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.

Intracerebral inflammation resulting from injury or disease is implicated in disruption of neural regeneration and may lead to irreversible neuronal dysfunction. Analysis of inflammation-related microRNA profiles in various tissues, including the brain, has identified miR-155 among the most prominent miRNAs linked to inflammation. Here, we hypothesize that miR-155 mediates inflammation-induced suppression of neural stem cell (NSC) self-renewal. Using primary mouse NSCs and human NSCs derived from induced pluripotent stem (iPS) cells, we demonstrate that three important genes involved in NSC self-renewal (Msi1, Hes1 and Bmi1) are suppressed by miR-155. We also demonstrate that suppression of self-renewal genes is mediated by the common transcription factor C/EBPβ, which is a direct target of miR-155. Our study describes an axis linking inflammation and miR-155 to expression of genes related to NSC self-renewal, suggesting that regulation of miR-155 may hold potential as a novel therapeutic strategy for treating neuroinflammatory diseases.