Gu Tianyi, Shen Bo, Li Binghang, Guo Yuecheng, Li Fei, Ma Zhenzeng, Chen Liuying, Zhang Qidi, Qu Ying, Dong Hui, Cai Xiaobo, Lu Lungen
Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
FASEB J. 2021 May;35(5):e21571. doi: 10.1096/fj.202002694R.
Liver fibrosis is a common feature of liver dysfunction during chronic liver diseases and is frequently associated with angiogenesis, a dynamic process that forms new blood vessels from preexisting vasculature. MicroRNAs (miRNAs), which act as posttranscriptional regulators of gene expression, have been shown to regulate liver fibrosis; however, how miRNAs regulate angiogenesis and its mechanism in fibrosis are not well understood. We aimed to elucidate the role and mechanism of miR-30c in attenuating liver fibrosis. Using miRNA profiling of fibrotic murine livers, we identified differentially regulated miRNAs and discovered that miR-30c is aberrantly expressed and targets endothelial delta-like ligand 4 (DLL4) in either carbon tetrachloride-treated or bile duct ligated fibrotic mice, as well as in patients with liver fibrosis. Using CCK-8, wound healing and Matrigel tube formation assays, we found that miR-30c inhibited liver sinusoidal endothelial cell (LSEC) proliferation, migration, and angiogenesis capacity by targeting DLL4 in vitro. Importantly, nanoparticle-based delivery of miR-30c to LSECs inhibited the DLL4/Notch pathway and angiogenesis, thereby ameliorating liver fibrosis in vivo. Collectively, our findings demonstrate a protective role of miR-30c in liver fibrosis by regulating DLL4/Notch signaling and angiogenesis. Thus, miR-30c may serve as a potential treatment for chronic liver diseases.
肝纤维化是慢性肝病过程中肝功能障碍的常见特征，且常与血管生成相关，血管生成是一个从现有脉管系统形成新血管的动态过程。微小RNA（miRNA）作为基因表达的转录后调节因子，已被证明可调节肝纤维化；然而，miRNA如何调节血管生成及其在纤维化中的机制尚不清楚。我们旨在阐明miR-30c在减轻肝纤维化中的作用和机制。通过对纤维化小鼠肝脏进行miRNA分析，我们鉴定出差异调节的miRNA，并发现miR-30c在四氯化碳处理或胆管结扎的纤维化小鼠以及肝纤维化患者中表达异常，且靶向内皮细胞Delta样配体4（DLL4）。通过CCK-8、伤口愈合和基质胶管形成试验，我们发现miR-30c在体外通过靶向DLL4抑制肝窦内皮细胞（LSEC）的增殖、迁移和血管生成能力。重要的是，基于纳米颗粒将miR-30c递送至LSEC可抑制DLL4/Notch信号通路和血管生成，从而在体内改善肝纤维化。总体而言，我们的研究结果表明miR-30c通过调节DLL4/Notch信号通路和血管生成在肝纤维化中发挥保护作用。因此，miR-30c可能成为慢性肝病的一种潜在治疗方法。
