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Mesenchymal Stem Cell-Derived Extracellular Vesicles as Mediators of Anti-inflammatory Effects

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Stem Cell Transplantation for Autoimmune Diseases and Inflammation

Part of the book series: Stem Cells in Clinical Applications ((SCCA))

Abstract

Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs), which cover both microvesicles (MV) and exosomes, are increasingly in focus for immune-modulatory application as an alternative or substitute in MSC cellular therapy. Experimentally it has been documented that EVs take part in cell-to-cell communication, cell signaling, and changing cell or tissue physiological functions over short or long distances in the organism. It has been observed that MVs and exosomes influence the tissue responses to injury, infection, and disease. MSC-derived EVs contain cytokines, growth factors, signaling lipids, mRNAs, and regulatory miRNAs being able to modify the innate and adaptive immune response. The MSC EVs materials are not static but rather a product of the MSC tissue conditions and can be primed to an anti-inflammatory state.

Therefore, EVs have become the focus of clinical applications. EVs can potentially be used for prognosis and therapy, and as biomarkers for health and disease. MSC-derived EVs offer the chance for cell-free regenerative medicine with decreased risks. On their way to clinical application, much will depend on the quality and reproducibility of their effects and of the modifications to their delivery cargo of therapeutic substances and the upgrading of their production, in the same way that these parameters have influenced the development of cell-based MSC therapies in the past.

Sabine Conrad and Alexander Younsi contributed equally to this chapter.

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References

  1. Cai J, Wu Z, Xu X, Liao L, Chen J, Huang L, Wu W, Luo F, Wu C, Pugliese A, et al. Umbilical cord mesenchymal stromal cell with autologous bone marrow cell transplantation in established type 1 diabetes: a pilot randomized controlled open-label clinical study to assess safety and impact on insulin secretion. Diabetes Care. 2016;39:149–57.

    Article  CAS  PubMed  Google Scholar 

  2. Garcia-Olmo D, Garcia-Arranz M, Herreros D, Pascual I, Peiro C, Rodriguez-Montes JA. A phase I clinical trial of the treatment of Crohn’s fistula by adipose mesenchymal stem cell transplantation. Dis Colon Rectum. 2005;48:1416–23.

    Article  PubMed  Google Scholar 

  3. Pers YM, Rackwitz L, Ferreira R, Pullig O, Delfour C, Barry F, Sensebe L, Casteilla L, Fleury S, Bourin P, et al. Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: a phase I dose-escalation trial. Stem Cells Transl Med. 2016;5:847–56.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Tanna T, Sachan V. Mesenchymal stem cells: potential in treatment of neurodegenerative diseases. Curr Stem Cell Res Ther. 2014;9:513–21.

    Article  CAS  PubMed  Google Scholar 

  5. Kim DS, Jang IK, Lee MW, Ko YJ, Lee DH, Lee JW, Sung KW, Koo HH, Yoo KH. Enhanced immunosuppressive properties of human mesenchymal stem cells primed by interferon-gamma. EBioMedicine. 2018;28:261–73.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Bandeira E, Oliveira H, Silva JD, Menna-Barreto RFS, Takyia CM, Suk JS, Witwer KW, Paulaitis ME, Hanes J, Rocco PRM, et al. Therapeutic effects of adipose-tissue-derived mesenchymal stromal cells and their extracellular vesicles in experimental silicosis. Respir Res. 2018;19:104.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Biancone L, Bruno S, Deregibus MC, Tetta C, Camussi G. Therapeutic potential of mesenchymal stem cell-derived microvesicles. Nephrol Dial Transplant. 2012;27:3037–42.

    Article  CAS  PubMed  Google Scholar 

  8. Bier A, Berenstein P, Kronfeld N, Morgoulis D, Ziv-Av A, Goldstein H, Kazimirsky G, Cazacu S, Meir R, Popovtzer R, et al. Placenta-derived mesenchymal stromal cells and their exosomes exert therapeutic effects in Duchenne muscular dystrophy. Biomaterials. 2018;174:67–78.

    Article  CAS  PubMed  Google Scholar 

  9. Cosenza S, Toupet K, Maumus M, Luz-Crawford P, Blanc-Brude O, Jorgensen C, Noel D. Mesenchymal stem cells-derived exosomes are more immunosuppressive than microparticles in inflammatory arthritis. Theranostics. 2018;8:1399–410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ebrahim N, Mostafa O, El Dosoky RE, Ahmed IA, Saad AS, Mostafa A, Sabry D, Ibrahim KA, Farid AS. Human mesenchymal stem cell-derived extracellular vesicles/estrogen combined therapy safely ameliorates experimentally induced intrauterine adhesions in a female rat model. Stem Cell Res Ther. 2018;9:175.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Farinazzo A, Angiari S, Turano E, Bistaffa E, Dusi S, Ruggieri S, Bonafede R, Mariotti R, Constantin G, Bonetti B. Nanovesicles from adipose-derived mesenchymal stem cells inhibit T lymphocyte trafficking and ameliorate chronic experimental autoimmune encephalomyelitis. Sci Rep. 2018;8:7473.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Gebraad A, Kornilov R, Kaur S, Miettinen S, Haimi S, Peltoniemi H, Mannerstrom B, Seppanen-Kaijansinkko R. Monocyte-derived extracellular vesicles stimulate cytokine secretion and gene expression of matrix metalloproteinases by mesenchymal stem/stromal cells. FEBS J. 2018;285:2337–59.

