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Cited by 206Mesenchymal stem cell researchDrug-Induced Hepatotoxicity and ProtectionExtracellular vesicles in disease

Mesenchymal stem cells protect against ferroptosis via exosome-mediated stabilization of SLC7A11 in acute liver injury

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Lin, Feiyan, Chen, Wenyi, Zhou, Jiahang, Zhu, Jiaqi, Yao, Qigu, Feng, Bing, Feng, Xudong, Shi, Xiaowei +4 more·2022·Cell Death & Disease
DOI 10.1038/s41419-022-04708-wPMC PMC8960810
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Abstract

Mesenchymal stem cells (MSCs) have attracted interest for their potential to alleviate liver injury. Here, the protective effect of MSCs on carbon tetrachloride (CCl 4)-induced acute liver injury (ALI) was investigated. In this study, we illustrated a novel mechanism that ferroptosis, a newly recognized form of regulated cell death, contributed to CCl 4-induced ALI. Subsequently, based on the in vitro and in vivo evidence that MSCs and MSC-derived exosomes (MSC-Exo) treatment achieved pathological remission and inhibited the production of lipid peroxidation, we proposed an MSC-based therapy for CCl 4-induced ALI. More intriguingly, treatment with MSCs and MSC-Exo downregulated the mRNA level of prostaglandin-endoperoxide synthase 2 (Ptgs2) and lipoxygenases (LOXs) while it restored the protein level of SLC7A11 in primary hepatocytes and mouse liver, indicating that the inhibition of ferroptosis partly accounted for the protective effect of MSCs and MSC-Exo on ALI. We further revealed that MSC-Exo-induced expression of SLC7A11 protein was accompanied by increasing of CD44 and OTUB1. The aberrant expression of ubiquitinated SLC7A11 triggered by CCl 4 could be rescued with OTUB1-mediated deubiquitination, thus strengthening SLC7A11 stability and thereby leading to the activation of system X C− to prevent CCl 4-induced hepatocyte ferroptosis. In conclusion, we showed that MSC-Exo had a protective role against ferroptosis by maintaining SLC7A11 function, thus proposing a novel therapeutic strategy for ferroptosis-induced ALI.

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References 44 · Cited by 206

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Authors
Lin, F., Chen, W., Zhou, J., Zhu, J., Yao, Q., Feng, B., Feng, X., Shi, X., Pan, Q., Yu, J., Li, L., & Cao, H.
Affiliations
  • First Affiliated Hospital of Wenzhou Medical University (CN)
  • First Affiliated Hospital Zhejiang University (CN)
Corresponding author
Cao, Hongcui
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2022-03-26
Volume
13
Issue
3
Pages
271-271
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/s41419-022-04708-w
PMC
PMC8960810
OpenAlex
W4220817059
Cited by
206
References
44
Citations by year
2026: 20 · 2025: 65 · 2024: 61 · 2023: 52 · 2022: 8
FWCI
28.90
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death and Disease (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (81971756)
  • Stem Cell and Translational Research from National Key Research and Development Program of Chin
Topics
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
Keywords
mesenchymal stem cells, ferroptosis, acute liver injury, SLC7A11, exosomes, carbon tetrachloride, system xc-, OTUB1, deubiquitination, CD44, cyclooxygenase-2, lipoxygenase, lipid peroxidation, hepatoprotection, MSC-based therapy
MeSH terms
Ferroptosis, Animals, Liver, Hepatocytes, Mice, Exosomes, Mesenchymal Stem Cells

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