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The Ameliorative Effect of Adipose-Derived Mesenchymal Stem Cells and Their Exosomes in Non-alcoholic Steatohepatitis by Simultaneously Enhancing Autophagic Flux and Suppressing Endoplasmic Reticulum Stress

Articles InPress

Document Type : Original Article(s)

Authors

1 Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran

2 Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran

3 Health Policy Research Center (HPRC), Shiraz University of Medical Sciences, Shiraz, Iran.

4 Department of Pharmacology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

5 Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

6 Endocrine and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

7 Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

8 Abu Ali Sina Hospital for Medicine and Organ Transplant, Shiraz University of Medical Sciences, Shiraz, Iran

10.30476/ijms.2024.103376.3660

Abstract

Background: Due to the scarcity of treatment options, managing the progression of non-alcoholic fatty liver disease (NAFLD) from steatosis to cirrhosis necessitates innovative approaches. This study focused on endoplasmic reticulum (ER) stress, apoptosis, and autophagy as key mechanisms in NAFLD pathogenesis. It also highlighted the potential of adipose-derived mesenchymal stem cells (AD-MSCs) and their exosomes as promising therapeutic options.
Methods: The study was conducted at the Department of Regenerative Medicine, Shiraz University of Medical Sciences, (Shiraz, Iran) from November 2021 to December 2023. The mice (n=32) were divided into four groups: control, high-fat diet (HFD) without treatment, HFD with AD-MSCs treatment, and HFD with AD-MSCs-derived exosomes groups. The mice were fed HFD for 8 weeks. They received MSC and exosomes for the last 3 weeks. One week after the final injection, mice were tested for serum testing, stereological analysis, and real-time polymerase chain reaction (RT-PCR). The data were analyzed using the Graph-Pad Prism software by one-way analysis of variance (ANOVA) with Tukey analysis as a post hoc comparison between groups. P<0.05 indicated a significant difference. 
Results: AD-MSCs-exosomes significantly reduced ER stress indicators (IRE1α [P=0.0001], PERK [P=0.0006], ATF6 [P=0.0001], and GRP78 [P=0.0001]), apoptosis markers (Bax [P=0.005] and Cas3 [P=0.001]), and autophagic flux markers (P62 [P=0.0001] and LC3B/A [P=0.003]). 
Conclusion: In this investigation, AD-MSCs-exosomes significantly restored autophagy and suppressed unfolded protein response (UPR) pathways in the early stages of NAFLD.

Keywords

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Iranian Journal of Medical Sciences

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Available Online from 09 March 2025
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  • Received: 20 July 2024
  • Revised: 01 September 2024
  • Accepted: 22 September 2024
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