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.

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Elevation of the levels of reactive oxygen species (ROS) is a major tissue-degenerative phenomenon involved in aging and aging-related diseases. The detailed mechanisms underlying aging-related ROS generation remain unclear. Presently, the expression of microRNA (miR)-142-5p was significantly upregulated in bone marrow mesenchymal stem cells (BMMSCs) of aged mice. Overexpression of miR-142 and subsequent observation revealed that miR-142 involved ROS accumulation through the disruption of selective autophagy for peroxisomes (pexophagy). Mechanistically, attenuation of acetyltransferase Ep300 triggered the upregulation of miR-142 in aged BMMSCs, and miR-142 targeted endothelial PAS domain protein 1 (Epas1) was identified as a regulatory protein of pexophagy. These findings support a novel molecular mechanism relating aging-associated ROS generation and organelle degradation in BMMSCs, and suggest a potential therapeutic target for aging-associated disorders that are accompanied by stem cell degeneration.Aging worsens functions of human tissues and organs at multiple levels, causing a gradual reduction in the ability to resist stress, damage, and various related diseases. Cellular senescence is considered an important aging hallmark and the direct reason for the above mentioned changes 1,2 . In recent years, accumulating evidence has indicated that reactive oxygen species (ROS), which include superoxide anion and hydroxyl radicals, generated from both intrinsic and extrinsic events induce cell damage and senescence during aging. There are numerous studies, which report that ROS and oxidative damage increase with age 3,4 , that reducing oxidative damage extends the lifespan of various model organisms, and increased production of ROS shortens their lifespan 5 . ROS contribute to cellular senescence onset and progression by damaging mitochondrial DNA (mtDNA) and modifying the telomerase reverse transcriptase (TERT) enzyme 6 , histones, and DNA by acting in interconnected epigenetic phases 7,8 . Furthermore, high ROS levels provoke p53 activation, which induces p53-mediated apoptosis and cell senescence 9 . Although all cells in an organism can be affected by the accumulation of ROS, the effects of ROS on stem cells are particularly important for understanding the processes of aging and its related diseases 10,11 . Accumulation of oxidative damage in stem cells can lead to loss of stemness, cell transformation, tumorigenesis, or tissue injury 11 . Thus, elucidating the molecular mechanisms underlying ROS accumulation in stem cells is important to develop therapies for inhibiting the underlying cause of aging-related tissue dysfunction or diseases.Degenerated cellular organelles are a major source of ROS. Oxygen is consumed in various metabolic reactions in different intracellular locations, with mitochondria, ER, and peroxisomes being the major sites; thus, dysfunction of these organelles directly leads to the generation of a large amount of ROS 12 . Among these, the peroxisome is a very important source of ROS, which ...

Tissue renewal and muscle regeneration largely rely on the proliferation and differentiation of muscle stem cells called muscular satellite cells (MuSCs). MuSCs are normally quiescent, but they are activated in response to various stimuli, such as inflammation. Activated MuSCs proliferate, migrate, differentiate, and fuse to form multinucleate myofibers. Meanwhile, inappropriate cues for MuSC activation induce premature differentiation and bring about stem cell loss. Recent studies revealed that stem cell regulation is disrupted in various aged tissues. We found that the expression of microRNA (miR)-155, which is an inflammation-associated miR, is upregulated in MuSCs of aged muscles, and this upregulation activates the differentiation process through suppression of C/ebpβ, which is an important molecule for maintaining MuSC self-renewal. We also found that Notch1 considerably repressed miR-155 expression, and loss of Notch1 induced miR-155 overexpression. Our findings suggest that miR-155 can act as an activator of muscular differentiation and might be responsible for accelerating aging-associated premature differentiation of MuSCs.

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