Upregulated TSG-6 Expression in ADSCs Inhibits the BV2 Microglia-Mediated Inflammatory Response

Objectives The microglial cells are immune surveillance cells in the central nervous system and can be activated during neurological disorders. Adipose-derived stem cells (ADSCs) were reported to inhibit the inflammatory response in microglia by secreting proteins like tumor necrosis factor-inducible gene 6 protein (TSG-6). We aim to explore the mechanisms and the associated microRNAs. Methods ADSCs were cultured and TSG-6 expression was evaluated. ADSCs were cocultured with lipopolysaccharide- (LPS-) induced BV2 microglia and the supernatant was harvested for detecting cytokines. The total RNA was extracted and sequenced by high-throughput sequencing. MicroRNA profiles were compared between two treatment groups of ADSCs. A comprehensive bioinformatics analysis and confirmation experiments were performed to identify the microRNAs targeting at TSG-6. Results We found that ADSCs could secrete TSG-6 to inhibit the proinflammatory cytokines, including interleukin-1 beta and interleukin-6, and tumor necrosis factor alpha (TNFα), produced by LPS-induced microglia-mediated inflammatory response. Bioinformatics analysis showed a total of 35 microRNAs differentially expressed between the two groups of ADSCs, and miR-214-5p was identified as a regulator of TSG-6 mRNA. Conclusion Following a treatment with TNFα, ADSCs can regulate the inflammatory response in LPS-activated BV2 microglia by upregulating TSG-6 expression, which itself is under the negative control of miR-214-5p.

[1]  Krishna Sundar Twayana,et al.  Prolonged lipopolysaccharide exposure induces transient immunosuppression in BV2 microglia , 2018, Journal of cellular physiology.

[2]  Woo-Jin Song,et al.  TSG-6 released from intraperitoneally injected canine adipose tissue-derived mesenchymal stem cells ameliorate inflammatory bowel disease by inducing M2 macrophage switch in mice , 2018, Stem Cell Research & Therapy.

[3]  D. Prockop,et al.  TSG-6 as a biomarker to predict efficacy of human mesenchymal stem/progenitor cells (hMSCs) in modulating sterile inflammation in vivo , 2014, Proceedings of the National Academy of Sciences.

[4]  Guy C. Brown,et al.  Tumour necrosis factor alpha-induced neuronal loss is mediated by microglial phagocytosis , 2014, FEBS letters.

[5]  Y. Doki,et al.  Adipose Tissue-Derived Stem Cells Suppress Acute Cellular Rejection by TSG-6 and CD44 Interaction in Rat Kidney Transplantation , 2014, Transplantation.

[6]  Run Zhang,et al.  Mesenchymal stem cells inhibit lipopolysaccharide-induced inflammatory responses of BV2 microglial cells through TSG-6 , 2014, Journal of Neuroinflammation.

[7]  Zachary D. Kurtz,et al.  Alternatively activated macrophages derived from monocytes and tissue macrophages are phenotypically and functionally distinct. , 2014, Blood.

[8]  R. Medzhitov,et al.  Tissue-Specific Signals Control Reversible Program of Localization and Functional Polarization of Macrophages , 2014, Cell.

[9]  J. Nolta,et al.  Concise Review: MicroRNA Function in Multipotent Mesenchymal Stromal Cells , 2014, Stem cells.

[10]  Dorian B. McGavern,et al.  Microglia development and function. , 2014, Annual review of immunology.

[11]  Guy C. Brown,et al.  Microglial phagocytosis of live neurons , 2014, Nature Reviews Neuroscience.

[12]  Ping Zhang,et al.  Efficient Generation of Neural Stem Cell-Like Cells from Rat Adipose Derived Stem Cells After Lentiviral Transduction with Green Fluorescent Protein , 2014, Molecular Neurobiology.

[13]  H. Mizuno,et al.  Adipose-derived stem cells and periodontal tissue engineering. , 2013, The International journal of oral & maxillofacial implants.

