Zhang Caifeng, Ji Juanjuan, Du Xuefang, Zhang Lanfang, Song Yaxuan, Wang Yuyu, Jiang Yanan, Li Ke, Chang Tingmin
Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan Province, China.
First College for Clinical Medicine, Xinxiang Medical University, Xinxiang , Henan, 453003, China.
Cell Commun Signal. 2024 Dec 3;22(1):579. doi: 10.1186/s12964-024-01950-x.
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.
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.
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.
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.
背景/目的：间充质干细胞（MSCs）在治疗肝脏疾病如非酒精性脂肪性肝病（NAFLD）方面已显示出有前景的治疗潜力。基因修饰已被用于增强MSCs的特性以更有效地治疗疾病。在此，我们展示了关于自噬相关基因5（Atg5）缺陷的人脂肪来源的MSCs的研究结果，探讨它们在NAFLD中的治疗作用及相关机制。
在体外，使用短发夹RNA（shRNA）通过慢病毒转导下调人脂肪来源的MSCs中的Atg5或肝细胞生长因子（HGF）。随后，进行实验以评估细胞衰老、增殖、细胞周期、凋亡及其他相关方面。在体内，通过给小鼠喂食高脂饮食（HFD）建立非酒精性脂肪肝小鼠模型，并通过血清学、生化和病理学分析评估MSCs移植的效果。
我们的研究结果表明，Atg5缺陷的MSCs表现出增强的增殖活性。随后将MSCs与肝细胞共培养以及将Atg5缺陷的MSCs移植到NAFLD小鼠模型中，证明它们能够通过调节腺苷酸活化蛋白激酶α（AMPKα）/雷帕霉素靶蛋白（mTOR）/核糖体蛋白S6激酶（S6K）/固醇调节元件结合蛋白1（Srebp1）途径有效减少NAFLD疾病模型中的脂质积累。此外，我们观察到Atg5缺陷通过促进循环内体（RE）的产生增强了肝细胞生长因子（HGF）的分泌。最后，我们的研究表明，3-甲基腺嘌呤（3-MA）预处理的MSCs可以通过促进HGF的分泌改善NAFLD的特征。
我们的研究结果表明，Atg5缺陷的MSCs通过加速HGF分泌来预防NAFLD。这表明Atg5基因修饰的MSCs可能是治疗NAFLD的一种有前景的策略。