    Article  CAS  PubMed  Google Scholar 

  13. Gnecchi M, Zhang Z, Ni A, Dzau VJ. Paracrine mechanisms in adult stem cell signaling and therapy. Circ Res. 2008;103:1204–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Han YD, Bai Y, Yan XL, Ren J, Zeng Q, Li XD, Pei XT, Han Y. Co-transplantation of exosomes derived from hypoxia-preconditioned adipose mesenchymal stem cells promotes neovascularization and graft survival in fat grafting. Biochem Biophys Res Commun. 2018;497:305–12.

    Article  CAS  PubMed  Google Scholar 

  15. Harting MT, Srivastava AK, Zhaorigetu S, Bair H, Prabhakara KS, Toledano Furman NE, Vykoukal JV, Ruppert KA, Cox CS Jr, Olson SD. Inflammation-stimulated mesenchymal stromal cell-derived extracellular vesicles attenuate inflammation. Stem Cells. 2018;36:79–90.

    Article  CAS  PubMed  Google Scholar 

  16. Haumer A, Bourgine PE, Occhetta P, Born G, Tasso R, Martin I. Delivery of cellular factors to regulate bone healing. Adv Drug Deliv Rev. 2018;129:285–94.

    Article  CAS  PubMed  Google Scholar 

  17. Hyvarinen K, Holopainen M, Skirdenko V, Ruhanen H, Lehenkari P, Korhonen M, Kakela R, Laitinen S, Kerkela E. Mesenchymal stromal cells and their extracellular vesicles enhance the anti-inflammatory phenotype of regulatory macrophages by downregulating the production of interleukin (IL)-23 and IL-22. Front Immunol. 2018;9:771.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Katsuda T, Kosaka N, Takeshita F, Ochiya T. The therapeutic potential of mesenchymal stem cell-derived extracellular vesicles. Proteomics. 2013;13:1637–53.

    Article  CAS  PubMed  Google Scholar 

  19. Lo Sicco C, Reverberi D, Pascucci L, Tasso R. A method for isolating and characterizing mesenchymal stromal cell-derived extracellular vesicles. Curr Protoc Stem Cell Biol. 2018;46:e55.

    Article  PubMed  CAS  Google Scholar 

  20. Meng Y, Eirin A, Zhu XY, O’Brien DR, Lerman A, van Wijnen AJ, Lerman LO. The metabolic syndrome modifies the mRNA expression profile of extracellular vesicles derived from porcine mesenchymal stem cells. Diabetol Metab Syndr. 2018;10:58.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Miyaki S, Lotz MK. Extracellular vesicles in cartilage homeostasis and osteoarthritis. Curr Opin Rheumatol. 2018;30:129–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Spinosa M, Lu G, Su G, Bontha SV, Gehrau R, Salmon MD, Smith JR, Weiss ML, Mas VR, Upchurch GR Jr, et al. Human mesenchymal stromal cell-derived extracellular vesicles attenuate aortic aneurysm formation and macrophage activation via microRNA-147. FASEB J. 2018;fj201701138RR. https://doi.org/10.1096/fj.201701138RR.

    Article  CAS  PubMed Central  Google Scholar 

  23. Tofino-Vian M, Guillen MI, Perez Del Caz MD, Silvestre A, Alcaraz MJ. Microvesicles from human adipose tissue-derived mesenchymal stem cells as a new protective strategy in osteoarthritic chondrocytes. Cell Physiol Biochem. 2018;47:11–25.

    Article  CAS  PubMed  Google Scholar 

  24. Vonk LA, van Dooremalen SFJ, Liv N, Klumperman J, Coffer PJ, Saris DBF, Lorenowicz MJ. Mesenchymal stromal/stem cell-derived extracellular vesicles promote human cartilage regeneration in vitro. Theranostics. 2018;8:906–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Willis GR, Fernandez-Gonzalez A, Anastas J, Vitali SH, Liu X, Ericsson M, Kwong A, Mitsialis SA, Kourembanas S. Mesenchymal stromal cell exosomes ameliorate experimental bronchopulmonary dysplasia and restore lung function through macrophage immunomodulation. Am J Respir Crit Care Med. 2018;197:104–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhang S, Chuah SJ, Lai RC, Hui JHP, Lim SK, Toh WS. MSC exosomes mediate cartilage repair by enhancing proliferation, attenuating apoptosis and modulating immune reactivity. Biomaterials. 2018;156:16–27.

