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

Inflammation‐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.

[1]  A. Wagers,et al.  Stem cell aging: mechanisms, regulators and therapeutic opportunities , 2014, Nature Medicine.

[2]  Y. Nakabeppu,et al.  Therapeutic Approach to Neurodegenerative Diseases by Medical Gases: Focusing on Redox Signaling and Related Antioxidant Enzymes , 2012, Oxidative medicine and cellular longevity.

[3]  P. Hematti,et al.  Effects of Oxidative Stress on Mesenchymal Stem Cell Biology , 2016, Oxidative medicine and cellular longevity.

[4]  D. Standaert,et al.  microRNA-155 Regulates Alpha-Synuclein-Induced Inflammatory Responses in Models of Parkinson Disease , 2016, The Journal of Neuroscience.

[5]  H. T. Kim,et al.  Sp1 and C/EBP-related factor regulate the transcription of human Cu/Zn SOD gene. , 1996, Gene.

[6]  R. Ung,et al.  Inflammatory cytokines and reactive oxygen species as mediators of chronic kidney disease-related vascular calcification. , 2015, American journal of hypertension.

[7]  A. Newman,et al.  Inflammatory markers in population studies of aging , 2011, Ageing Research Reviews.

[8]  W. Fiers,et al.  Depletion of the mitochondrial electron transport abrogates the cytotoxic and gene‐inductive effects of TNF. , 1993, The EMBO journal.

[9]  Naoki Nakagawa,et al.  Anti-microRNA-21 oligonucleotides prevent Alport nephropathy progression by stimulating metabolic pathways. , 2015, The Journal of clinical investigation.

[10]  T. Rachner,et al.  Osteoporosis: now and the future , 2011, The Lancet.

[11]  G. Bommer,et al.  microRNA-155, Induced by Interleukin-1ß, Represses the Expression of Microphthalmia-Associated Transcription Factor (MITF-M) in Melanoma Cells , 2015, PloS one.

[12]  L. Ellis,et al.  Interleukin-1beta stimulates IL-8 expression through MAP kinase and ROS signaling in human gastric carcinoma cells. , 2004, Oncogene.

[13]  A. Martí,et al.  Noncoding RNAs, cytokines, and inflammation‐related diseases , 2015, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[14]  G. Bauer,et al.  Reactive oxygen species act at both TGF-beta-dependent and -independent steps during induction of apoptosis of transformed cells by normal cells. , 1996, Experimental cell research.

[15]  Haifa Hamdi,et al.  Micro‐RNA‐155‐mediated control of heme oxygenase 1 (HO‐1) is required for restoring adaptively tolerant CD4+ T‐cell function in rodents , 2015, European journal of immunology.

[16]  M. Valko,et al.  Importance of iron chelation in free radical-induced oxidative stress and human disease. , 2011, Current pharmaceutical design.

[17]  A. L. Cardoso,et al.  Early miR-155 upregulation contributes to neuroinflammation in Alzheimer's disease triple transgenic mouse model. , 2014, Human molecular genetics.

[18]  Chiang-Ching Huang,et al.  A Parallel Study of mRNA and microRNA Profiling of Peripheral Blood in Young Adult Women , 2011, Front. Gene..

[19]  Jay Shendure,et al.  Transcriptome-wide miR-155 binding map reveals widespread noncanonical microRNA targeting. , 2012, Molecular cell.

[20]  Shengshou Hu,et al.  Apoptosis of mesenchymal stem cells induced by hydrogen peroxide concerns both endoplasmic reticulum stress and mitochondrial death pathway through regulation of caspases, p38 and JNK , 2010, Journal of cellular biochemistry.

[21]  Hung Li,et al.  Nonsenescent Hsp27-Upregulated MSCs Implantation Promotes Neuroplasticity in Stroke Model , 2010, Cell transplantation.

[22]  C. Hamanishi,et al.  Induction of mesenchymal progenitor cells with chondrogenic property from mouse-induced pluripotent stem cells. , 2010, Cellular reprogramming.

