Human embryonic stem cell–derived mesenchymal stem cells ameliorate mitochondrial oxidative dysfunction in metabolic dysfunction–associated steatotic liver disease
Min Kyung Park, Yun Bin Lee, Se-Mi Jung, Yoo-Wook Kwon, Jung-Hwan YoonAbstract
Introduction
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common chronic liver disease with significant clinical burden. This study investigated the therapeutic potential of embryonic stem cell-derived mesenchymal stem cells (ESC-MSCs) in cellular and murine models of MASLD.
Methods
HepG2 cells were treated with palmitic acid (PA) and then co-cultured with ESC-MSCs. C57BL/6 mice were fed a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) or a standard diet for 24 weeks. Either ESC-MSCs or vehicles were administered via tail vein injection at week 20. Lipid accumulation was assessed using Oil red O staining. Mitochondrial status was assessed using MitoTracker Red fluorescence, mtDNA content, reactive oxygen species (ROS), and antioxidant parameters.
Results
ESC-MSC co-culture reduced PA-induced lipid accumulation, restored mitochondrial activity, decreased ROS, and increased superoxide dismutase (SOD) activity and glutathione redox balance. Expression of phosphorylated AMPK (p-AMPK), PGC1α, and PPARα was significantly upregulated. In CDAHFD-fed mice, ESC-MSC transplantation attenuated hepatic steatosis, restored mitochondrial DNA content, and reduced ROS accumulation with increased SOD activity and glutathione ratio. Hepatic expression of p-AMPK, PGC1α, and PPARα was also enhanced. These effects were abrogated by Compound C, an AMPK inhibitor. ESC-MSCs secreted hepatocyte growth factor (HGF), which activated AMPK, suggesting an HGF–AMPK axis may serve as a potential paracrine mechanism.
Conclusion
ESC-MSCs ameliorated hepatic steatosis in MASLD models by restoring mitochondrial activity and reducing oxidative stress, possibly involving HGF-associated AMPK pathway modulation. These findings support the potential of ESC-MSC therapy for MASLD.