Hepatocyte-derived exosomal miR-146a-5p inhibits hepatic stellate cell EMT process: a crosstalk between hepatocytes and hepatic stellate cells.
Zhichao LangYifei LiLifan LinXinmiao LiQiqi TaoYuhang HuMenglu BaoLei ZhengZhengping YuJianjian ZhengPublished in: Cell death discovery (2023)
Recently, Salidroside (Sal) has been demonstrated to suppress hepatic stellate cell (HSC) activation, a crucial event for liver fibrosis. Moreover, Sal has been reported to decrease hepatocyte injury. A growing number of reports have indicated that the crosstalk between hepatocytes and HSCs is very crucial for liver fibrosis development. Whether Sal-treated hepatocytes could inhibit HSC activation is unclear. Exosomes, as vital vehicles of intercellular communication, have been shown to transfer cargos between hepatocytes and HSCs. Herein, we aimed to investigate the roles of exosomal miRNAs from Sal-treated hepatocytes in HSC activation as well as liver fibrosis. Our results showed that Sal suppressed carbon tetrachloride (CCl 4 )-induced liver fibrosis in vivo. HSC activation as well as cell proliferation was repressed in HSCs co-cultured with Sal-treated hepatocytes. Interestingly, miR-146a-5p was up-regulated by Sal in CCl 4 -treated mice. Also, enhanced miR-146a-5p was found in hepatocytes isolated from Sal-treated CCl 4 mice and hepatocyte-derived exosomes. Notably, hepatocyte exosomal miR-146a-5p contributed to HSC inactivation. Inhibiting miR-146a-5p in hepatocyte exosomes resulted in reduced E-cadherin (E-cad) and increased desmin in HSCs, indicating that miR-146a-5p caused HSC inactivation via epithelial-mesenchymal transition (EMT). miR-146a-5p inhibition-mediated HSC activation and EMT process were blocked down by loss of EIF5A2. Further studies revealed that EIF5A2 was a target of miR-146a-5p. Furthermore, exosomes with miR-146a-5p overexpression inhibited liver fibrosis in CCl 4 mice. Collectively, exosomal miR-146a-5p from Sal-treated hepatocytes inhibits HSC activation and liver fibrosis, at least in part, by suppressing EIF5A2 and EMT process.
Keyphrases
- liver fibrosis
- liver injury
- drug induced
- epithelial mesenchymal transition
- mesenchymal stem cells
- cell proliferation
- stem cells
- signaling pathway
- single cell
- transforming growth factor
- newly diagnosed
- metabolic syndrome
- high fat diet induced
- coronary artery disease
- induced apoptosis
- skeletal muscle
- oxidative stress
- transcription factor
- adipose tissue
- pi k akt
- high glucose
- cell cycle arrest
- adverse drug
- stress induced