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Cited by 44Mesenchymal stem cell researchAutophagy in Disease and TherapyExtracellular vesicles in disease

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Mesenchymal stem cells exosomal let-7a-5p improve autophagic flux and alleviate liver injury in acute-on-chronic liver failure by promoting nuclear expression of TFEB

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Lin, Dengna, Chen, Hao, Xiong, Jing, Zhang, Jing, Hu, Zhaoxia, Gao, Juan, Gao, Bin, Zhang, Shaoquan, Chen, Junfeng, Cao, Huijuan, Li, Zhihui, Lin, Bingliang, Gao, Zhiliang·2022·Cell Death & Disease
DOI 10.1038/s41419-022-05303-9PMC PMC9556718
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Abstract

Acute-on-chronic liver failure is a distinct clinical syndrome characterized by a dysregulated immune response and extensive hepatocyte death without satisfactory therapies. As a cytoplasmic degradative and quality-control process, autophagy was implicated in maintaining intracellular homeostasis, and decreased hepatic autophagy was found in many liver diseases and contributes to disease pathogenesis. Previously, we identified the therapeutic potential of mesenchymal stem cells (MSCs) in ACLF patients; however, the intrinsic mechanisms are incompletely understood. Herein, we showed that MSCs restored the impaired autophagic flux and alleviated liver injuries in ACLF mice, but these effects were abolished when autophago-lysosomal maturation was inhibited by leupeptin (leu), suggesting that MSCs exerted their hepatoprotective function in a pro-autophagic dependent manner. Moreover, we described a connection between transcription factor EB (TFEB) and autophagic activity in this context, as evidenced by increased nuclei translocation of TFEB elicited by MSCs were capable of promoting liver autophagy. Mechanistically, we confirmed that let-7a-5p enriched in MSCs derived exosomes (MSC-Exo) could activate autophagy by targeting MAP4K3 to reduce TFEB phosphorylation, and MAP4K3 knockdown partially attenuates the effect of anti-let-7a-5p oligonucleotide via decreasing the inflammatory response, in addition, inducing autophagy. Altogether, these findings revealed that the hepatoprotective effect of MSCs may partially profit from its exosomal let-7a-5p mediating autophagy repairment, which may provide new insights for the therapeutic target of ACLF treatment.

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  • let-7a-5p, a microRNA enriched in MSC-Exos, improves autophagic flux through the promotion of nuclear translocation of transcriptional factor EB, mediated by the dephosphorylation of MAP4K3.

    “It has been reported that let-7a-5p, a microRNA enriched in MSC-Exos, improves autophagic flux through the promotion of nuclear translocation of transcriptional factor EB, which is mediated by the dephosphorylation of MAP4K3 [104].”

    From Mechanisms, efficacy, and future perspectives of cellular-based therapies for liver fibrosis/cirrhosis: focusing on mesenchymal stromal cells (2025) · cites this paper as [104]

    The Results sections report that let-7a-5p is enriched in MSC exosomes and promotes TFEB nuclear translocation and autophagic flux repair. They describe inhibition of MAP4K3 expression leading to dephosphorylation of TFEB—not dephosphorylation of MAP4K3. Page numbers were not supplied in the copy. (LLM, conf=0.90)

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Metadata

Authors
Lin, D., Chen, H., Xiong, J., Zhang, J., Hu, Z., Gao, J., Gao, B., Zhang, S., Chen, J., Cao, H., Li, Z., Lin, B., & Gao, Z.
Affiliations
  • Third Affiliated Hospital of Sun Yat-sen University (CN)
  • First Affiliated Hospital of Nanchang University (CN)
  • Sun Yat-sen University (CN)
Corresponding author
  • Lin, Bingliang
  • Gao, Zhiliang
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2022-10-12
Volume
13
Issue
10
Pages
865-865
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/s41419-022-05303-9
PMC
PMC9556718
OpenAlex
W4304606361
Cited by
44
References
6
Citations by year
2026: 8 · 2025: 14 · 2024: 11 · 2023: 11
FWCI
5.59
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 (81901940, 2018ZX10302204, 82070612)
  • Natural Science Foundation of Guangdong Province (2021A1515010306)
  • National Science and Technology Major Project (2018ZX10302-204)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
Keywords
acute-on-chronic liver failure, mesenchymal stem cells, exosomes, let-7a-5p, autophagy, autophagic flux, TFEB nuclear translocation, MAP4K3, hepatoprotection, liver injury
MeSH terms
Animals, Autophagy, Leupeptins, Oligonucleotides, MicroRNAs, Mice, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Mesenchymal Stem Cells, Acute-On-Chronic Liver Failure

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