Download PDF
Transfusionsmedizin 2015; 5(03): 131-137
DOI: 10.1055/s-0041-102981
Übersicht
Georg Thieme Verlag KG Stuttgart · New York

Therapeutisches Potenzial von extrazellulären Vesikeln aus mesenchymalen Stamm- bzw. Stromazellen

The Therapeutic Potential of Mesenchymal Stem/Stromal Cell-Derived Extracellular Vesicles
V. Börger
1   Institut für Transfusionsmedizin, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen
,
A. Görgens
1   Institut für Transfusionsmedizin, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen
,
E. Rohde
2   Universitätsklinik für Blutgruppenserologie und Transfusionsmedizin, Universitätsklinikum der Paracelsus Medizinischen Privatuniversität, Salzburg, Österreich
3   Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS) der Paracelsus Medizinischen Privatuniversität, Salzburg, Österreich
,
B. Giebel
1   Institut für Transfusionsmedizin, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen
› Author Affiliations
Further Information

Publication History

Publication Date:
21 August 2015 (online)

Also available at
    Permissions and Reprints

Zusammenfassung

Seit der Beschreibung, dass sich mesenchymale Stamm- bzw. Stromazellen (MSC) des Menschen in verschiedene Zelltypen differenzieren können bzw. immunmodulierende Effekte vermitteln, sind sie in mehr als 500 beim NIH registrierten Studien zur Behandlung verschiedenster Erkrankungen eingesetzt worden. Allem Anschein nach erzielen sie ihre therapeutische Wirkung jedoch nicht wie lange angenommen durch die Integration in betroffene Gewebe, sondern durch die Freisetzung parakriner Faktoren, insbesondere durch extrazelluläre Vesikel (EV) wie Exosomen und Mikrovesikel. EV stellen extrazelluläre Organellen dar, die sehr spezifisch interzelluläre Kommunikation auch über größere Distanzen hinweg vermitteln, von verschiedensten Zellen abgegeben werden und in sämtlichen Körperflüssigkeiten nachweisbar sind. Sie besitzen einen heterogenen Gehalt an Lipiden, Proteinen und nicht kodierenden RNA-Molekülen. Als nicht selbstreplizierende Einheiten, die sich steril filtrieren lassen, weisen sie für therapeutische Anwendungen prinzipiell nennenswerte Vorteile gegenüber Zellen auf. Neben verschiedenen präklinischen Modellen wurden aus MSC-Kulturüberständen gewonnene EV bereits in einem ersten individuellen Heilversuch zur Behandlung einer steroidrefraktären Graft-versus-Host-Disease (GvHD)-Patientin eingesetzt. Sowohl in den bislang durchgeführten präklinischen Versuchen als auch in der behandelten GvHD-Patientin ließen sich nach MSC-EV-Applikation vielversprechende therapeutische Effekte beobachten, ohne erkennbare Nebenwirkungen hervorzurufen. MSC-EV erfüllen somit allem Anschein nach wichtige Voraussetzungen, um als neues Behandlungsmittel in der Immuntherapie und der regenerativen Medizin in Betracht gezogen zu werden.

Summary

Following the discoveries that human mesenchymal stem or stromal cells (MSC) contain multilineage differentiation potentials and can modulate immune responses, more than 500 clinical trials have been registered at the NIH to test for the therapeutic potentials of MSC in various diseases. In contrast to the initial hypothesis that MSCs mediate their therapeutic effects by intercalating into affected tissues, novel results suggest that they exert their therapeutic impacts in a paracrine rather than in a cellular manner. To this end, extracellular vesicles (EV), like exosomes and microvesicles, have been found to mediate at least a proportion of the MSCsʼ therapeutic functions. EV are considered to be extracellular organelles which mediate intercellular communication processes very specifically, also between cells at distance sites. EV are formed by almost all cell types and have been detected in all body liquids. Depending on their origin, they contain specific mixtures of lipids, proteins and non-coding RNAs. As non-self-replicating units which can be sterilized by filtration, EVs provide a number of advantages over cellular therapeutics. In addition to a variety of different preclinical models, EVs harvested from MSC-conditioned media have been administered in an individual treatment attempt to a steroid-refractory Graft-versus-Host Disease (GvHD) patient. Positive therapeutic effects, but no side effects were observed in all preclinical models tested so far as well as in the GvHD patient. Thus, MSC-EVs appear to be a promising new tool in immune therapy and in regenerative medicine.

