Abstract
AimTo investigate the association of serum exosomes miR-574-5p with liver fibrosis, and explore the effect and mechanism of serum exosomes on HSC activation.Materials and methodsUsing serum samples collected from healthy adults and patients with liver cirrhosis, we extracted human serum exosomes via ultra-high-speed centrifugation, and co-cultured them with hepatic stellate cells (HSCs) line LX2. LX-2-mediated intake of human serum exosomes was examined by confocal microscopy. To induce liver fibrosis, we administered 20% CCl4 to mice intraperitoneally and adopted an exoEasy MIDI kit to extract serum exosomes.Liver fibrosis-related molecules were determined via qRT-PCR, Western blot, Masson staining, and Immunohistochemical staining.ResultsSignificantly high miR-574-5p levels were expressed in serum exosomes and were positively correlated with the expression of miR-574-5p, collagen deposition, and α-SMA expression in liver tissues of mice during liver fibrosis. Compared to healthy subjects, serum exosomes from cirrhosis patients were associated with higher expression of miR-574-5p. MiR-574-5p mimic promoted the expression of α-SMA and COL1A1 mRNA and protein in LX-2, whereas miR-574-5p inhibitor exerted no effect.ConclusionThis article demonstrates that miR-574-5p expression in serum exosomes is positively correlated with collagen deposition and HSC activation in liver tissues during liver fibrosis.Serum exosomes potentially activate HSC through the transfer of miR-574-5p to HSC during liver fibrosis.
Highlights
Liver fibrosis occurs due to chronic liver damage and is attributed to multiple predisposing factors, including alcohol consumption, non-alcoholic steatohepatitis(NASH), viral hepatitis, autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD), and cholestatic liver disease [1, 2]
Exosomes are small vesicles secreted by various cells and widely localized in plasma, saliva, urine, and other body fluids [7, 8]. They comprise proteins, lipids, nucleic acids, and other bioactive substances, which influence the progression of diseases via intercellular material and information transduction, or direct action on target cells [9, 10]. miRNAs enriched exosomes are delivered to hepatic stellate cells (HSCs) [11], which is a crucial event in liver fibrosis
Following an injury to the liver, HSCs transform into myofibroblast-like cells and synthesize a large amount of extracellular matrix, one of the most important sections associated with liver fibrosis [25]. miRNA, a small (20-24nt) noncoding RNA, blocks mRNA expression through specific interaction with the 3’untranslated regions (UTR) of target gene mRNA [26]
Summary
Liver fibrosis occurs due to chronic liver damage and is attributed to multiple predisposing factors, including alcohol consumption, non-alcoholic steatohepatitis(NASH), viral hepatitis, autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD), and cholestatic liver disease [1, 2]. Factors, including toxins, hepatitis, steatohepatitis, and autoimmune diseases may trigger the activation of HSCs and transformation into myofibroblasts. Exosomes are small vesicles (about 30–150 nm in diameter) secreted by various cells and widely localized in plasma, saliva, urine, and other body fluids [7, 8]. They comprise proteins, lipids, nucleic acids, and other bioactive substances, which influence the progression of diseases via intercellular material and information transduction, or direct action on target cells [9, 10]. MiRNAs enriched exosomes are delivered to HSCs [11], which is a crucial event in liver fibrosis. Recent reports show that normal serum exosomes exhibit anti-fibrotic properties, and contain miRNAs with therapeutic effects against HSCs activation [14]
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