[23]  Hyeyoung Min,et al.  Age-Associated Changes in MicroRNA Expression in Bone Marrow Derived Dendritic Cells , 2013, Immunological investigations.

[24]  S. Anton,et al.  Molecular inflammation: Underpinnings of aging and age-related diseases , 2009, Ageing Research Reviews.

[25]  U. Galderisi,et al.  Clinical Trials with Mesenchymal Stem Cells: An Update , 2016, Cell transplantation.

[26]  A. Eid,et al.  Statins modulate transcriptional activity of heme‐oxygenase‐1 promoter in NIH 3T3 Cells , 2012, Journal of cellular biochemistry.

[27]  S. Morrison,et al.  The bone marrow niche for haematopoietic stem cells , 2014, Nature.

[28]  M. Pittenger,et al.  Mesenchymal stem cells and their potential as cardiac therapeutics. , 2004, Circulation research.

[29]  A. Miyawaki,et al.  Prospective identification, isolation, and systemic transplantation of multipotent mesenchymal stem cells in murine bone marrow , 2009, The Journal of experimental medicine.

[30]  J. Rubin,et al.  Epigenetic Plasticity Drives Adipogenic and Osteogenic Differentiation of Marrow-derived Mesenchymal Stem Cells* , 2016, The Journal of Biological Chemistry.

[31]  L. Ellis,et al.  Interleukin-1β stimulates IL-8 expression through MAP kinase and ROS signaling in human gastric carcinoma cells , 2004, Oncogene.

[32]  R. Lo,et al.  The cumate gene-switch: a system for regulated expression in mammalian cells , 2006 .

[33]  Devanand Sarkar,et al.  Molecular mechanisms of aging-associated inflammation. , 2006, Cancer letters.

[34]  R. Siow,et al.  Regulation of the Nrf2 antioxidant pathway by microRNAs: New players in micromanaging redox homeostasis. , 2013, Free radical biology & medicine.

[35]  J. Ryan,et al.  IL-10–Induced miR-155 Targets SOCS1 To Enhance IgE-Mediated Mast Cell Function , 2016, The Journal of Immunology.

[36]  Y. Lacasse,et al.  From the authors , 2005, European Respiratory Journal.

[37]  P. Laloi,et al.  Mesenchymal stem cells improve small intestinal integrity through regulation of endogenous epithelial cell homeostasis , 2010, Cell Death and Differentiation.

[38]  V. Natarajan,et al.  Reactive oxygen species at the crossroads of inflammasome and inflammation , 2014, Front. Physiol..

[39]  Kunihiro Matsumoto,et al.  ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity , 2005, Nature Immunology.

[40]  Shengdi Chen,et al.  Oxidative stress: A major pathogenesis and potential therapeutic target of antioxidative agents in Parkinson’s disease and Alzheimer’s disease , 2016, Progress in Neurobiology.

[41]  T. Peng,et al.  MicroRNA-195 promotes palmitate-induced apoptosis in cardiomyocytes by down-regulating Sirt1. , 2011, Cardiovascular research.

[42]  D. Bartel.  MicroRNAs: Target Recognition and Regulatory Functions , 2009, Cell.

[43]  Yi Zhang,et al.  A protocol for isolation and culture of mesenchymal stem cells from mouse compact bone , 2010, Nature Protocols.

[44]  Dandan Wu,et al.  ROS and ROS-Mediated Cellular Signaling , 2016, Oxidative medicine and cellular longevity.

[45]  Kai Stühler,et al.  MicroRNA-15b regulates mitochondrial ROS production and the senescence-associated secretory phenotype through sirtuin 4/SIRT4 , 2016, Aging.

[46]  S. Reddy,et al.  Reactive oxygen species in inflammation and tissue injury. , 2014, Antioxidants & redox signaling.

[47]  Y. Kan,et al.  NRF2, a member of the NFE2 family of transcription factors, is not essential for murine erythropoiesis, growth, and development. , 1996, Proceedings of the National Academy of Sciences of the United States of America.