Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models
Open accessAbstract
Introduction: Mesenchymal stem cell-conditioned medium (MSC-CM) has been shown to have protective effects against various cellular-injury models. This mechanism of protection, however, has yet to be elucidated. Recently, exosomes were identified as the active component in MSC-CM. The aim of this study is to investigate the effect of MSC-derived exosomes in an established carbon tetrachloride (CCl 4)-induced liver injury mouse model. This potential effect is then validated by using in vitro xenobiotic-induced liver-injury assays: (1) acetaminophen (APAP)- and (2) hydrogen peroxide (H 2 O 2)-induced liver injury. Methods: The exosomes were introduced concurrent with CCl 4 into a mouse model through different routes of administration. Biochemical analysis was performed based on the blood and liver tissues. Subsequently the exosomes were treated in APAP and H 2 O 2-toxicants with in vitro models. Cell viability was measured, and biomarkers indicative of regenerative and oxidative biochemical responses were determined to probe the mechanism of any hepatoprotective activity observed. Results: In contrast to mice treated with phosphate-buffered saline, CCl 4 injury in mice was attenuated by concurrent-treatment exosomes, and characterized by an increase in hepatocyte proliferation, as demonstrated with proliferating cell nuclear antigen (PCNA) elevation. Significantly higher cell viability was demonstrated in the exosomes-treated group compared with the non-exosome-treated group in both injury models. The higher survival rate was associated with upregulation of the priming-phase genes during liver regeneration, which subsequently led to higher expression of proliferation proteins (PCNA and cyclin D1) in the exosomes-treated group. Exosomes also inhibited the APAP- and H 2 O 2-induced hepatocytes apoptosis through upregulation of Bcl-xL protein expression. However, exosomes do not mitigate hepatocyte injury via modulation of oxidative stress. Conclusions: In summary, these results suggest that MSC-derived exosomes can elicit hepatoprotective effects against toxicants-induced injury, mainly through activation of proliferative and regenerative responses.
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MSC-derived exosomes have broad-spectrum therapeutic efficacy validated in multiple disease models.
“the broad-spectrum therapeutic efficacy of MSC-derived exosomes have also been validated in multiple disease models, including carbon tetrachloride (CCl4)-induced liver injury [16], myocardial ischemia/reperfusion injury [17], LPS-induced acute respiratory distress syndrome [18], and graft-versus-host disease [19].”
From A tailored bioactive 3D porous poly(lactic-acid)-exosome scaffold with osteo-immunomodulatory and osteogenic differentiation properties (2022) · cites this paper as [16]
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- Authors
- Tan, C. Y., Lai, R. C., Wong, W., Dan, Y. Y., Lim, S.-K., & Ho, H. K.
- Affiliations
- National University of Singapore (SG)
- Agency for Science, Technology and Research (SG)
- National University Hospital (SG)
- Corresponding author
- Ho, Han Kiat
- Venue
- Stem Cell Research & Therapy
- Published
- 2014-06-10
- Volume
- 5
- Issue
- 3
- Pages
- 76-76
- ISSN
- 1757-6512 (ISSN-L)
- PMC
- PMC4229780
- OpenAlex
- W2109179710
- Cited by
- 548
- References
- 43
- Citations by year
- 2026: 18 · 2025: 23 · 2024: 40 · 2023: 43 · 2022: 48 · 2021: 72 · 2020: 70 · 2019: 60 · 2018: 57 · 2017: 53 · 2016: 45 · 2015: 15 · 2014: 2
- FWCI
- 15.73
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Stem Cell Research & Therapy (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion)
- Funders
- National Medical Research Council
- Biomedical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- mesenchymal stem cell-derived exosomes, liver regeneration, drug-induced liver injury, carbon tetrachloride, acetaminophen hepatotoxicity, hepatoprotection, hepatocyte proliferation, PCNA, cyclin D1, Bcl-xL, apoptosis, oxidative stress, xenobiotic toxicity
- MeSH terms
- Acetaminophen, Animals, Carbon Tetrachloride, Disease Models, Animal, Humans, Hydrogen Peroxide, Liver Regeneration, Male, Mice, Inbred C57BL, Blotting, Western, Reverse Transcriptase Polymerase Chain Reaction, Hepatocytes, Cell Proliferation, Mice, Exosomes, Chemical and Drug Induced Liver Injury, Mesenchymal Stem Cells, Real-Time Polymerase Chain Reaction
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