Prevention of liver fibrosis and liver reconstitution of DMN‐treated rat liver by transplanted EPCs
Open accessAbstract
Eur J Clin Invest 2012; 42 (7): 717–728 Background Using the dimethylnitrosamine (DMN) rat model of induced fibrosis, we investigated whether transfer of in vitro–expanded endothelial progenitor cells (EPCs) could reconstitute liver tissue and protect against liver fibrosis. Materials and methods Low‐density, adherent, rat bone marrow‐derived mononuclear cells were cultured for one week in medium supporting the growth of chemokine (C‐X‐C motif) receptor 4 (CXCR4)‐positive EPCs that were used for transplantation. Test rats were treated with weekly intraperitoneal injections of DMN over a period of 4 weeks. During that period, the rats were also transplanted weekly with in vivo–expanded EPCs. Results Transplanted CXCR4‐positive expanded EPCs entered around the portal tracts, fibrous septa and hepatic sinusoids, locations at which stromal cell–derived factor 1 (SDF‐1), a ligand attracting CXCR4‐positive cells, was expressed nearby. In EPC‐transplanted rats, we observed suppression of liver fibrogenesis, reduced deposition of type I collagen and fibronectin, fewer α‐smooth muscle actin‐positive cells and lower expression of transforming growth factor (TGF)‐β. The expression of growth factors promoting hepatic regeneration (hepatocyte growth factor, transforming growth factor‐α (TGF‐α), epidermal growth factor and vascular endothelial growth factor) was significantly increased in EPC‐transplanted rats, resulting in hepatocyte proliferation. Immunohistochemical analyses of eNOS and isolectin B4 demonstrated that the livers of EPC‐transplanted animals had markedly increased vascular density, suggesting reconstitution of sinusoidal blood vessels with endothelium. Liver function tests of transaminase, total bilirubin, total protein and albumin demonstrated that normal levels were maintained in EPC‐transplanted rats. Conclusions EPC transplantation effectively promotes the remodelling of tissues damaged by liver fibrosis; it can also reconstitute sinusoids in chronic liver injury.
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In cirrhotic rat models, single or multiple transplanted EPCs clustered around the portal tracts, fibrotic septa, inflammatory sites, or hepatic sinusoids, colocalized with CD31+ vessels during one to four weeks, and then ameliorated portal hypertension, liver fibrosis, and vascular dysfunction.
“In cirrhotic rat models, single or multiple transplanted EPCs have been observed to cluster around the portal tracts, fibrotic septa, inflammatory sites, or hepatic sinusoids, colocalized with CD31+ vessels during one to four weeks, and then ameliorate portal hypertension, liver fibrosis, and vascular dysfunction [71–74].”
From Mechanisms, efficacy, and future perspectives of cellular-based therapies for liver fibrosis/cirrhosis: focusing on mesenchymal stromal cells (2025) · cites this paper as [72]
EPCs play a crucial role in the reconstruction of sinusoidal blood vessels through upregulating VEGF and endothelial NO synthase-derived nitric oxide, while downregulating endothelin-1 and caveolin.
“In addition, EPCs play a crucial role in the reconstruction of sinusoidal blood vessels through upregulating VEGF and endothelial NO synthase (eNOS)-derived nitric oxide (NO), while downregulating endothelin-1 and caveolin [72, 74].”
From Mechanisms, efficacy, and future perspectives of cellular-based therapies for liver fibrosis/cirrhosis: focusing on mesenchymal stromal cells (2025) · cites this paper as [72]
EPC transplantation enhanced hepatocyte proliferation and improved liver functions, accompanied by increased expression of EGF, HGF, and TGF-α, ultimately resulting in improved survival rates.
“Moreover, EPC transplantation enhanced hepatocyte proliferation and improved liver functions, accompanied by an increased expression of EGF, HGF, and transforming growth factor-α (TGF-α), ultimately resulting in improved survival rates [72, 73].”
From Mechanisms, efficacy, and future perspectives of cellular-based therapies for liver fibrosis/cirrhosis: focusing on mesenchymal stromal cells (2025) · cites this paper as [72]
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“In addition, EPCs play a crucial role in the reconstruction of sinusoidal blood vessels through upregulating VEGF and endothelial NO synthase (eNOS)-derived nitric oxide (NO), while downregulating endothelin-1 and caveolin [72, 74].”
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- Authors
- Nakamura, T., Torimura, T., Iwamoto, H., Masuda, H., Naitou, M., Koga, H., Abe, M., Hashimoto, O., Tsutsumi, V., Ueno, T., & Sata, M.
- Affiliations
- Kurume University (JP)
- Venue
- European Journal of Clinical Investigation
- Publisher
- Wiley
- Published
- 2012-01-07
- Volume
- 42
- Issue
- 7
- Pages
- 717-728
- ISSN
- 0014-2972 (ISSN-L)
- 1365-2362
- OpenAlex
- W2153248511
- Cited by
- 27
- References
- 38
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 4 · 2020: 4 · 2019: 1 · 2018: 1 · 2017: 1 · 2016: 3 · 2015: 2 · 2014: 3 · 2013: 3 · 2012: 1
- FWCI
- 1.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Journal of Clinical Investigation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (23790822, 22590752)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- liver fibrosis, endothelial progenitor cells, cell transplantation, N-nitrosodimethylamine, CXCR4, CXCL12, liver regeneration, hepatocyte proliferation, TGF-beta, vessel density, bone marrow-derived cells, type I collagen
- MeSH terms
- Animals, Bone Marrow Cells, Dimethylnitrosamine, Liver Cirrhosis, Experimental, Liver Regeneration, Male, Biomarkers, Rats, Sprague-Dawley, Models, Animal, Stem Cell Transplantation, Endothelial Cells, Rats, Cell- and Tissue-Based Therapy
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