    Article  CAS  PubMed  Google Scholar 

  27. Zulueta A, Colombo M, Peli V, Falleni M, Tosi D, Ricciardi M, Baisi A, Bulfamante G, Chiaramonte R, Caretti A. Lung mesenchymal stem cells-derived extracellular vesicles attenuate the inflammatory profile of cystic fibrosis epithelial cells. Cell Signal. 2018;51:110–8.

    Article  CAS  PubMed  Google Scholar 

  28. Abels ER, Breakefield XO. Introduction to extracellular vesicles: biogenesis, RNA cargo selection, content, release, and uptake. Cell Mol Neurobiol. 2016;36:301–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bryzgunova OE, Zaripov MM, Skvortsova TE, Lekchnov EA, Grigor’eva AE, Zaporozhchenko IA, Morozkin ES, Ryabchikova EI, Yurchenko YB, Voitsitskiy VE, et al. Comparative study of extracellular vesicles from the urine of healthy individuals and prostate cancer patients. PLoS One. 2016;11:e0157566.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Camussi G, Deregibus MC, Bruno S, Grange C, Fonsato V, Tetta C. Exosome/microvesicle-mediated epigenetic reprogramming of cells. Am J Cancer Res. 2011;1:98–110.

    PubMed  Google Scholar 

  31. Iraci N, Leonardi T, Gessler F, Vega B, Pluchino S. Focus on extracellular vesicles: physiological role and signalling properties of extracellular membrane vesicles. Int J Mol Sci. 2016;17:171.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Tamkovich S, Tutanov O, Laktionov P. Exosomes: generation, structure, transport, biological activity, and diagnostic application, vol. 10. New York: Springer; 2016.

    Google Scholar 

  33. Borges FT, Melo SA, Ozdemir BC, Kato N, Revuelta I, Miller CA, Gattone VH 2nd, LeBleu VS, Kalluri R. TGF-beta1-containing exosomes from injured epithelial cells activate fibroblasts to initiate tissue regenerative responses and fibrosis. J Am Soc Nephrol. 2013;24:385–92.

    Article  CAS  PubMed  Google Scholar 

  34. Ciardiello C, Cavallini L, Spinelli C, Yang J, Reis-Sobreiro M, de Candia P, Minciacchi VR, Di Vizio D. Focus on extracellular vesicles: new frontiers of cell-to-cell communication in cancer. Int J Mol Sci. 2016;17:175.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Zmigrodzka M, Guzera M, Miskiewicz A, Jagielski D, Winnicka A. The biology of extracellular vesicles with focus on platelet microparticles and their role in cancer development and progression. Tumour Biol. 2016;37:14391–401.

    Article  CAS  PubMed  Google Scholar 

  36. Gonda DD, Akers JC, Kim R, Kalkanis SN, Hochberg FH, Chen CC, Carter BS. Neuro-oncologic applications of exosomes, microvesicles, and other nano-sized extracellular particles. Neurosurgery. 2013;72:501–10.

    Article  PubMed  Google Scholar 

  37. Hu G, Drescher KM, Chen XM. Exosomal miRNAs: biological properties and therapeutic potential. Front Genet. 2012;3:56.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Yanez-Mo M, Siljander PR, Andreu Z, Zavec AB, Borras FE, Buzas EI, Buzas K, Casal E, Cappello F, Carvalho J, et al. Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles. 2015;4:27066.

    Article  PubMed  Google Scholar 

  39. Cheng L, Zhang K, Wu S, Cui M, Xu T. Focus on mesenchymal stem cell-derived exosomes: opportunities and challenges in cell-free therapy. Stem Cells Int. 2017;2017:6305295.

    PubMed  PubMed Central  Google Scholar 

  40. Fatima F, Ekstrom K, Nazarenko I, Maugeri M, Valadi H, Hill AF, Camussi G, Nawaz M. Non-coding RNAs in mesenchymal stem cell-derived extracellular vesicles: deciphering regulatory roles in stem cell potency, inflammatory resolve, and tissue regeneration. Front Genet. 2017;8:161.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Grange C, Iampietro C, Bussolati B. Stem cell extracellular vesicles and kidney injury. Stem Cell Investig. 2017;4:90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Lou G, Chen Z, Zheng M, Liu Y. Mesenchymal stem cell-derived exosomes as a new therapeutic strategy for liver diseases. Exp Mol Med. 2017;49:e346.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Shi Y, Wang Y, Li Q, Liu K, Hou J, Shao C, Wang Y. Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases. Nat Rev Nephrol. 2018;14:493–507.

    Article  CAS  PubMed  Google Scholar 

  44. Tofino-Vian M, Guillen MI, Alcaraz MJ. Extracellular vesicles: a new therapeutic strategy for joint conditions. Biochem Pharmacol. 2018;153:134–46.

