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Cited by 25Mesenchymal stem cell researchLiver physiology and pathologyOrgan Transplantation Techniques and Outcomes

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TNF-α/IL-1β-licensed hADSCs alleviate cholestatic liver injury and fibrosis in mice via COX-2/PGE2 pathway

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Luan, Xiaoyu, Chen, Peng, Li, Yaxin, Yuan, Xinying, Miao, Longyu, Zhang, Pengyu, Cao, Qilong, Song, Xiaomin, Di, Guohu·2023·Stem Cell Research & Therapy
DOI 10.1186/s13287-023-03342-3PMC PMC10127380
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Abstract

Background: Adipose tissue-derived stem cell (ADSC) transplantation has been shown to be effective for the management of severe liver disorders. Preactivation of ADSCs enhanced their therapeutic efficacy. However, these effects have not yet been examined in relation to cholestatic liver injury. Methods: In the present study, a cholestatic liver injury model was established by bile duct ligation (BDL) in male C57BL/6 mice. Human ADSCs (hADSCs) with or without tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) pretreatment were administrated into the mice via tail vein injections. The efficacy of hADSCs on BDL-induced liver injury was assessed by histological staining, real-time quantitative PCR (RT-qPCR), Western blot, and enzyme-linked immune sorbent assay (ELISA). In vitro, the effects of hADSC conditioned medium on the activation of hepatic stellate cells (HSCs) were investigated. Small interfering RNA (siRNA) was used to knock down cyclooxygenase-2 (COX-2) in hADSCs. Results: TNF-α/IL-1β preconditioning could downregulate immunogenic gene expression and enhance the engraftment efficiency of hADSCs. Compared to control hADSCs (C-hADSCs), TNF-α/IL-1β-pretreated hADSCs (P-hADSCs) significantly alleviated BDL-induced liver injury, as demonstrated by reduced hepatic cell death, attenuated infiltration of Ly6G + neutrophils, and decreased expression of pro-inflammatory cytokines TNF-α, IL-1β, C-X-C motif chemokine ligand 1 (CXCL1), and C-X-C motif chemokine ligand 2 (CXCL2). Moreover, P-hADSCs significantly delayed the development of BDL-induced liver fibrosis. In vitro, conditioned medium from P-hADSCs significantly inhibited HSC activation compared to that from C-hADSCs. Mechanistically, TNF-α/IL-1β upregulated COX-2 expression and increased prostaglandin E2 (PGE2) secretion. The blockage of COX-2 by siRNA transfection reversed the benefits of P-hADSCs for PGE2 production, HSC activation, and liver fibrosis progression. Conclusion: In conclusion, our results suggest that TNF-α/IL-1β pretreatment enhances the efficacy of hADSCs in mice with cholestatic liver injury, partially through the COX-2/PGE2 pathway.

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Metadata

Authors
Luan, X., Chen, P., Li, Y., Yuan, X., Miao, L., Zhang, P., Cao, Q., Song, X., & Di, G.
Affiliations
  • Qingdao University (CN)
  • Haier Group (China) (CN)
Corresponding author
Di, Guohu
ORCID
Venue
Stem Cell Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2023-04-24
Volume
14
Issue
1
Pages
100-100
ISSN
1757-6512 (ISSN-L)
DOI
10.1186/s13287-023-03342-3
PMC
PMC10127380
OpenAlex
W4366823121
Cited by
25
References
4
Citations by year
2026: 8 · 2025: 6 · 2024: 9 · 2023: 2
FWCI
4.33
Type
journal article
Language
en
Open access
Licence
Locations
  • Stem Cell Research & Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Key R&D Program of China Grants (2018YFA0109800)
  • Postdoctoral Research Foundation of China (No.2019M652328)
  • Shandong Provincial Natural Science Foundation grant (ZR2022MH183)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
Keywords
adipose-derived stem cells, cholestatic liver injury, liver fibrosis, cyclooxygenase-2, prostaglandin E2, hepatic stellate cell activation, bile duct ligation, stem cell transplantation, neutrophil infiltration, immunogenicity, engraftment
MeSH terms
Animals, Cholestasis, Fibrosis, Humans, Ligands, Liver, Liver Cirrhosis, Male, Mice, Inbred C57BL, Tumor Necrosis Factor-alpha, Dinoprostone, Culture Media, Conditioned, Chemokines, Mice, Cyclooxygenase 2, Chemical and Drug Induced Liver Injury, Chronic

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