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Synthase-2 2 Stem Cells by Targeting Prostaglandin E Immunoregulatory MicroRNA-146a Negatively Regulates the Immunoregulatory Activity of Bone Marrow Stem Cells by Targeting Prostaglandin E2 Synthase-2 This information is current as of September 30, 2021. Mariola Matysiak, Maria Fortak-Michalska, Bozena Szymanska, Wojciech Orlowski, Anna Jurewicz and Krzysztof Selmaj J Immunol 2013; 190:5102-5109; Prepublished online 15 April 2013; Downloaded from doi: 10.4049/jimmunol.1202397 http://www.jimmunol.org/content/190/10/5102 http://www.jimmunol.org/ References This article cites 45 articles, 17 of which you can access for free at: http://www.jimmunol.org/content/190/10/5102.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 30, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology MicroRNA-146a Negatively Regulates the Immunoregulatory Activity of Bone Marrow Stem Cells by Targeting Prostaglandin E2 Synthase-2 Mariola Matysiak, Maria Fortak-Michalska, Bozena_ Szymanska, Wojciech Orlowski, Anna Jurewicz, and Krzysztof Selmaj The molecular mechanisms that regulate the immune function of bone marrow–derived mesenchymal stem cells (BMSCs) are not known. We have shown previously that freshly isolated BMSCs when induced to express neuronal stem cell markers lose immunoregulatory function when transferred into mice sensitized to develop experimental autoimmune encephalomyelitis. Re- cently, microRNAs (miRs) have been shown to be involved in the regulation of several immune responses in both innate and acquired immunity. We now show that among several differentially expressed miRs, miR-146a was strongly upregulated in Downloaded from neuronally differentiated when compared with miR-146a expression in freshly isolated BMSCs or control BMSCs cultured in parallel but in nondifferentiating medium. Inhibition of miR-146a with a selective antagomir restored the immunoregulatory activity of nBMSCs. We mapped miR-146a to its multiple predicted target mRNA transcripts and found that miR-146a was predicted to block PGE2 synthase (ptges-2). We then showed that Ptges-2 was directly targeted by miR-146a using a luciferase reporter assay. Furthermore, increased expression of miR-146a in BMSCs correlated with inhibition of PGE synthase-2 and inhibition of PGE2 release. Accordingly, inhibition of miR-146a restored synthesis of PGE2. These data support the conclusion that http://www.jimmunol.org/ miR-146a plays a critical role in the control of the immunoregulatory potential of BMSCs. The Journal of Immunology, 2013, 190: 5102–5109. ultiple sclerosis (MS) is a chronic inflammatory de- have also been shown to modulate immune responses by influ- myelinating condition of the human CNS charac- encing some T cell, B lymphocyte, NK, and dendritic cell func- M terized by recurrent episodes of immune-mediated tions (13–15). The mechanisms underlying these effects are largely demyelination and axonal loss (1). Among recently proposed unknown but are likely to be mediated either by direct cell–cell therapeutic strategies, transplantation of myelin-forming precursor contact and/or soluble factors such as TGF-b1 (16), hepatocyte by guest on September 30, 2021 cells or stem cells (SC) has generated both interest and reserva- growth factor (17), NO (18), and PGE2 (19–21). tions (2–4). Bone marrow–derived mesenchymal stem cells (BMSCs) MicroRNAs (miRs) have become recognized as important gene provide the structural and functional support for the generation of regulators in eukaryotic organisms, including SCs (22). miRs blood cell lineages from hematopoietic SCs (5). BMSCs expanded are a class of nonprotein-coding small RNAs that have a spe- in vitro can generate progeny that differentiate into multiple cell cific secondary stem-loop hairpin structure within their primary lineages (6). Several recent reports have demonstrated that under transcripts with a higher minimal folding free energy index (23). specific experimental conditions, BMSCs can differentiate into miRs negatively regulate gene expression at the posttranscrip- bone cells (7), fat cells (8), hepatocytes (9), glia, and neurons (10, tional level through direct mRNA cleavage (24), translational 11). The neuron-differentiation potential of BMSCs has attracted repression (25), or mRNA decay mediated by miR deadenylation intense interest in the possible application of BMSCs in cell and (26). Although many endogenous miRs have been