from Yiguanjian-primed bone-marrow mesenchymal stem cells reduced liver fibrosis signals through in cell and mouse models.
Evidence
This preclinical study tested YGJ-EVs in TGF-beta1-activated and CCl4-treated mice, with microarray and transfection experiments implicating miR-7045-5p and the Akt/AMPK/TFEB pathway.
Caveat
The evidence comes from mechanistic cell and mouse experiments, so it does not establish safety or antifibrotic efficacy in humans.
Simplified
BACKGROUND: Liver fibrosis is a crucial pathological stage in the progression of chronic liver diseases. Yiguanjian (YGJ), a Chinese herbal formula, exhibits anti-inflammatory, anti-fibrotic, and hepatoprotective effects. from bone-marrow mesenchymal stem cells (BMSC-EVs) have shown potential in treating various disorders, including liver fibrosis. This study investigated the regulatory effects of EVs from YGJ-preconditioned BMSCs (YGJ-EVs) on TGF-β1-stimulated (HSCs) and their therapeutic potential in a mouse model of liver fibrosis, with a focus on identifying the causative microRNA cargo.
METHODS: YGJ-EVs and control EVs were isolated from BMSC culture supernatants and characterized via western blotting, transmission electron microscopy, and nanoparticle tracking analysis. Their cellular uptake in vitro and in vivo was evaluated using DIR labeling. To identify candidate miRNAs mediating YGJ-EV bioactivity, miRNA microarray analysis was conducted. To assess the effect of YGJ-EVs on liver fibrosis, TGF-β1-activated HSC cells were treated with YGJ-EVs or control-EVs for 24 h, and then the expression of proteins related to fibrotic activation (COL1-A1 and α-SMA), lysosomal biogenesis (LAMP1, TPP1, CTSD, and CTSB) mitophagy (p62, LC3, PINK1, and Parkin), and the Akt/AMPK/TFEB pathway was assessed. To determine whether is the causative factor, HSC cells transfected with miR-7045-5p were similarly analyzed.
RESULTS: miRNA microarray analysis revealed miR-7045-5p upregulation in YGJ-EVs versus control EVs. In CCl-treated mice, YGJ-EV-derived miR-7045-5p ameliorated the liver fibrosis, improved the hepatic function, and suppressed the HSC activation by inhibiting the Akt/AMPK/TFEB pathway. In vitro, miR-7045-5p overexpression attenuated TGF-β1-induced HSC activation. 4
CONCLUSION: YGJ increases miR-7045-5p abundance in BMSC-EVs. YGJ-EVs alleviate liver fibrosis by delivering the anti-fibrotic miRNA miR-7045-5p, which inhibits the Akt/AMPK/TFEB pathway, thereby promoting lysosomal biogenesis and mitophagy in HSCs.
Key numbers
Not quantified
Increase in abundance
levels in - compared to control .
Not quantified
Reduction in and levels
Serum biochemical analysis in treated vs. control groups.
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