    Article  CAS  PubMed  Google Scholar 

  45. Tsuchiya A, Kojima Y, Ikarashi S, Seino S, Watanabe Y, Kawata Y, Terai S. Clinical trials using mesenchymal stem cells in liver diseases and inflammatory bowel diseases. Inflamm Regen. 2017;37:16.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Veronesi F, Borsari V, Sartori M, Orciani M, Mattioli-Belmonte M, Fini M. The use of cell conditioned medium for musculoskeletal tissue regeneration. J Cell Physiol. 2018;233:4423–42.

    Article  CAS  PubMed  Google Scholar 

  47. Willis GR, Fernandez-Gonzalez A, Reis M, Mitsialis SA, Kourembanas S. Macrophage Immunomodulation: the gatekeeper for mesenchymal stem cell derived-exosomes in pulmonary arterial hypertension? Int J Mol Sci. 2018;19(9) https://doi.org/10.3390/ijms19092534.

    Article  PubMed Central  CAS  Google Scholar 

  48. Zheng G, Huang R, Qiu G, Ge M, Wang J, Shu Q, Xu J. Mesenchymal stromal cell-derived extracellular vesicles: regenerative and immunomodulatory effects and potential applications in sepsis. Cell Tissue Res. 2018;374:1–15.

    Article  CAS  PubMed  Google Scholar 

  49. Mathivanan S, Ji H, Simpson RJ. Exosomes: extracellular organelles important in intercellular communication. J Proteomics. 2010;73:1907–20.

    Article  CAS  PubMed  Google Scholar 

  50. Kim SM, Kim HS. Engineering of extracellular vesicles as drug delivery vehicles. Stem Cell Invest. 2017;4:74.

    Article  CAS  Google Scholar 

  51. Junker K, Heinzelmann J, Beckham C, Ochiya T, Jenster G. Extracellular vesicles and their role in urologic malignancies. Eur Urol. 2016;70:323–31.

    Article  PubMed  Google Scholar 

  52. Moon YW, Hajjar J, Hwu P, Naing A. Targeting the indoleamine 2,3-dioxygenase pathway in cancer. J Immunother Cancer. 2015;3:51.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Munn DH, Mellor AL. Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol. 2013;34:137–43.

    Article  CAS  PubMed  Google Scholar 

  54. Wiemer AJ, Hegde S, Gumperz JE, Huttenlocher A. A live imaging cell motility screen identifies prostaglandin E2 as a T cell stop signal antagonist. J Immunol. 2011;187:3663–70.

    Article  CAS  PubMed  Google Scholar 

  55. Mittal M, Tiruppathi C, Nepal S, Zhao YY, Grzych D, Soni D, Prockop DJ, Malik AB. TNFalpha-stimulated gene-6 (TSG6) activates macrophage phenotype transition to prevent inflammatory lung injury. Proc Natl Acad Sci U S A. 2016;113:E8151–e8158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Nasef A, Mathieu N, Chapel A, Frick J, Francois S, Mazurier C, Boutarfa A, Bouchet S, Gorin NC, Thierry D, et al. Immunosuppressive effects of mesenchymal stem cells: involvement of HLA-G. Transplantation. 2007;84:231–7.

    Article  CAS  PubMed  Google Scholar 

  57. Carosella ED. The tolerogenic molecule HLA-G. Immunol Lett. 2011;138:22–4.

    Article  CAS  PubMed  Google Scholar 

  58. Deschaseaux F, Delgado D, Pistoia V, Giuliani M, Morandi F, Durrbach A. HLA-G in organ transplantation: towards clinical applications. Cell Mol Life Sci. 2011;68:397–404.

    Article  CAS  PubMed  Google Scholar 

  59. Witwer KW, Buzas EI, Bemis LT, Bora A, Lasser C, Lotvall J, Nolte-‘t Hoen EN, Piper MG, Sivaraman S, Skog J, et al. Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J Extracell Vesicles. 2013;2 https://doi.org/10.3402/jev.v2i0.20360. eCollection 2013.

    Article  CAS  Google Scholar 

  60. Ha D, Yang N, Nadithe V. Exosomes as therapeutic drug carriers and delivery vehicles across biological membranes: current perspectives and future challenges. Acta Pharm Sin B. 2016;6:287–96.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Thery C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol. 2009;9:581–93.

    Article  CAS  PubMed  Google Scholar 

  62. Yokoi A, Yoshioka Y, Ochiya T. Towards the realization of clinical extracellular vesicle diagnostics: challenges and opportunities. Expert Rev Mol Diagn. 2015;15:1555–66.

    Article  CAS  PubMed  Google Scholar 

  63. Keerthikumar S, Chisanga D, Ariyaratne D, Al Saffar H, Anand S, Zhao K, Samuel M, Pathan M, Jois M, Chilamkurti N, et al. ExoCarta: a web-based compendium of exosomal cargo. J Mol Biol. 2016;428:688–92.

