Mechanistic Study of Mesenchymal Stem Cell-Derived Exosomes from Induced Pluripotent Stem Cells in Mitigating Ischemia-Reperfusion Injury in Mice Liver

Background: Human induced pluripotent stem cell-derived mesenchymal stem cells (iPSC-MSCs) provide a unique, non-tissue-derived source of mesenchymal stem cells. The exosomes they secrete have been shown to limit tissue injury, modulate immune responses, and promote cellular self-repair following damage. However, the potential of iPSC-MSCs-Exo to improve hepatic ischemia-reperfusion injury, along with the specific mechanisms involved, remains unclear. This study aimed to establish a mouse model of hepatic ischemia-reperfusion injury to investigate the protective effects of exosomes derived from iPSC-MSCs and explore the underlying mechanisms. Methods: iPSC-MSCs-Exo was prepared and extracted in vitro. Seventy-two mice with hepatic ischemia-reperfusion injury were randomly divided into four groups: Ham group, IR group, IR+PBS group, and IR+Exo group. The Exo group received iPSC-MSCs-Exo via inferior vena cava injection, while the R+PBS group received an equivalent dose of PBS. Postoperative effects of iPSC-MSCs-Exo on hepatic ischemia-reperfusion injury were evaluated at 6, 12, and 24 hours through serum transaminase levels, oxidative stress markers, HE staining of liver tissue, transmission electron microscopy, and Western blotting. Results: IPSC-MSCs-Exo were successfully isolated, with sizes ranging from 45 to 120 nanometers. Following the injection of iPSC-MSCs-Exo into the hepatic ischemia-reperfusion injury model, peripheral blood levels of AST and ALT were significantly reduced compared to the control group. Hepatocyte necrosis and sinusoidal congestion were markedly alleviated, reflected by a significant decrease in Suzuki scores. The number of TUNEL-positive and caspase-3-positive cells also decreased significantly. Among oxidative stress markers, SOD levels increased while MDA and MPO levels decreased. Furthermore, the expression levels of apoptosis-related proteins Bax, HMGB1, and Bcl-2 significantly decreased, while Parkin expression increased. Conclusion: IPSC-MSCs-Exo alleviate hepatic ischemia-reperfusion injury, potentially by reducing oxidative stress and inhibiting apoptosis.