Exosomes, which are one of the smallest extracellular vesicles released from cells, have been shown to carry different nucleic acids, including microRNAs (miRNAs). miRNAs significantly regulate cell growth and metabolism by posttranscriptional inhibition of gene expression. The rapidly changing understanding of exosomes’ formation and function in delivering miRNAs from cell to cell has prompted us to review current knowledge in exosomal miRNA secretion mechanisms as well as possible therapeutic applications for personalized medicine.

In chronic liver disease leading to fibrosis, hepatic stellate cells (HSC) differentiate into myofibroblasts. Myofibroblastic HSC have taken center stage during liver fibrogenesis, due to their remarkable synthesis of extracellular matrix proteins, their secretion of profibrogenic mediators and their contribution to hypertension, due to elevated contractility. MicroRNAs (miRNAs) are small, noncoding RNA molecules of 19–24 nucleotides in length. By either RNA interference or inhibition of translational initiation and elongation, each miRNA is able to inhibit the gene expression of a wide panel of targeted transcripts. Recently, it was shown that altered miRNA patterns after chronic liver disease highly affect the progression of fibrosis by their potential to target the expression of extracellular matrix proteins and the synthesis of mediators of profibrogenic pathways. Here, we underline the role of miRNAs in the interplay of the profibrogenic cell communication pathways upon myofibroblastic differentiation of hepatic stellate cells in the chronically injured liver.

MicroRNA dysregulation is a hallmark of hepatocellular carcinoma (HCC), leading to tumor growth and metastasis. Previous screening on patient specimens identified miR-198 as the most downregulated miRNA in HCC. Here, we show that miR-198 compensation leads to self-release into extracellular vesicles (EVs). Importantly, the vesicular secretion is mediated by autophagy-related pathway, initiated by sequestration of p62/miR-198 complexes in autophagosome-associated vesicle fractions. miR-198 is selectively recognized and loaded by p62 into autophagosomal fractions, whereas mutated miR-198 forms neither induce autophagy and nor interact with p62. Gain and loss of function experiments, using a CRIPR/Cas knockout (KO) and transgenic site-specific p62 mutants, identified p62 as an essential repressor of cellular miR-198 abundancy. Notably, EVs, harboring miR-198/p62 protein complexes, can be uptaken by cells in the close vicinity, leading to change of gene expression in recipient cells. In conclusion, miR-198 enhances autophagy; conversely autophagic protein p62 reduces the miR-198 levels by sorting into extracellular space. Graphical abstract miR-198 is at first transcribed as primary miRNA, after being processed into single stranded mature miR-198 form, it is transported into cytoplasm ①. By interaction with p62 protein, miR-198 conglomerates and forms a binding complex ②. Since LC3 protein is an interaction partner of p62 protein, hence miR-198 is included into autophagosomes ③. By fusion with multivesicular bodies (MVB), miR-198-binding complex was recruited into amphisomes ④, the latter of which quickly turns into secretory MVB containing intraluminal vesicles⑤. By fusion with cell membrane, intraluminal vesicles were released into extracellular space as EVs ⑥.

MicroRNAs miR-29a and miR-192 are involved in inflammatory and fibrotic processes of chronic liver disease, and circulating miR-29a is suggested to diagnose fibrosis progression due to hepatitis C virus (HCV) infection. This study aimed to evaluate the expression profile of circulating miR-192 and 29a in a patient cohort with a high frequency of HCV genotype-3. A total of 222 HCV blood samples were collected and serum were separated. Patients were classified into mild, moderate, and severe liver injury based on their Child–Turcotte–Pugh CTP score. RNA was isolated from the serum and used for quantitative real-time PCR. The HCV genotype-3 (62%) was the predominant HCV genotype. In HCV patients, the serum miR-192 and miR-29a levels were significantly upregulated in comparison to healthy controls (p = 0.0017 and p = 0.0001, respectively). The progression rate of miR-192 and 29a in the patient group with mild was highly upregulated compared to patients with moderate and severe hepatitis infection. The ROC curve of miR-192 and miR-29a of moderate liver disease had a significant diagnostic performance compared to the other HCV-infected groups. The increase in miR-29a and miR-192 serum levels was even slightly higher in patients with HCV genotype-3 than in non-genotype-3 patients. In conclusion, serum miR-192 and miR-29a levels significantly increased during the progression of chronic HCV infection. The marked upregulation in patients with HCV genotype-3 suggests them as potential biomarkers for hepatic disease, independently of the HCV genotype.