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脂肪来源间充质干细胞及其外泌体通过同时增强自噬通量和抑制内质网应激对非酒精性脂肪性肝炎的改善作用

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.

作者信息

Moayedfard Zahra, Bagheri Lankarani Kamran, Alizadeh Ali Akbar, Nekooeian Ali Akbar, Dara Mahintaj, Koohpeyma Farhad, Parsa Shima, Nikeghbalian Saman, Hosseinpouri Arghavan, Azarpira Negar

机构信息

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

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

出版信息

Iran J Med Sci. 2025 May 1;50(5):334-350. doi: 10.30476/ijms.2024.103376.3660. eCollection 2025 May.

DOI:10.30476/ijms.2024.103376.3660
PMID:40438157
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12116527/
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 comparison between groups. P<0.05 indicated a significant difference.

RESULTS

AD-MSCs-exosomes significantly reduced ER stress indicators ( [P=0.0001], [P=0.0006], [P=0.0001], and [P=0.0001]), apoptosis markers ( [P=0.005] and [P=0.001]), and autophagic flux markers ( [P=0.0001] and [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.

摘要

背景

由于治疗选择有限，管理非酒精性脂肪性肝病（NAFLD）从脂肪变性发展到肝硬化需要创新方法。本研究聚焦内质网（ER）应激、细胞凋亡和自噬，将其作为NAFLD发病机制中的关键机制。研究还强调了脂肪间充质干细胞（AD-MSCs）及其外泌体作为有前景的治疗选择的潜力。

方法

该研究于2021年11月至2023年12月在设拉子医科大学再生医学系（伊朗设拉子）进行。将小鼠（n = 32）分为四组：对照组、未治疗的高脂饮食（HFD）组、AD-MSCs治疗的HFD组和AD-MSCs来源外泌体的HFD组。小鼠喂食HFD 8周。在最后3周给予它们间充质干细胞和外泌体。最后一次注射后1周，对小鼠进行血清检测、体视学分析和实时聚合酶链反应（RT-PCR）检测。使用Graph-Pad Prism软件通过单因素方差分析（ANOVA）和Tukey分析对数据进行分析，以比较组间差异。P<0.05表示差异有统计学意义。

结果

AD-MSCs外泌体显著降低了ER应激指标（[P = 0.0001]，[P = 0.0006]，[P = 0.0001]，以及[P = 0.0001]）、细胞凋亡标志物（[P = 0.005]和[P = 0.001]）和自噬通量标志物（[P = 0.0001]和[P = 0.003]）。

结论

在本研究中，AD-MSCs外泌体在NAFLD早期显著恢复了自噬并抑制了未折叠蛋白反应（UPR）途径。

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