    Article  CAS  PubMed  Google Scholar 

  64. Vlassov AV, Magdaleno S, Setterquist R, Conrad R. Exosomes: current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials. Biochim Biophys Acta. 2012;1820:940–8.

    Article  CAS  PubMed  Google Scholar 

  65. Di Ianni M, Del Papa B, De Ioanni M, Moretti L, Bonifacio E, Cecchini D, Sportoletti P, Falzetti F, Tabilio A. Mesenchymal cells recruit and regulate T regulatory cells. Exp Hematol. 2008 Mar;36(3):309–18. https://doi.org/10.1016/j.exphem.2007.11.007.

    Article  CAS  Google Scholar 

  66. Svobodova E, Krulova M, Zajicova A, Pokorna K, Prochazkova J, Trosan P, Holan V. The role of mouse mesenchymal stem cells in differentiation of naive T-cells into anti-inflammatory regulatory T-cell or proinflammatory helper T-cell 17 population. Stem Cells Dev. 2012;21:901–10.

    Article  CAS  PubMed  Google Scholar 

  67. Raker VK, Domogalla MP, Steinbrink K. Tolerogenic dendritic cells for regulatory T cell induction in man. Front Immunol. 2015;6:569.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Najar M, Raicevic G, Fayyad-Kazan H, Bron D, Toungouz M, Lagneaux L. Mesenchymal stromal cells and immunomodulation: A gathering of regulatory immune cells. Cytotherapy. 2016;18:160–71.

    Article  CAS  PubMed  Google Scholar 

  69. Vizoso FJ, Eiro N, Cid S, Schneider J, Perez-Fernandez R. Mesenchymal stem cell secretome: toward cell-free therapeutic strategies in regenerative medicine. Int J Mol Sci. 2017 Aug 25;18(9). pii: E1852. https://doi.org/10.3390/ijms18091852. Review. PubMed PMID: 28841158; PubMed Central PMCID: PMC5618501.

    Article  PubMed Central  CAS  Google Scholar 

  70. Bermudez MA, Sendon-Lago J, Eiro N, Trevino M, Gonzalez F, Yebra-Pimentel E, Giraldez MJ, Macia M, Lamelas ML, Saa J, et al. Corneal epithelial wound healing and bactericidal effect of conditioned medium from human uterine cervical stem cells. Invest Ophthalmol Vis Sci. 2015;56:983–92.

    Article  CAS  PubMed  Google Scholar 

  71. Bermudez MA, Sendon-Lago J, Seoane S, Eiro N, Gonzalez F, Saa J, Vizoso F, Perez-Fernandez R. Anti-inflammatory effect of conditioned medium from human uterine cervical stem cells in uveitis. Exp Eye Res. 2016;149:84–92.

    Article  CAS  PubMed  Google Scholar 

  72. Eiro N, Sendon-Lago J, Seoane S, Bermudez MA, Lamelas ML, Garcia-Caballero T, Schneider J, Perez-Fernandez R, Vizoso FJ. Potential therapeutic effect of the secretome from human uterine cervical stem cells against both cancer and stromal cells compared with adipose tissue stem cells. Oncotarget. 2014;5:10692–708.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Ferguson SW, Wang J, Lee CJ, Liu M, Neelamegham S, Canty JM, Nguyen J. The microRNA regulatory landscape of MSC-derived exosomes: a systems view. Sci Rep. 2018;8:1419.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Durinck S, Spellman PT, Birney E, Huber W. Mapping identifiers for the integration of genomic datasets with the R/Bioconductor package biomaRt. Nat Protoc. 2009;4:1184–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Carlson M. KEGG.db: a set of annotation maps for KEGG. R package version 3.2.3. 2016.

    Google Scholar 

  76. Tenenbaum D. KEGGREST: client-side REST access to KEGG. R package version 1.16.1. 2017.

    Google Scholar 

  77. Bluthgen N, Brand K, Cajavec B, Swat M, Herzel H, Beule D. Biological profiling of gene groups utilizing Gene Ontology. Genome Inform. 2005;16:106–15.

    PubMed  Google Scholar 

  78. Alexa A, Rahnenfuhrer J. topGO: enrichment analysis for gene ontology. R package version 2.28.0. 2016.

    Google Scholar 

  79. Perrier S, Darakhshan F, Hajduch E. IL-1 receptor antagonist in metabolic diseases: Dr Jekyll or Mr Hyde? FEBS Lett. 2006;580:6289–94.

    Article  CAS  PubMed  Google Scholar 

  80. Bouffi C, Bony C, Courties G, Jorgensen C, Noel D. IL-6-dependent PGE2 secretion by mesenchymal stem cells inhibits local inflammation in experimental arthritis. PLoS One. 2010;5:e14247.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Luz-Crawford P, Djouad F, Toupet K, Bony C, Franquesa M, Hoogduijn MJ, Jorgensen C, Noel D. Mesenchymal stem cell-derived interleukin 1 receptor antagonist promotes macrophage polarization and inhibits B cell differentiation. Stem Cells. 2016;34:483–92.

