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Cited by 336Liver physiology and pathologyLiver Disease Diagnosis and TreatmentDrug-Induced Hepatotoxicity and Protection

Hepatocytes Do Not Undergo Epithelial-Mesenchymal Transition in Liver Fibrosis in Mice

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Taura, Kojiro, Miura, Kouichi, Iwaisako, Keiko, Österreicher, Christoph H., Kodama, Yuzo, Penz-Österreicher, Melitta, Brenner, David A.·2010·Hepatology
DOI 10.1002/hep.23368PMC PMC2906231
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Abstract

The origin of fibrogenic cells in liver fibrosis remains controversial. We assessed the emerging concept that hepatocytes contribute to production of extracellular matrix (ECM) in liver fibrosis through epithelial-mesenchymal transition (EMT). We bred triple transgenic mice expressing ROSA26 stop β-galactosidase (β-gal), albumin Cre, and collagen α1(I) green fluorescent protein (GFP), in which hepatocyte-derived cells are permanently labeled by β-gal and type I collagen-expressing cells are labeled by GFP. We induced liver fibrosis by repetitive carbon tetrachloride (CCl4) injections. Liver sections and isolated cells were evaluated for GFP and β-gal as well as expression of α-smooth muscle actin (α-SMA) and fibroblast-specific protein 1 (FSP-1). Upon stimulation with transforming growth factor β-1, cultured hepatocytes isolated from untreated liver expressed both GFP and β-gal with a fibroblast-like morphological change but lacked expression of other mesenchymal markers. Cells from CCl4-treated livers never showed double-positivity for GFP and β-gal. All β-gal-positive cells exhibited abundant cytoplasm, a typical morphology of hepatocytes, and expressed none of the mesenchymal markers including α-SMA, FSP-1, desmin, and vimentin. In liver sections of CCl4-treated mice, GFP-positive areas were coincident with fibrotic septa and never overlapped X-gal-positive areas. Conclusion: Type I collagen-producing cells do not originate from hepatocytes. Hepatocytes in vivo neither acquire mesenchymal marker expression nor exhibit a morphological change clearly distinguishable from normal hepatocytes. Our results strongly challenge the concept that hepatocytes in vivo acquire a mesenchymal phenotype through EMT to produce the ECM in liver fibrosis. (Hepatology 2009.)

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  • This cytoplasmic localisation of MRTFB may help to understand the partial mesenchymal phenotype of PH acquired in stiff conditions.

    “This cytoplasmic localisation of MRTFB may help to understand the partial mesenchymal phenotype of PH acquired in stiff conditions [64].”

    From Mechanical stiffness orchestrates distinct regulation of <scp>MRTFs</scp> and <scp>YAP</scp> / <scp>TAZ</scp> transcriptional cofactors in hepatocytes (2026) · cites this paper as [64]

    The Results section reports that primary hepatocytes developed fibroblast-like morphology and expressed collagen α1(I) after TGFβ-1 stimulation, while lacking other mesenchymal markers. That supports a limited phenotypic change, but the paper does not address MRTFB localisation, stiffness, or a link between them and that phenotype. Page numbers are unavailable in our copy. (LLM, conf=0.83)

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Research works printed but not linked: 23

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Cited by

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Authors
Taura, K., Miura, K., Iwaisako, K., Österreicher, C. H., Kodama, Y., Penz-Österreicher, M., & Brenner, D. A.
Affiliations
University of California San Diego (US)
Corresponding author
Brenner, David A.
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2010-03
Volume
51
Issue
3
Pages
1027-1036
ISSN
0270-9139 (ISSN-L)
DOI
10.1002/hep.23368
PMC
PMC2906231
OpenAlex
W2035617243
Cited by
336
References
0
Citations by year
2026: 2 · 2025: 5 · 2024: 14 · 2023: 18 · 2022: 7 · 2021: 10 · 2020: 16 · 2019: 15 · 2018: 17 · 2017: 22 · 2016: 23 · 2015: 27 · 2014: 31 · 2013: 29 · 2012: 30
FWCI
21.31
Type
journal article
Language
en
Open access
Licence
doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 2010 d)
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of General Medical Sciences (R01GM041804)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK048252)
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
liver fibrosis, epithelial-mesenchymal transition, hepatocytes, extracellular matrix synthesis, carbon tetrachloride-induced fibrosis, type I collagen, alpha-smooth muscle actin, S100A4, transgenic mice
MeSH terms
Animals, Cell Differentiation, Cells, Cultured, Epithelial Cells, Liver Cirrhosis, Mesoderm, Mice, Transgenic, Hepatocytes, Collagen Type I, Mice

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