Extracellular vesicles from bone marrow mesenchymal stem cells alleviate acute rejection injury after liver transplantation by carrying miR-22-3p and inducing M2 polarization of kupffer cells.

BACKGROUND: Acute rejection (AR) is a major problem following liver transplantation (LT). Extracellular vesicles (EVs) are involved in various pathological processes including liver disease. Effect of EVs derived from bone marrow mesenchymal stem cells (BMSCs) on AR injury after orthotopic liver transplantation (OLT) in mice was investigated in this study.

METHODS: BMSCs and EVs were isolated and identified. OLT mouse model was established using Kamada's two cuff method and injected with EVs, followed by liver function detection and measurement of inflammatory cytokines (IL-10, IFN-γ, and TNF-α), M1 and M2 markers (TNF-α, iNOS, Retnla, and Arg1) were detected. KCs were cultured and treated with lipopolysaccharides. miR-22-3p expression was detected. The effect of EVs-shuttled miR-22-3p on Kupffer cells (KCs) polarization was studied. Binding relation of miR-22-3p and interferon regulatory factor 8 (IRF8) was verified. Effect of IRF8 on KCs polarization was verified.

RESULTS: BMSCs-EVs treatment enhanced liver function of OLT mice and alleviated AR and apoptosis, which were annulled after removing KCs. EVs induced KCs M2 polarization. Mechanically, EVs carried miR-22-3p into KCs, upregulated miR-22-3p in KCs and inhibited IRF8 expression. Upregulation of IRF8 in KCs inhibited the EVs-induced KCs M2 polarization.

CONCLUSIONS: BMSCs-EVs carry miR-22-3p into KCs and upregulate miR-22-3p, inhibit IRF8 expression, induce KCs M2 polarization and attenuate AR injury after LT.