Mesenchymal stromal cells alleviate APAP-induced liver injury via extracellular vesicle-mediated regulation of the miR-186-5p/CXCL1 axis.

Abstract

Background: Acetaminophen (APAP) overdose is a significant cause of drug-induced liver injury (DILI). N-acetylcysteine (NAC) is the first-line agent used in the clinic. However, it rarely benefits patients with advanced APAP toxicity. Mesenchymal stromal cells (MSCs) have demonstrated potential in treating DILI. However, the specific mechanism by which MSCs protect against APAP-induced liver injury remains unclear.

Methods: APAP was injected intraperitoneally to induce a liver injury model. We then detected histopathology, biochemical indices, and inflammatory cytokine levels to assess the efficacy of MSCs and MSC extracellular vesicles (MSC-EVs). Flow cytometry was performed to reveal the immunoregulatory effects of MSCs and MSC-EVs on the neutrophils. RNA sequencing (RNA-Seq) of liver tissues was used to identify critical target genes for MSC treatment.

Results: MSC and MSC-EV treatment effectively alleviated APAP-induced liver injury and inhibited neutrophil infiltration. RNA-Seq analysis and ELISA data indicated that C-X-C motif chemokine 1 (CXCL1), a chemoattractant for neutrophils, was a key molecule in the MSC-mediated amelioration of APAP-induced liver damage. In addition, neutralization of CXCL1 reduced APAP-induced liver damage, which was accompanied by decreased neutrophil infiltration. Importantly, we verified that MSC-EV-derived miR-186-5p directly binds to the 3'-UTR of Cxcl1 to inhibit its expression in hepatocytes. The agomir miR-186-5p showed excellent potential for the treatment of DILI.

Conclusions: Our findings suggest that MSCs and MSC-EVs are an effective approach to mitigate DILI. Targeting the miR-186-5p/CXCL1 axis is a promising approach to improve the efficacy of MSCs and MSC-EVs in the treatment of DILI.