identified in gene therapy strategies for neurologic diseases (12). BMSCs mammals, specific functions have remained largely undefined. However, recent studies indicate that the expression profiles of miRs in SCs are different from other tissues (27). This suggests Department of Neurology, Medical University of Lodz, 90-153 Lodz, Poland that miRs may play an essential role in SC self-renewal, differ- Received for publication August 27, 2012. Accepted for publication March 19, 2013. entiation, and other functions (28). With respect to immunoreg- This work was supported by Medical University of Lodz Grant 502-11-741 and ulation, miRs have been shown to be involved in the regu- Polish Ministry of Science and Higher Education Grant N N401 031637. lation of several immune responses in both innate and acquired The sequences presented in this article have been submitted to Gene Expression immunity. Omnibus (http://www.ncbi.nlm.nih.gov/geo) under accession number GSE43621. In this study, we analyzed the expression profile of miRs in Address correspondence and reprint requests to Dr. Krzysztof Selmaj, Department BMSCs as a correlate of their immunoregulatory potential. We of Neurology, Medical University of Lodz, Kopcinskiego Street 22, 90-153 Lodz, Poland. E-mail address: [email protected] found that several miRs were significantly upregulated, including miR-146a, in neuronally differentiated BMSCs that had lost im- Abbreviations used in this article: bFGF, basic fibroblast growth factor; BMSC, bone marrow–derived mesenchymal stem cell; cBMSC, cultured nondifferentiated Lin2 munoregulatory activity in mice with experimental autoimmune 1 Sca-1 bone marrow-derived mesenchymal stem cell; cPGES, cytosolic PGE syn- encephalomyelitis (EAE), an animal model for MS. We found thase; EAE, experimental autoimmune encephalomyelitis; fBMSC, freshly isolated Lin2Sca-1+ bone marrow–derived mesenchymal stem cell; miR, microRNA; mPGES, that miR-146a targeted PGE2-synthase 2, which resulted in microsomal PGE synthase; MSC, mesenchymal stem cell; nBMSC, neural-differenti- decreased secretion of PGE . Because PGE was shown to con- 2 1 2 2 ated Lin Sca-1 bone marrow–derived mesenchymal stem cell; SC, stem cell; UTR, tribute to the immunosuppressive activity of BMSCs (19–21), we untranslated region. analyzed whether the functional relation between miR-146a Copyright Ó 2013 by The American Association of Immunologists, Inc. 0022-1767/13/$16.00 and BMSC-induced immunosuppression depended on PGE2. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1202397 The Journal of Immunology 5103 Materials and Methods BMSC cultures during differentiation and in nondifferentiated medium (on Isolation of BMSCs 4 and 7 d) or in 24-h culture of fBMSCs. Supernatants were frozen and analyzed according to the manufacturer’s instructions. Standard, control, Normal SJL mice, 6–8 wk old, were used for the isolation of BMSC. Bone and test samples were added to each well and incubated for appropriate marrow cells were obtained from the femurs and tibias of euthanized mice time with adequate primary Ab and conjugate. After washing, substrate by flushing with PBS. Cells were washed twice in sorting medium that solution was added to each well for 30 min at room temperature in the consisted of PBS supplemented with 0.5% BSA (Sigma-Aldrich, St. Louis, dark. Finally, Stop Solution was added and the OD of each well was de- MO), and subjected to negative magnetic sorting using the Lineage Cell termined within 30 min using a microplate reader (wavelength 450 nm). Depletion Kit (Miltenyi Biotec, Bergisch Gladbach, Germany). Depletion of cells expressing lineage Ags by mAbs and magnetic beads resulted in Western blotting 2 2 a pure fraction of Lin cells. Purity of the Lin fraction was invariably Cell lysates were obtained from cultures of fBMSCs (24 h), nBMSCs, and . 98%, as assessed by flow cytometry using Lineage Cocktail (anti-CD3e, cBMSCs. Cells were pelleted and lysed in lysing buffer (20 mM Tris-HCl anti-CD11b, anti-CD45R/B220, anti-Ly6G and Ly-6C, and anti–TER-119; [pH 7.4], 0.15 M NaCl, 1% Triton, 2.5 mM sodium pyrophosphate, 1 mM BD Biosciences, San Jose, CA) (29). Cells retained differentiation capacity Na VO , 1 mM PMSF, 1 mg/ml aprotinin and leupeptin). Lysates were and were characterized by lack of CD34, CD11b, and CD45. Isolation of 3 4 2 + 2 + centrifuged at 14,000 rpm for 5 min. An equal amount of protein
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