hPMSC-derived Exosomal miR-26-5p modulates macrophage polarization for liver repair in DILI via PTEN/mTOR signaling.

Abstract

BACKGROUND: The paracrine mechanisms of Mesenchymal Stem Cells (MSCs) involve the release of bioactive components, including exosomes. Although the crucial role of macrophage polarization in acute liver injury has been established by previous studies, further elucidation is needed regarding the influence of exosome-mediated liver repair on macrophage polarization. METHODS: Mice were intravenously administered with exosomes derived from human placental mesenchymal stem cells (hPMSC-Exo) 2 h prior to LPS/GalN exposure. The effects of hPMSC-Exo were assessed through analyses of serum biochemistry, TUNEL assay, and H&E staining. To elucidate the mechanisms involved in acute liver injury therapy, gene expression levels were determined through qPCR and Western blot analysis, respectively. Exosomes transfected with miR-26-5p were utilized to investigate the involvement of mTOR signaling in hPMSC-Exo-based therapy. In a mouse model of D-galN/LPS-induced DILI (drug-induced liver injury), hPMSC-Exo mitigated liver inflammation and facilitated liver repair. Subsequent investigations demonstrated that hPMSC-Exo induced the shift of M1 macrophages towards an M2 phenotype, both in vivo and in vitro. miRNA sequencing and Bioinformatics analysis identified miR-26-5p as a potential mediator that drives macrophage polarization, with PTEN identified as its downstream target. Reducing the levels of miR-26-5p in hPMSC-Exo resulted in attenuated modulation of macrophage polarization. Knockdown of PTEN similarly exhibited hepatoprotective efficacy and reduced inflammation levels in a mouse model of DILI. CONCLUSION: Based on our findings, it is suggested that the PTEN/mTOR/TGF-β1 signaling pathway is involved in regulating macrophage activation through hPMSC exosomal miR-26-5p, thereby highlighting its therapeutic potential in liver injury treatment.