Deletion of miR-126a Promotes Hepatic Aging and Inflammation in a Mouse Model of Cholestasis

Abstract

MicroRNAs (miRNAs) act as regulators of aging at the tissue or organism level or as regulators of cellular senescence. Targeted deletion of miR-126 in mice causes partial embryonic lethality, but its biological function in the liver is still largely unknown. Here, we deleted miR-126a , using the CRISPR/Cas9 system in vitro and in vivo . miR-126a was reduced in the aging livers, and disruption of miR-126a in bone mesenchymal stem cells (BMSCs) induced age-associated telomere shortening, DNA damage responses, and proinflammatory cytokines. Moreover, disruption of miR-126a in mice caused hepatocyte senescence, inflammation, and metabolism deficiency. In addition, disruption of miR-126a via BMSC transplantation aggravated the severity of liver defects induced by cholestasis compared with that in the functional miR-126a BMSC group. Mechanistically, we identified versican (VCAN) as a novel direct miR-126a-5p target that induces telomere shortening, BMSC senescence, and nuclear factor κB (NF-κB) pathway activation. This study identified aging-related reduced expression of miR-126a and promotion of its target VCAN as a key mechanism in the regulation of hepatic metabolic function during aging and hepatic damage by inducing NF-κB pathway activation, DNA repair function disorder, and telomere attrition. The findings indicate that miR-126a may be a drug target for the treatment of hepatic failure.

<p>Downregulation of miR-486-5p Enhances the Anti-Tumor Effect of 5-Fluorouracil on Pancreatic Cancer Cells</p>

“…9,10 Meanwhile, miRNAs play important roles in the mediation of gene expression. [11][12][13] It has been shown that miRNAs have emerged as key regulators during the development of cancer initiates, and play vital roles in tumor growth, biosynthesis, and drug resistance. 14 Zhao et al indicated that miRNAs acted as novel chemo-resistance regulators, which could regulate the levels of drug resistance-related genes.…”

Versican—A Critical Extracellular Matrix Regulator of Immunity and Inflammation

“…Using polyinosinic-polycytidylic acid (poly I:C) and lipopolysaccharide (LPS) to activate TLR3 and TLR4, respectively, we showed that the signaling cascade that includes TLR3 or TLR4, the TLR adaptor molecule, Trif, type I interferons (IFNs), and the type I IFN receptor (IFNAR1), increases versican expression by mouse macrophages, which implicates versican as an IFN-stimulated gene (60). Versican synthesis is also controlled by several different miRNAs which are modulated during inflammation (61)(62)(63).…”

MiR-126 Regulates Properties of SOX9+ Liver Progenitor Cells during Liver Repair by Targeting Hoxb6

“…Recent investigation has revealed that miRNAs are involved in liver regeneration and might serve as the therapeutic approach to liver fibrosis ( John et al., 2014 ; Tsay et al., 2019 ). Our previous research has shown that miR-126 contributes to hepatic anti-aging and damage repair ( Yan et al., 2019 ). To reveal the effect of miR-126 on anti-aging, we first detected the expression of stem cell-associated genes in C3H10 cells from which the miR- 126 has been deleted.…”

“…Two pairs of CRISPR guide RNAs (gRNAs) targeting pre-miR-126 gene were initially screened in NIH3T3cells. The gRNA targeting sgRNA3 displayed ∼50% mutagenesis at the on-target site in pre-miR-126 , as determined by PCR and a T7EN1 cleavage assay ( Yan et al., 2019 ). After targeting efficiency was confirmed, the sgRNAs were constructed into lentivirus and adenovirus plasmids.…”

“…Moreover, our previous research has shown that miR-126 was involved in regulating liver aging. To be more specific, the knockdown of miR-126 in bone marrow stromal cells (BMSCs) accelerated cell aging and inhibited hepatic repair functions of BMSCs ( Yan et al., 2019 ). These results indicated that miR- 126 might be involved in hepatic aging through liver stem cells (LSCs) or liver progenitor cells (LPCs).…”