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Cited by 15Mesenchymal stem cell researchLiver physiology and pathologyTelomeres, Telomerase, and Senescence

Administration of AG490 decreases the senescence of umbilical cord-mesenchymal stem cells and promotes the cytotherapeutic effect in liver fibrosis

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Jiang, Chenhao, Chen, Huaxin, Kang, Yinqian, He, Xinyi, Huang, Jianyang, Lu, Tongyu, Sui, Xin, Chen, Haitian +8 more·2023·Cell Death Discovery
DOI 10.1038/s41420-023-01546-3PMC PMC10382487
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Abstract

The therapeutic potential of umbilical cord-mesenchymal stem cell (UC-MSC) transplantation in liver fibrosis has been highlighted. However, the fate of transplanted MSCs in the fibrotic microenvironment remains unclear. In this study, we aim to uncover the fate of transplanted MSCs and develop targeting strategies that could enhance the therapeutic efficacy of MSC therapy in liver fibrosis. We used human UC-MSCs as the study object. For in vitro experiments, we stimulated UC-MSCs with several fibrotic-related factors (Liver fibrotic Factors, LF), including TGFβ, TNFα and IFNγ for downstream investigations. We co-cultured LF-treated UC-MSCs with hepatic stellate cell line LX-2 to assess the anti-fibrotic effect. We showed that upon LF stimulation, UC-MSCs exhibited reduced anti-fibrotic activity and underwent rapid senescence. Pathway analysis showed that JAK/STAT3 signaling was highly activated upon LF stimulation, which significantly elevated senescence-associated secretory phenotype (SASP) and senescence in UC-MSCs and could be reversed by a specific JAK inhibitor AG490. Moreover, using both carbon tetrachloride (CCl 4 ) and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induce fibrosis models, we demonstrated that AG490 pretreatment promoted UC-MSCs survival within the fibrotic liver microenvironment and exhibited enhance therapeutic efficacy. Overall, we showed that targeting MSC senescence in vivo through AG490 pretreatment could enhance the anti-fibrotic activities of UC-MSCs.

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Cited by

Sorted by citations

Authors
Jiang, C., Chen, H., Kang, Y., He, X., Huang, J., Lu, T., Sui, X., Chen, H., Xiao, J., Zhang, J., Zhang, H., Zheng, J., Yang, Y., Yao, J., Cai, J., & Zhang, Y.
Affiliations
  • Sun Yat-sen University (CN)
  • Sun Yat-sen University Cancer Center (CN)
  • Third Affiliated Hospital of Sun Yat-sen University (CN)
  • Emory University (US)
Corresponding author
  • Yao, Jia
  • Cai, Jianye
  • Zhang, Yingcai
ORCID
Venue
Cell Death Discovery
Publisher
Springer Science and Business Media LLC
Published
2023-07-28
Volume
9
Issue
1
Pages
273-273
ISSN
2058-7716 (ISSN-L)
DOI
10.1038/s41420-023-01546-3
PMC
PMC10382487
OpenAlex
W4385341465
Cited by
15
References
3
Citations by year
2026: 5 · 2025: 4 · 2024: 4 · 2023: 2
FWCI
2.60
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death Discovery (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 (82270689, 82170631, 81970567, 2021M700174, 82100663)
  • China Postdoctoral Science Foundation (82100663, 2021M700174)
  • Natural Science Foundation of Guangdong Province (2023A1515010160, 2022A1515012331, 2021A1515111058, 2020A1515110687, 2021A1515010571, 2023A1515030052, 2021A1515012136, 2022A1515012453)
Topics
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
Keywords
human umbilical cord mesenchymal stem cells, liver fibrosis, AG490, JAK/STAT3 signaling, cellular senescence, senescence-associated secretory phenotype, hepatic stellate cells, TGF-beta, TNF-α, interferon-gamma, cytotherapy, carbon tetrachloride-induced fibrosis

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