Human skeletal muscle stem cells alleviate liver injury and fibrosis through conferring glutathione-mediated cytoprotection of hepatocytes

Human skeletal muscle stem cells (hMuSCs) are pivotal in the growth, repair, and maintenance of skeletal muscle. This dissertation investigates the therapeutic potential of hMuSCs in liver fibrosis, specifically their ability to protect hepatocytes from carbon tetrachloride (CCl4)-induced apoptosis. The administration of hMuSCs significantly reduced hepatocyte DNA damage, restored polyploid ratios, and mitigated hepatocellular apoptosis. Transcriptomic analysis indicated that hMuSC treatment enhanced oxidoreductase activity in hepatocytes, thereby restoring normal liver lipid reactive oxygen species (ROS) levels. Mechanistic studies identified hMuSC-derived glutathione as a key factor in reducing oxidative stress and preventing hepatocyte apoptosis. Inhibition of glutathione synthesis in hMuSCs abolished their protective effects and negated their therapeutic benefits in liver fibrosis. Additionally, glutathione was secreted via exosomes, and inhibition of exosome secretion compromised the antiapoptotic effects of hMuSCs on hepatocytes. Overall, this research underscores the protective role of hMuSCs in mitigating hepatocyte apoptosis and oxidative damage through glutathione secretion, offering a novel stem cell-based therapeutic strategy for the treatment of liver injury and fibrosis.