[14]  D. Prockop,et al.  Administration of TSG-6 improves memory after traumatic brain injury in mice , 2013, Neurobiology of Disease.

[15]  K. Selmaj,et al.  MicroRNA-146a Negatively Regulates the Immunoregulatory Activity of Bone Marrow Stem Cells by Targeting Prostaglandin E2 Synthase-2 , 2013, The Journal of Immunology.

[16]  Li-li Zhou,et al.  Mesenchymal stem cells transplantation suppresses inflammatory responses in global cerebral ischemia: contribution of TNF-α-induced protein 6 , 2013, Acta Pharmacologica Sinica.

[17]  C. Teunissen,et al.  Macrophages in inflammatory multiple sclerosis lesions have an intermediate activation status , 2013, Journal of Neuroinflammation.

[18]  G. Brewer,et al.  miR-155 Regulates Immune Modulatory Properties of Mesenchymal Stem Cells by Targeting TAK1-binding Protein 2* , 2013, The Journal of Biological Chemistry.

[19]  Yali Hu,et al.  MicroRNA‐181a Regulates Local Immune Balance by Inhibiting Proliferation and Immunosuppressive Properties of Mesenchymal Stem Cells , 2012, Stem cells.

[20]  W. Gong,et al.  ER Stress Negatively Modulates the Expression of the miR-199a/214 Cluster to Regulates Tumor Survival and Progression in Human Hepatocellular Cancer , 2012, PloS one.

[21]  D. Prockop,et al.  Anti-inflammatory protein TSG-6 secreted by activated MSCs attenuates zymosan-induced mouse peritonitis by decreasing TLR2/NF-κB signaling in resident macrophages. , 2011, Blood.

[22]  J. Bagley,et al.  Costimulation-Dependent Expression of MicroRNA-214 Increases the Ability of T Cells To Proliferate by Targeting Pten , 2010, The Journal of Immunology.

[23]  A. Ciccodicola,et al.  Uncovering the Complexity of Transcriptomes with RNA-Seq , 2010, Journal of biomedicine & biotechnology.

[24]  Tian Sheng Chen,et al.  Mesenchymal stem cell secretes microparticles enriched in pre-microRNAs , 2009, Nucleic acids research.

[25]  J. Uney,et al.  Twist-1 regulates the miR-199a/214 cluster during development , 2008, Nucleic acids research.

[26]  A. P. Robinson,et al.  Stem/progenitor cells from bone marrow decrease neuronal death in global ischemia by modulation of inflammatory/immune responses , 2008, Proceedings of the National Academy of Sciences.

[27]  A. Uccelli,et al.  Mesenchymal stem cells in health and disease , 2008, Nature Reviews Immunology.

[28]  S. Ranade,et al.  Stem cell transcriptome profiling via massive-scale mRNA sequencing , 2008, Nature Methods.

[29]  R. Zhao,et al.  Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. , 2008, Cell stem cell.

[30]  B. McEwen,et al.  Microglia derived from aging mice exhibit an altered inflammatory profile , 2007, Glia.

[31]  J. G. Patton,et al.  Zebrafish miR-214 modulates Hedgehog signaling to specify muscle cell fate , 2007, Nature Genetics.

[32]  F. Helmchen,et al.  Resting Microglial Cells Are Highly Dynamic Surveillants of Brain Parenchyma in Vivo , 2005, Science.

[33]  D. Bartel.  MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[34]  Min Zhu,et al.  Human adipose tissue is a source of multipotent stem cells. , 2002, Molecular biology of the cell.

[35]  H. Lorenz,et al.  Multilineage cells from human adipose tissue: implications for cell-based therapies. , 2001, Tissue engineering.

[36]  J. Claverie,et al.  The significance of digital gene expression profiles. , 1997, Genome research.

[37]  Krisztián Németh,et al.  Bone marrow stromal cells attenuate sepsis via prostaglandin E2–dependent reprogramming of host macrophages to increase their interleukin-10 production , 2009, Nature Medicine.