Glutathione Peroxidase 3 Delivered by hiPSC-MSCs Ameliorated Hepatic IR Injury via Inhibition of Hepatic Senescence

Abstract

Background and Aims: Down-regulation of GPx3 accelerated hepatic senescence, which further caused overwhelming inflammation and severe liver graft injury. MSCs derived from human induced pluripotent stem cells (hiPSC-MSCs) have been developed as more efficient delivery vehicle with the property of injury tropism. Here, we aimed to explore the suppressive role of GPx3 in hepatic IR injury using novel delivery system of hiPSC-MSCs.Methods: The mice IR injury model with partial hepatectomy was established. The engineered hiPSC-MSCs delivering GPx3 was constructed. All the mice were segregated into three groups. hiPSC-MSC-GPx3, hiPSC-MSC-pCDH (vector control) or PBS were injected via portal vein after reperfusion. Liver injury was evaluated by histological and serological test. Hepatic apoptosis was detected by Tunel staining and remnant liver regeneration was assessed by Ki67 staining. The role of hepatic senescence in liver graft injury was evaluated in rat orthotopic liver transplantation model. The suppressive effect of GPx3 on hepatic senescence was examined in mice IR injury model and confirmed in vitro. Hepatic senescence was detected by SA-β-Gal and P16/ink4a staining.Results: GPx3 can be successfully delivered by hiPSC-MSCs into liver tissues. Histological examination showed that hiPSC-MSC-GPx3 treatment significantly ameliorated hepatic IR injury post-operation. Significantly lower LDH (891.43±98.45 mU/mL, P<0.05) and AST (305.77±36.22 IU/L, P<0.01) were observed in hiPSC-MSC-GPx3 group compared with control groups. Less apoptotic hepatocytes were observed and the remnant liver regeneration was more active in hiPSC-MSC-GPx3 group. In rat orthotopic liver transplantation model, more senescent hepatocytes were observed in small-for-size liver graft, in which GPx3 expression was significantly compromised. In mice IR injury model, hiPSC-MSC-GPx3 significantly suppressed hepatic senescence. In addition, rGPx3 inhibited cellular senescence of liver cells in a dose dependent manner. Four candidate genes (CD44, Nox4, IFNG, SERPERINB2) were identified to be responsible for suppressive effect of GPx3 on hepatic senescence.Conclusion: Engineered hiPSC-MSCs delivering GPx3 ameliorated hepatic IR injury via inhibition of hepatic senescence.

Gene Expression Profiling in Ischemic Postconditioning to Alleviate Mouse Liver Ischemia/Reperfusion Injury

“…Several reports investigated the pivotal role of PSCs on I/R injury. For instance, glutathione peroxidase 3 delivered in human-induced PSCs (hiPSCs) attenuated hepatic I/R injury by inhibiting hepatic senescence and extracellular vesicles released from MSCs, which protect against murine renal and hepatic I/R injury 31-33. Insulin is an important hormone that reduces plasma glucose in vivo and is regulated by insulin signalling.…”

Liver Macrophage Depletion Ameliorates The Effect of Mesenchymal Stem Cell Transplantation in a Murine Model of Injured Liver

“…On the basis of the recently recognized potential of MSCs to contribute to tissue repair after injury in different diseases including heart and liver diseases 15–17 , MSC transplantation has recently gained widespread enthusiasm to use them to treat acute and chronic liver diseases. However, controversy has arisen as various situations of liver damage could affect the potential of MSCs to show a full beneficial effect 18–20 .…”

Involvement of glutathione peroxidases in the occurrence and development of breast cancers

“…However, to date, the methods used to increase GPx expression are mainly the artificial over-expression of GPxs through transfections or infections. After confirming the clinical significance and potential therapeutic role of GPx3 in tumor recurrence after liver transplantation [116], Qi et al constructed and verified a delivery system by composed of mesenchymal stem cells derived from human induced pluripotent stem cells (hiPSC-MSCs) to increase the expression level of GPx3 in vivo [117]. The engineered hiPSC-MSCs successfully delivered GPx3 to the liver and ameliorated hepatic injury by inhibiting hepatic senescence [117]; this result provides potential therapeutic strategies and prospects for breast cancer treatment.…”

“…After confirming the clinical significance and potential therapeutic role of GPx3 in tumor recurrence after liver transplantation [116], Qi et al constructed and verified a delivery system by composed of mesenchymal stem cells derived from human induced pluripotent stem cells (hiPSC-MSCs) to increase the expression level of GPx3 in vivo [117]. The engineered hiPSC-MSCs successfully delivered GPx3 to the liver and ameliorated hepatic injury by inhibiting hepatic senescence [117]; this result provides potential therapeutic strategies and prospects for breast cancer treatment. Based on the review of key role of ROS in the occurrence and development of breast cancer, it is inspired that the changed expression level of GPxs may achieve the therapeutic purpose after determining its clinical significance in breast cancer.…”