Hepatic stellate cells and portal fibroblasts are the major cellular sources of collagens and lysyl oxidases in normal liver and early after injury
Open accessAbstract
Liver fibrosis is characterized by excessive deposition of extracellular matrix proteins by myofibroblasts derived from hepatic stellate cells and portal fibroblasts. Activation of these precursors to myofibroblasts requires matrix stiffness, which results in part from increased collagen cross-linking mediated by lysyl oxidase (LOX) family proteins. The aims of this study were to characterize the mechanical changes of early fibrosis, to identify the cells responsible for LOX production in early injury, and to determine which cells in normal liver produce collagens and elastins, which serve as substrates for LOXs early after injury. Hepatocytes and liver nonparenchymal cells were isolated from normal and early-injured liver and examined immediately for expression of LOXs and matrix proteins. We found that stellate cells and portal fibroblasts were the major cellular sources of fibrillar collagens and LOXs in normal liver and early after injury (1 day after bile duct ligation and 2 and 7 days after CCl(4) injury). Activity assays using stellate cells and portal fibroblasts in culture demonstrated significant increases in LOX family enzymatic activity as cells became myofibroblastic. LOX family-mediated deoxypyridinoline and pyridinoline cross-links increased after CCl(4)-mediated injury. There was a significant association between liver stiffness (as quantified by the shear storage modulus G') and deoxypyridinoline levels; increased deoxypyridinoline levels were also coincident…
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During liver fibrosis, extracellular matrix deposition causes a progressive increase in tissue stiffness.
“In parallel, the extracellular matrix (ECM) deposition causes a progressive increase of stiffness [1, 2].”
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 [1]
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- Authors
- Perepelyuk, M., Terajima, M., Wang, A. Y., Georges, P. C., Janmey, P. A., Yamauchi, M., & Wells, R. G.
- Affiliations
- University of Pennsylvania (US)
- North Carolina Oral Health Institute, Durham, North Carolina
- University of Virginia Health System (US)
- Corresponding author
- Wells, Rebecca G.
- ORCID
- Venue
- American Journal of Physiology-Gastrointestinal and Liver Physiology
- Publisher
- American Physiological Society
- Published
- 2013-03-15
- Volume
- 304
- Issue
- 6
- Pages
- G605-G614
- ISSN
- 0193-1857 (ISSN-L)
- 1522-1547
- PMC
- PMC3602686
- OpenAlex
- W2098477897
- Cited by
- 184
- References
- 1
- Citations by year
- 2026: 12 · 2025: 6 · 2024: 9 · 2023: 11 · 2022: 16 · 2021: 15 · 2020: 19 · 2019: 8 · 2018: 21 · 2017: 11 · 2016: 14 · 2015: 19 · 2014: 14 · 2013: 8
- FWCI
- 11.42
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- American Journal of Physiology-Gastrointestinal and Liver Physiology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM083272)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32-DK07066, T32DK007066, R01DK058123, P30DK050306)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R21AR060978)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
- Keywords
- hepatic stellate cells, portal fibroblasts, lysyl oxidase, liver fibrosis, collagen cross-linking, extracellular matrix stiffness, myofibroblast activation, bile duct ligation, deoxypyridinoline, pyridinoline, liver stiffness, elastin
- MeSH terms
- Amino Acids, Animals, Collagen, Disease Models, Animal, Extracellular Matrix, Fibroblasts, Fibrosis, Kupffer Cells, Liver, Protein-Lysine 6-Oxidase, Time Factors, Rats, Sprague-Dawley, Hepatocytes, Rats, Elastic Modulus, Hepatic Stellate Cells, Chemical and Drug Induced Liver Injury
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