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. Extracellular vesicles (EVs) are involved in various pathological processes including liver disease. The present study investigated the effect of EVs derived from bone marrow mesenchymal stem cells (BMSCs) on AR injury after orthotopic liver transplantation (OLT) in mice.

METHODS

BMSCs and EVs were isolated and identified. The OLT mouse model was established using Kamada's two-cuff method and injection with EVs, followed by liver function detection and measurement of inflammatory cytokines (interleukin-10, interferon-γ, and tumor necrosis factor-α), M1 and M2 markers (tumor necrosis factor-α, inducible nitric oxide synthase, resistin like alpha, and Arg1) were detected. Kupffer cells (KCs) were cultured and treated with lipopolysaccharides. miR-22-3p expression was detected. The effect of EVs-shuttled miR-22-3p on Kupffer cell polarization was studied. Binding relation of miR-22-3p and interferon regulatory factor 8 (IRF8) was verified. The effect of IRF8 on KC polarization was verified.

RESULTS

BMSC-EV treatment enhanced liver function of OLT mice and alleviated AR and apoptosis, which were annulled after removing KCs. EVs induced KC 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 EV-induced KC M2 polarization.

CONCLUSIONS

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