Melatonin‐mediated miR‐526b‐3p and miR‐590‐5p upregulation promotes chondrogenic differentiation of human mesenchymal stem cells

Bone marrow‐derived mesenchymal stem cells (BMSCs), with inherent chondrogenic differentiation potential appear to be ideally suited for therapeutic use in cartilage regeneration. Accumulating evidence has demonstrated that melatonin can promote chondrogenic differentiation in human BMSCs. However, little is known about the mechanism. MicroRNAs (miRNAs) have been shown to regulate the differentiation of BMSCs, but their roles in melatonin‐promoted chondrogenic differentiation have not been characterized. Here, we demonstrate that melatonin promoted chondrogenic differentiation of human BMSCs via upregulation of miR‐526b‐3p and miR‐590‐5p. Mechanistically, the elevated miR‐526b‐3p and miR‐590‐5p enhanced SMAD1 phosphorylation by targeting SMAD7. Additionally, administration of miR‐526b‐3p mimics or miR‐590‐5p mimics successfully promoted the chondrogenic differentiation of human BMSCs. Collectively, our study suggests that modification of BMSCs using melatonin or miRNA transduction could be an effective therapy for cartilage damage and degeneration.     

Serum miR‐122 may serve as a biomarker for response to direct acting antivirals: effect of paritaprevir/R with dasabuvir or ombitasvir on miR‐122 in HCV‐infected subjects

Circulating microRNAs (miRNA) have been intensely investigated as biomarkers in disease and therapy. Several studies have identified miR‐122 as an important regulator of HCV replication. The effect of new therapies that directly target the HCV replication life cycle on circulating microRNA levels has not been elucidated. We performed expression profiling of circulating miRNA in serum in subjects treated with HCV direct‐acting antiviral agents (DAAs). Serum miRNA levels were evaluated from two studies in HCV GT1‐infected treatment‐naïve subjects and prior nonresponders to pegylated interferon (pegIFN) and ribavirin (RBV) who received paritaprevir/ritonavir + dasabuvir + RBV for 12 weeks, and in treatment‐naïve genotype (GT)1‐3‐infected subjects who received paritaprevir/ritonavir + ombitasvir ± RBV for 12 weeks. Over 100 different miRNA species were detected in serum. Of these, levels of miR‐122 showed the most consistent change in response to treatment across all HCV genotypes. In all subjects, miR‐122 showed an average four‐fold reduction between baseline and week 2, and remained below baseline through post‐treatment week 12 in subjects who achieved sustained virological response. In contrast, in subjects who did not achieve SVR, miR‐122 levels began to return to baseline levels after the second week of treatment. The change in miR‐122 levels was similar across genotypes, and was comparable with or without RBV. This is the first report comparing expression levels of circulating miRNA in HCV GT1‐3 subjects treated with IFN‐free combinations of DAAs. The results suggest that serum levels of miR‐122 are reduced following treatment in subjects who achieve SVR, and correlate with HCV RNA levels across genotypes.     

Adipose may actively delay progression of NAFLD by releasing tumor‐suppressing,anti‐fibrotic miR‐122 into circulation

Nonalcoholic fatty liver disease (NAFLD) is the most common liver pathology. Here we propose tissue‐cooperative, homeostatic model of NAFLD. During early stages of NAFLD the intrahepatic production of miR‐122 falls, while the secretion of miRNA‐containing exosomes by adipose increases. Bloodstream carries exosome to the liver, where their miRNA cargo is released to regulate their intrahepatic targets. When the deterioration of adipose catches up with the failing hepatic parenchyma, the external supply of liver‐supporting miRNAs gradually tapers off, leading to the fibrotic decompensation of the liver and an increase in hepatic carcinogenesis. This model may explain paradoxical observations of the disease‐associated decrease in intrahepatic production of certain miRNAs with an increase in their levels in serum. Infusions of miR‐122 and, possibly, some other miRNAs may be efficient for preventing NAFLD‐associated hepatocellular carcinoma. The best candidates for exosome‐wrapped miRNA producer are adipose tissue‐derived mesenchymal stem cells (MSCs), known for their capacity to shed large amounts of exosomes into the media. Notably, MSC‐derived exosomes with no specific loading are already tested in patients with liver fibrosis. Carrier exosomes may be co‐manufactured along with their cargo. Exosome‐delivered miRNA cocktails may augment functioning of human organs suffering from a variety of chronic diseases.