, compared to WT mice (˜65% reduction; P < 0.01), which was accompanied by a decrease in the expression of HSC-activation markers (alpha smooth muscle actin, beta platelet-derived growth factor receptor, and collagen I). Similar results were observed after BDL. Associated with HSC depletion in both fibrosis models, there was marked attenuation of fibrosis and liver injury, as indicated by Sirius Red/Fast Green, hematoxylin and eosin quantification, and serum alanine/aspartate aminotransferase. Hepatic expression of interleukin-10 and interferon-gamma was increased after HSC depletion. No toxicity of GCV in either WT or Tg mice accounted for the differences in injury. Conclusion : Activated HSCs significantly amplify the response to liver injury, further expanding this cell type's repertoire in orchestrating hepatic injury and repair. (Hepatology 2013)
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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 [17]
The Discussion (page not available) says earlier gliotoxin studies found no effect on injury, whereas this paper’s GFAP-HSV-Tk model found reduced injury after HSC depletion; it also raises concerns about gliotoxin’s specificity. It does not report inconsistent effects on liver regeneration or establish that GFAP-Tk has lower specificity; regeneration is identified as a topic for future study. (LLM, conf=0.85)
Experimental — accuracy not yet measuredStudies in which HSCs are deleted lead to increases in the numbers of CD4+, CD8+ T cells, DCs, NK cells, regulatory T cells, and Ly-6C+ macrophages.
“Supporting these physiologic roles in promoting hepatic immune tolerance are studies in which HSCs are deleted, leading to increases in the numbers of CD4+, CD8+ T cells, DCs, natural killer (NK) cells, regulatory T cells, and Ly-6C+ macrophages (53).”
From Hepatic Stellate Cell-Immune Interactions in NASH (2022) · cites this paper as [53]
Most myofibroblasts in chemically injured mouse models come from HSCs, and depleting them reduces liver fibrosis.
“The majority of myofibroblasts in chemically-injured mouse models also derive from HSCs, and their depletion reduces liver fibrosis (52-54).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [54]
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- Authors
- Puche, J. E., Lee, Y. A., Jiao, J., Aloman, C., Fiel, M. I., Muñoz, U., Kraus, T., Lee, T., Yee, H. F., & Friedman, S. L.
- Affiliations
- Universidad San Pablo CEU (ES)
- Icahn School of Medicine at Mount Sinai (US)
- University of California, San Francisco (US)
- Corresponding author
- Friedman, Scott L.
- ORCID
- Venue
- Hepatology
- Published
- 2013-01
- Volume
- 57
- Issue
- 1
- Pages
- 339-350
- ISSN
- 0270-9139 (ISSN-L)
- PMC
- PMC3522764
- OpenAlex
- W1969604127
- Cited by
- 136
- References
- 28
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 4 · 2023: 8 · 2022: 8 · 2021: 11 · 2020: 14 · 2019: 12 · 2018: 10 · 2017: 8 · 2016: 14 · 2015: 12 · 2014: 11 · 2013: 12
- FWCI
- 7.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- National Institute on Alcohol Abuse and Alcoholism (K05AA018408, R01AA020709, P20AA017067)
- National Institute of Diabetes and Digestive and Kidney Diseases (R56DK056621, K08DK088954, R01DK056621, DK 56621, P30DK026743)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- hepatic stellate cells, HSC depletion, liver fibrosis, liver injury, ganciclovir, GFAP promoter, carbon tetrachloride, allyl alcohol, bile duct ligation, IL-10, interferon-gamma, liver repair
- MeSH terms
- Animals, Carbon Tetrachloride, Cell Line, Fibrosis, Glial Fibrillary Acidic Protein, Liver, Male, Mice, Transgenic, Nerve Tissue Proteins, Promoter Regions, Genetic, Thymidine Kinase, Viral Proteins, Ganciclovir, Cytokines, Apoptosis, Propanols, Mice, Hepatic Stellate Cells, Chemical and Drug Induced Liver Injury
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