    Article  CAS  PubMed  Google Scholar 

  82. Wang K, Jiang Z, Webster KA, Chen J, Hu H, Zhou Y, Zhao J, Wang L, Wang Y, Zhong Z, et al. Enhanced cardioprotection by human endometrium mesenchymal stem cells driven by exosomal MicroRNA-21. Stem Cells Transl Med. 2017;6:209–22.

    Article  CAS  PubMed  Google Scholar 

  83. Tokar T, Pastrello C, Rossos AEM, Abovsky M, Hauschild AC, Tsay M, Lu R, Jurisica I. mirDIP 4.1-integrative database of human microRNA target predictions. Nucleic Acids Res. 2018;46:D360–70.

    Article  CAS  PubMed  Google Scholar 

  84. Dong C, Davis RJ, Flavell RA. MAP kinases in the immune response. Annu Rev Immunol. 2002;20:55–72.

    Article  CAS  PubMed  Google Scholar 

  85. Fan W, Morinaga H, Kim JJ, Bae E, Spann NJ, Heinz S, Glass CK, Olefsky JM. FoxO1 regulates Tlr4 inflammatory pathway signalling in macrophages. EMBO J. 2010;29:4223–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Cai Y, Sukhova GK, Wong HK, Xu A, Tergaonkar V, Vanhoutte PM, Tang EH. Rap1 induces cytokine production in pro-inflammatory macrophages through NFkappaB signaling and is highly expressed in human atherosclerotic lesions. Cell Cycle. 2015;14:3580–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Weichhart T, Saemann MD. The PI3K/Akt/mTOR pathway in innate immune cells: emerging therapeutic applications. Ann Rheum Dis. 2008;67(Suppl 3):iii70–4.

    Article  CAS  PubMed  Google Scholar 

  88. Noerholm M, Balaj L, Limperg T, Salehi A, Zhu LD, Hochberg FH, Breakefield XO, Carter BS, Skog J. RNA expression patterns in serum microvesicles from patients with glioblastoma multiforme and controls. BMC Cancer. 2012;12:22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Katakowski M, Buller B, Wang X, Rogers T, Chopp M. Functional microRNA is transferred between glioma cells. Cancer Res. 2010;70:8259–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Katakowski M, Buller B, Zheng X, Lu Y, Rogers T, Osobamiro O, Shu W, Jiang F, Chopp M. Exosomes from marrow stromal cells expressing miR-146b inhibit glioma growth. Cancer Lett. 2013;335:201–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Mizrak A, Bolukbasi MF, Ozdener GB, Brenner GJ, Madlener S, Erkan EP, Strobel T, Breakefield XO, Saydam O. Genetically engineered microvesicles carrying suicide mRNA/protein inhibit schwannoma tumor growth. Mol Ther. 2013;21:101–8.

    Article  CAS  PubMed  Google Scholar 

  92. Chuang TJ, Lin KC, Chio CC, Wang CC, Chang CP, Kuo JR. Effects of secretome obtained from normoxia-preconditioned human mesenchymal stem cells in traumatic brain injury rats. J Trauma Acute Care Surg. 2012;73:1161–7.

    Article  CAS  PubMed  Google Scholar 

  93. Kim DK, Nishida H, An SY, Shetty AK, Bartosh TJ, Prockop DJ. Chromatographically isolated CD63+CD81+ extracellular vesicles from mesenchymal stromal cells rescue cognitive impairments after TBI. Proc Natl Acad Sci U S A. 2016;113:170–5.

    Article  CAS  PubMed  Google Scholar 

  94. Zhang Y, Chopp M, Meng Y, Katakowski M, Xin H, Mahmood A, Xiong Y. Effect of exosomes derived from multipluripotent mesenchymal stromal cells on functional recovery and neurovascular plasticity in rats after traumatic brain injury. J Neurosurg. 2015;122:856–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Ophelders DR, Wolfs TG, Jellema RK, Zwanenburg A, Andriessen P, Delhaas T, Ludwig AK, Radtke S, Peters V, Janssen L, et al. Mesenchymal stromal cell-derived extracellular vesicles protect the fetal brain after hypoxia-ischemia. Stem Cells Transl Med. 2016;5:754–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Drommelschmidt K, Serdar M, Bendix I, Herz J, Bertling F, Prager S, Keller M, Ludwig AK, Duhan V, Radtke S, et al. Mesenchymal stem cell-derived extracellular vesicles ameliorate inflammation-induced preterm brain injury. Brain Behav Immun. 2017;60:220–32.

