Published online Nov 21, 2021. doi: 10.3748/wjg.v27.i43.7509
Peer-review started: April 21, 2021
First decision: July 14, 2021
Revised: July 21, 2021
Accepted: September 14, 2021
Article in press: September 14, 2021
Published online: November 21, 2021
Serum small extracellular vesicles (sEVs) and their small RNA (sRNA) cargoes could be promising biomarkers for the diagnosis of liver injury. However, the dynamic changes in serum sEVs and their sRNA components during liver injury have not been well characterized. Given that hepatic macrophages can quickly clear intravenously injected sEVs, the effect of liver injury-related serum sEVs on hepatic macrophages deserves to be explored.
To identify the characteristics of serum sEVs and the sRNAs during liver injury and explore their effects on hepatic macrophages.
To identify serum sEV biomarkers for liver injury, we established a CCL4-induced mouse liver injury model in C57BL/6 mice to simulate acute liver injury (ALI), chronic liver injury (CLI) and recovery. Serum sEVs were obtained and characterized by transmission electron microscopy and nanoparticle tracking analysis. Serum sEV sRNAs were profiled by sRNA sequencing. Differentially expressed microRNAs (miRNAs) were compared to mouse liver-enriched miRNAs and previously reported circulating miRNAs related to human liver diseases. The biological significance was evaluated by Ingenuity Pathway Analysis of altered sEV miRNAs and conditioned cultures of ALI serum sEVs with primary hepatic macrophages.
We found that both ALI and CLI changed the concentration and morphology of serum sEVs. The proportion of serum sEV miRNAs increased upon liver injury, with the liver as the primary contributor. The altered serum sEV miRNAs based on mouse studies were consistent with human liver disease-related circulating miRNAs. We established serum sEV miRNA signatures for ALI and CLI and a panel of miRNAs (miR-122-5p, miR-192-5p, and miR-22-3p) as a common marker for liver injury. The differential serum sEV miRNAs in ALI contributed mainly to liver steatosis and inflammation, while those in CLI contributed primarily to hepatocellular carcinoma and hyperplasia. ALI serum sEVs decreased both CD86 and CD206 expression in monocyte-derived macrophages but increased CD206 expression in resident macrophages in vitro.
Serum sEVs acquired different concentrations, sizes, morphologies and sRNA contents upon liver injury and could change the phenotype of liver macrophages. Serum sEVs therefore have good diagnostic and therapeutic potential for liver injury.
Core Tip: The liver injury changed the concentration, morphology and small RNA contents of serum small extracellular vesicles (sEVs). Altered serum sEV microRNAs (miRNAs) based on mouse studies were highly consistent with the circulating miRNAs reported in human liver diseases. Serum sEV miRNA signatures for acute liver injury and chronic liver injury and a panel of miRNAs that can be used as a common marker for liver injury were established. Acute liver injury serum sEVs depolarized monocyte-derived macrophages and educated resident liver macrophages to transform into M2-like cells. Serum sEVs have good diagnostic and therapeutic potential for liver injury.