Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China.
Department of Otolaryngology-Head and Neck Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China.
Stem Cell Res Ther. 2024 Nov 3;15(1):392. doi: 10.1186/s13287-024-03995-8.
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.
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.
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.
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.
对乙酰氨基酚（APAP）过量是导致药物性肝损伤（DILI）的一个重要原因。N-乙酰半胱氨酸（NAC）是临床上使用的一线药物。然而，它很少使晚期 APAP 毒性患者受益。间充质基质细胞（MSCs）在治疗 DILI 方面显示出了潜力。然而，MSCs 如何保护 APAP 诱导的肝损伤的具体机制尚不清楚。
通过腹腔内注射 APAP 诱导肝损伤模型。然后，我们检测了组织病理学、生化指标和炎症细胞因子水平，以评估 MSCs 和 MSC 细胞外囊泡（MSC-EVs）的疗效。通过流式细胞术揭示了 MSCs 和 MSC-EVs 对中性粒细胞的免疫调节作用。对肝组织进行 RNA 测序（RNA-Seq）以鉴定 MSC 治疗的关键靶基因。
MSC 和 MSC-EV 治疗可有效缓解 APAP 诱导的肝损伤并抑制中性粒细胞浸润。RNA-Seq 分析和 ELISA 数据表明，趋化因子 C-X-C 基序 1（CXCL1），一种中性粒细胞的趋化因子，是 MSC 介导的改善 APAP 诱导的肝损伤的关键分子。此外，中和 CXCL1 减少了 APAP 诱导的肝损伤，伴随着中性粒细胞浸润的减少。重要的是，我们验证了 MSC-EV 衍生的 miR-186-5p 可直接结合 Cxcl1 的 3'-UTR 以抑制其在肝细胞中的表达。agomir miR-186-5p 显示出治疗 DILI 的巨大潜力。
我们的研究结果表明，MSCs 和 MSC-EVs 是减轻 DILI 的有效方法。靶向 miR-186-5p/CXCL1 轴是提高 MSCs 和 MSC-EVs 治疗 DILI 疗效的一种有前途的方法。
