Atg5-deficient mesenchymal stem cells protect against non-alcoholic fatty liver by accelerating hepatocyte growth factor secretion.

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  • Additional Information
    • Source:
      Publisher: BioMed Central Country of Publication: England NLM ID: 101170464 Publication Model: Electronic Cited Medium: Internet ISSN: 1478-811X (Electronic) Linking ISSN: 1478811X NLM ISO Abbreviation: Cell Commun Signal Subsets: MEDLINE
    • Publication Information:
      Original Publication: [London] : BioMed Central, c2003-
    • Subject Terms:
      Mesenchymal Stem Cells*/metabolism ; Mesenchymal Stem Cells*/cytology ; Non-alcoholic Fatty Liver Disease*/metabolism ; Non-alcoholic Fatty Liver Disease*/pathology ; Non-alcoholic Fatty Liver Disease*/genetics ; Hepatocyte Growth Factor*/metabolism ; Hepatocyte Growth Factor*/genetics ; Autophagy-Related Protein 5*/genetics ; Autophagy-Related Protein 5*/metabolism; Animals ; Humans ; Mice ; Cell Proliferation ; Mesenchymal Stem Cell Transplantation ; Male ; Mice, Inbred C57BL ; Disease Models, Animal ; Hepatocytes/metabolism ; Diet, High-Fat/adverse effects
    • Abstract:
      Background/aims: Mesenchymal stem cells (MSCs) have shown promising therapeutic potential in treating liver diseases, such as non-alcoholic fatty liver disease (NAFLD). Genetic modification has been employed to enhance the characteristics of MSCs for more effective disease treatment. Here, we present findings on human adipose-derived MSCs with Atg5 deficiency, investigating their therapeutic impact and the associated mechanisms in NAFLD.
      Methods: In vitro, lentiviral transduction was employed to downregulate Atg5 or HGF in human adipose-derived MSCs using short hairpin RNA (shRNA). Subsequently, experiments were conducted to evaluate cell senescence, proliferation, cell cycle, apoptosis, and other pertinent aspects. In vivo, a non-alcoholic fatty liver mouse model was established by feeding them a high-fat diet (HFD), and the effects of MSCs transplantation were assessed through serological, biochemical, and pathological analyses.
      Results: Our research findings indicate that Atg5-deficient MSCs display heightened proliferative activity. Subsequent co-culturing of MSCs with hepatocytes and the transplantation of Atg5-deficient MSCs into NAFLD mouse models demonstrated their ability to effectively reduce lipid accumulation in the NAFLD disease model by modulating the AMPKα/mTOR/S6K/Srebp1 pathway. Furthermore, we observed that Atg5 deficiency enhances the secretion of hepatocyte growth factor (HGF) by promoting recycling endosome (RE) production. Lastly, our study revealed that 3-MA-primed MSCs can improve the characteristics of NAFLD by boosting the secretion of HGF.
      Conclusions: Our research findings suggest that Atg5-deficient MSCs protect against NAFLD by accelerating HGF secretion. This indicates that Atg5 gene-modified MSCs may represent a promising strategy for treating NAFLD.
      Competing Interests: Declarations. Competing interests: The authors declare no competing interests.
      (© 2024. The Author(s).)
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    • Grant Information:
      LHGJ20210531 the research project on medical science and technology in Henan Province
    • Contributed Indexing:
      Keywords: Atg5; HGF; Mesenchymal stem cells; Non-alcoholic fatty liver disease; Recycling endosomes
    • Accession Number:
      67256-21-7 (Hepatocyte Growth Factor)
      0 (Autophagy-Related Protein 5)
      0 (ATG5 protein, human)
    • Publication Date:
      Date Created: 20241203 Date Completed: 20241204 Latest Revision: 20241207
    • Publication Date:
      20241209
    • Accession Number:
      PMC11613616
    • Accession Number:
      10.1186/s12964-024-01950-x
    • Accession Number:
      39627775