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.
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.
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.
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.