Mesenchymal stem cells derived exosomes ameliorate D-galN/LPS induced acute liver injury via PTEN-mediated macrophage polarization

Abstract

Background: It is widely acknowledged that Mesenchymal Stem Cells (MSCs) exert their effects through paracrine mechanisms by releasing bioactive components, such as exosomes, while previous studies have confirmed the critical role of macrophage polarization in acute liver injury, the impact of exosome-mediated liver repair on macrophage polarization requires further clarification. Methods: Human placental mesenchymal stem cell-derived exosomes (hPMSC-Exo) were intravenously administered to the mice 2 hours before exposure to LPS/GalN. The effects of hPMSC-Exo were evaluated using serum biochemical analysis, TUNEL assay, and H&E staining. In order to elucidate the mechanisms underlying acute liver injury therapy, the expression levels of relevant genes were evaluated using qPCR and WB analysis, respectively. The exosome transfected miR-26-5p were used for further determine the mTOR signaling in hPMSC-Exo based threapy. Results: hPMSC-Exo alleviated liver inflammation and promoted liver repair in a mouse model of D-galN/LPS-induced DILI (drug-induced liver injury). Subsequent investigations revealed that hPMSC-Exo induced the polarization of M1 macrophages towards an M2 phenotype, both in vivo and in vitro. Bioinformatics analysis identified miR-26-5p as a potential mediator of macrophage polarization and PTEN as its downstream target. Attenuation of macrophage polarization modulation was observed when miR-26-5p levels were reduced in hPMSC-Exo. Similarly, knockdown of PTEN also demonstrated hepatoprotective efficacy and reduced inflammation levels in a mouse model of DILI. Conclusion: Our findings suggest the involvement of the PTEN/mTOR/TGF-β1 signaling pathway in regulating macrophage activation through hPMSC exosomal miR-26-5p, highlighting its therapeutic potential in the treatment of liver injury.