miR‐155 induces ROS generation through downregulation of antioxidation‐related genes in mesenchymal stem cells

Abstract

SummaryInflammation‐induced reactive oxygen species (ROS) are implicated in cellular dysfunction and an important trigger for aging‐ or disease‐related tissue degeneration. Inflammation‐induced ROS in stem cells lead to deterioration of their properties, altering tissue renewal or regeneration. Pathological ROS generation can be induced by multiple steps, and dysfunction of antioxidant systems is a major cause. The identification of the central molecule mediating the above‐mentioned processes would pave the way for the development of novel therapeutics for aging, aging‐related diseases, or stem cell therapies. In recent years, microRNAs (miRNAs) have been shown to play important roles in many biological reactions, including inflammation and stem cell functions. In inflammatory conditions, certain miRNAs are highly expressed and mediate some cytotoxic actions. Here, we focused on miR‐155, which is one of the most prominent miRNAs in inflammation and hypothesized that miR‐155 participates to inflammation‐induced ROS generation in stem cells. We observed mesenchymal stem cells (MSCs) from 1.5‐year‐old aged mice and determined that antioxidants, Nfe2l2, Sod1, and Hmox1, were suppressed, while miR‐155‐5p was highly expressed. Subsequent in vitro studies demonstrated that miR‐155‐5p induces ROS generation by suppression of the antioxidant genes by targeting the common transcription factor C/ebpβ. Moreover, this mechanism occurred during the cell transplantation process, in which ROS generation is triggering loss of transplanted stem cells. Finally, attenuation of antioxidants and ROS accumulation were partially prevented in miR‐155 knockout MSCs. In conclusion, our study suggests that miR‐155 is an important mediator connecting aging, inflammation, and ROS generation in stem cells.

Ch IP ‐Atlas: a data‐mining suite powered by full integration of public Ch IP ‐seq data

“…In addition to the above‐mentioned analyses, ChIP‐Atlas Enrichment Analysis (formerly designated “ in silico ChIP”) has been used for various other purposes. For example, this tool has been applied to analyze TR enrichment at genomic ROIs such as expression quantitative trait loci (eQTLs), a user's own ChIP‐seq peak‐call data, and evolutionarily accelerated regions as well as genes whose expression levels are changed by drug exposure, aging, or cancer development (see http://chip-atlas.org/publications for the full list of publications citing ChIP‐Atlas). The results generated by ChIP‐Atlas are all assigned unique URLs (see ChIP‐Atlas document in https://github.com/inutano/chip-atlas/wiki for details) and are publicly available, and they are thus ready for sharing seamlessly among researchers for subsequent analysis in command lines and for interconnecting with other biodatabases such as the DeepBlue Epigenomic Data Server and RegulatorTrail , where ChIP‐Atlas data have been imported and subjected to analyses.…”

Integrative analysis of transcription factor occupancy at enhancers and disease risk loci in noncoding genomic regions

“…This tool is also able to accept a batch of gene symbols and can therefore discover TFs that collectively regulate the gene set of interest (e.g. Chatterjee et al 2018;Onodera et al 2017;Chen et al 2017).…”

miR‐155‐5p inhibition rejuvenates aged mesenchymal stem cells and enhances cardioprotection following infarction

“…Overexpression of miR‐335 leads to cellular senescence of MSCs as evidenced by increased SA‐β‐gal activity and p16 protein level and decreased cell proliferation, impairing the immunomodulatory capacity, and differentiation capacity (Tome et al, 2014). Importantly, Onodera et al (2017) reported that the expression level of miR‐155‐5p is significantly enhanced in MSCs isolated from aged mice compared with MSCs collected from young mice. Consistent with these findings, we observed that miR‐155‐5p was significantly increased in human AMSCs and serum from aging donors in the current study, suggesting that miR‐155‐5p may be a potential factor in regulating MSC senescence.…”