    Article  CAS  PubMed  Google Scholar 

  97. Ruppert KA, Nguyen TT, Prabhakara KS, Toledano Furman NE, Srivastava AK, Harting MT, Cox CS Jr, Olson SD. Human mesenchymal stromal cell-derived extracellular vesicles modify microglial response and improve clinical outcomes in experimental spinal cord injury. Sci Rep. 2018;8:480.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Otero-Ortega L, Laso-Garcia F, Gomez-de Frutos MD, Rodriguez-Frutos B, Pascual-Guerra J, Fuentes B, Diez-Tejedor E, Gutierrez-Fernandez M. White matter repair after extracellular vesicles administration in an experimental animal model of subcortical stroke. Sci Rep. 2017;7:44433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Raisi A, Azizi S, Delirezh N, Heshmatian B, Farshid AA, Amini K. The mesenchymal stem cell-derived microvesicles enhance sciatic nerve regeneration in rat: a novel approach in peripheral nerve cell therapy. J Trauma Acute Care Surg. 2014;76:991–7.

    Article  PubMed  Google Scholar 

  100. Doeppner TR, Herz J, Gorgens A, Schlechter J, Ludwig AK, Radtke S, de Miroschedji K, Horn PA, Giebel B, Hermann DM. Extracellular vesicles improve post-stroke neuroregeneration and prevent postischemic immunosuppression. Stem Cells Transl Med. 2015;4:1131–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Hu B, Chen S, Zou M, He Z, Shao S, Liu B. Effect of extracellular vesicles on neural functional recovery and immunologic suppression after rat cerebral apoplexy. Cell Physiol Biochem. 2016;40:155–62.

    Article  CAS  PubMed  Google Scholar 

  102. Xin H, Li Y, Cui Y, Yang JJ, Zhang ZG, Chopp M. Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J Cereb Blood Flow Metab. 2013;33:1711–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Xin H, Li Y, Buller B, Katakowski M, Zhang Y, Wang X, Shang X, Zhang ZG, Chopp M. Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells. 2012;30:1556–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Xin H, Li Y, Liu Z, Wang X, Shang X, Cui Y, Zhang ZG, Chopp M. MiR-133b promotes neural plasticity and functional recovery after treatment of stroke with multipotent mesenchymal stromal cells in rats via transfer of exosome-enriched extracellular particles. Stem cells (Dayton, Ohio). 2013;31:2737–46.

    Article  CAS  Google Scholar 

  105. Lee JY, Kim E, Choi SM, Kim DW, Kim KP, Lee I, Kim HS. Microvesicles from brain-extract-treated mesenchymal stem cells improve neurological functions in a rat model of ischemic stroke. Sci Rep. 2016;6:33038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Xin H, Wang F, Li Y, Lu QE, Cheung WL, Zhang Y, Zhang ZG, Chopp M. Secondary release of exosomes from astrocytes contributes to the increase in neural plasticity and improvement of functional recovery after stroke in rats treated with exosomes harvested from microrNA 133b-overexpressing multipotent mesenchymal stromal cells. Cell Transplant. 2017;26:243–57.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Bruno S, Grange C, Collino F, Deregibus MC, Cantaluppi V, Biancone L, Tetta C, Camussi G. Microvesicles derived from mesenchymal stem cells enhance survival in a lethal model of acute kidney injury. PLoS One. 2012;7:e33115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Reis LA, Borges FT, Simoes MJ, Borges AA, Sinigaglia-Coimbra R, Schor N. Bone marrow-derived mesenchymal stem cells repaired but did not prevent gentamicin-induced acute kidney injury through paracrine effects in rats. PLoS One. 2012;7:e44092.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. He J, Wang Y, Sun S, Yu M, Wang C, Pei X, Zhu B, Wu J, Zhao W. Bone marrow stem cells-derived microvesicles protect against renal injury in the mouse remnant kidney model. Nephrology (Carlton). 2012;17:493–500.

    Article  Google Scholar 

  110. Lai RC, Arslan F, Lee MM, Sze NS, Choo A, Chen TS, Salto-Tellez M, Timmers L, Lee CN, El Oakley RM, et al. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res. 2010;4:214–22.

    Article  CAS  PubMed  Google Scholar 

  111. Zhao Y, Sun X, Cao W, Ma J, Sun L, Qian H, Zhu W, Xu W. Exosomes derived from human umbilical cord mesenchymal stem cells relieve acute myocardial ischemic injury. Stem Cells Int. 2015;2015:761643.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Teng X, Chen L, Chen W, Yang J, Yang Z, Shen Z. Mesenchymal stem cell-derived exosomes improve the microenvironment of infarcted myocardium contributing to angiogenesis and anti-inflammation. Cell Physiol Biochem. 2015;37:2415–24.

    Article  CAS  PubMed  Google Scholar 

  113. Wang SS, Jia J, Wang Z. Mesenchymal stem cell-derived extracellular vesicles suppresses iNOS expression and ameliorates neural impairment in Alzheimer’s disease mice. J Alzheimers Dis. 2018;61:1005–13.

    Article  CAS  PubMed  Google Scholar 

  114. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol. 2011;29:341–5.

    Article  CAS  PubMed  Google Scholar 

  115. Morel L, Regan M, Higashimori H, Ng SK, Esau C, Vidensky S, Rothstein J, Yang Y. Neuronal exosomal miRNA-dependent translational regulation of astroglial glutamate transporter GLT1. J Biol Chem. 2013;288:7105–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Sun D, Zhuang X, Xiang X, Liu Y, Zhang S, Liu C, Barnes S, Grizzle W, Miller D, Zhang HG. A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol Ther. 2010;18:1606–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Zhuang X, Xiang X, Grizzle W, Sun D, Zhang S, Axtell RC, Ju S, Mu J, Zhang L, Steinman L, et al. Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. Mol Ther. 2011;19:1769–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Kordelas L, Rebmann V, Ludwig AK, Radtke S, Ruesing J, Doeppner TR, Epple M, Horn PA, Beelen DW, Giebel B. MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease. Leukemia. 2014;28:970–3.

    Article  CAS  PubMed  Google Scholar 

  119. Nassar W, El-Ansary M, Sabry D, Mostafa MA, Fayad T, Kotb E, Temraz M, Saad AN, Essa W, Adel H. Umbilical cord mesenchymal stem cells derived extracellular vesicles can safely ameliorate the progression of chronic kidney diseases. Biomater Res. 2016;20:21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Verderio C, Muzio L, Turola E, Bergami A, Novellino L, Ruffini F, Riganti L, Corradini I, Francolini M, Garzetti L, et al. Myeloid microvesicles are a marker and therapeutic target for neuroinflammation. Ann Neurol. 2012;72:610–24.

    Article  CAS  PubMed  Google Scholar 

  121. Coleman BM, Hanssen E, Lawson VA, Hill AF. Prion-infected cells regulate the release of exosomes with distinct ultrastructural features. FASEB J. 2012;26:4160–73.

    Article  CAS  PubMed  Google Scholar 

  122. Yang Y, Keene CD, Peskind ER, Galasko DR, Hu SC, Cudaback E, Wilson AM, Li G, Yu CE, Montine KS, et al. Cerebrospinal fluid particles in Alzheimer disease and parkinson disease. J Neuropathol Exp Neurol. 2015;74:672–87.

    Article  CAS  PubMed  Google Scholar 

  123. Saman S, Kim W, Raya M, Visnick Y, Miro S, Saman S, Jackson B, McKee AC, Alvarez VE, Lee NC, et al. Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease. J Biol Chem. 2012;287:3842–9.

    Article  CAS  PubMed  Google Scholar 

  124. Kawikova I, Askenase PW. Diagnostic and therapeutic potentials of exosomes in CNS diseases. Brain Res. 2015;1617:63–71.

    Article  CAS  PubMed  Google Scholar 

  125. Redzic JS, Ung TH, Graner MW. Glioblastoma extracellular vesicles: reservoirs of potential biomarkers. Pharmgenomics Pers Med. 2014;7:65–77.

    PubMed  PubMed Central  Google Scholar 

  126. Shao H, Chung J, Balaj L, Charest A, Bigner DD, Carter BS, Hochberg FH, Breakefield XO, Weissleder R, Lee H. Protein typing of circulating microvesicles allows real-time monitoring of glioblastoma therapy. Nat Med. 2012;18:1835–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Tübingen, Germany

    Sabine Conrad

  2. Neurochirurgische Klinik, Universitätsklinikum Heidelberg, Heidelberg, Germany

    Alexander Younsi

  3. MicroDiscovery GmbH, Berlin, Germany

    Chris Bauer

  4. Stiftung Tierärztliche Hochschule Hannover, Klinik für Pferde, Hannover, Germany

    Florian Geburek

  5. Institute for Anatomy and Cell Biology, University of Heidelberg, Heidelberg, Germany

    Thomas Skutella

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  1. Sabine Conrad
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  2. Alexander Younsi
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  3. Chris Bauer
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  4. Florian Geburek
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  5. Thomas Skutella
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Correspondence to Thomas Skutella .

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  1. Laboratory of Stem Cell Research and Application, University of Science, VNU-HCM, Stem Cell Institute, University of Science, VNU-HCM, Ho Chi Minh City, Vietnam

    Phuc Van Pham

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Conrad, S., Younsi, A., Bauer, C., Geburek, F., Skutella, T. (2019). Mesenchymal Stem Cell-Derived Extracellular Vesicles as Mediators of Anti-inflammatory Effects. In: Pham, P. (eds) Stem Cell Transplantation for Autoimmune Diseases and Inflammation. Stem Cells in Clinical Applications. Springer, Cham. https://doi.org/10.1007/978-3-030-23421-8_6

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