Schlüsselwörter

MSC - Stammzelltherapie - extrazelluläre Vesikel - Exosomen - Immunmodulation - zellfreie Therapie

Key words

MSC - stem cell therapy - extracellular vesicles - exosomes - immunomodulation - cell-free therapy
 

  • Literatur

  • 1 Friedenstein AJ, Deriglasova UF, Kulagina NN et al. Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method. Exp Hematol 1974; 2: 83-92
    PubMedGoogle Scholar
  • 2 Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation 1968; 6: 230-247
    CrossrefPubMedGoogle Scholar
  • 3 Pittenger MF, Mackay AM, Beck SC et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284: 143-147
    CrossrefPubMedGoogle Scholar
  • 4 Mezey E, Chandross KJ, Harta G et al. Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science 2000; 290: 1779-1782
    CrossrefPubMedGoogle Scholar
  • 5 Bjornson CR, Rietze RL, Reynolds BA et al. Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo. Science 1999; 283: 534-537
    CrossrefPubMedGoogle Scholar
  • 6 Wei G, Schubiger G, Harder F et al. Stem cell plasticity in mammals and transdetermination in Drosophila: common themes?. Stem Cells 2000; 18: 409-414
    CrossrefPubMedGoogle Scholar
  • 7 Jiang Y, Jahagirdar BN, Reinhardt RL et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002; 418: 41-49
    CrossrefPubMedGoogle Scholar
  • 8 Wei X, Yang X, Han ZP et al. Mesenchymal stem cells: a new trend for cell therapy. Acta Pharmacol Sin 2013; 34: 747-754
    CrossrefPubMedGoogle Scholar
  • 9 Prockop DJ, Kota DJ, Bazhanov N et al. Evolving paradigms for repair of tissues by adult stem/progenitor cells (MSCs). J Cell Mol Med 2010; 14: 2190-2199
    CrossrefPubMedGoogle Scholar
  • 10 Wang Y, Chen X, Cao W et al. Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. Nat Immunol 2014; 15: 1009-1016
    CrossrefPubMedGoogle Scholar
  • 11 Di Nicola M, Carlo-Stella C, Magni M et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002; 99: 3838-3843
    CrossrefPubMedGoogle Scholar
  • 12 Beyth S, Borovsky Z, Mevorach D et al. Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood 2005; 105: 2214-2219
    CrossrefPubMedGoogle Scholar
  • 13 Corcione A, Benvenuto F, Ferretti E et al. Human mesenchymal stem cells modulate B-cell functions. Blood 2006; 107: 367-372
    CrossrefPubMedGoogle Scholar
  • 14 Casiraghi F, Azzollini N, Cassis P et al. Pretransplant infusion of mesenchymal stem cells prolongs the survival of a semiallogeneic heart transplant through the generation of regulatory T cells. J Immunol 2008; 181: 3933-3946
    CrossrefPubMedGoogle Scholar
  • 15 Di Ianni M, Del Papa B, De Ioanni M et al. Mesenchymal cells recruit and regulate T regulatory cells. Exp Hematol 2008; 36: 309-318
    CrossrefPubMedGoogle Scholar
  • 16 Bartholomew A, Sturgeon C, Siatskas M et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol 2002; 30: 42-48
    CrossrefPubMedGoogle Scholar
  • 17 Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005; 105: 1815-1822
    CrossrefPubMedGoogle Scholar
  • 18 Jiang XX, Zhang Y, Liu B et al. Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood 2005; 105: 4120-4126
    CrossrefPubMedGoogle Scholar
  • 19 Selmani Z, Naji A, Zidi I et al. Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highFOXP3+ regulatory T cells. Stem Cells 2008; 26: 212-222
    CrossrefPubMedGoogle Scholar
  • 20 De Miguel MP, Fuentes-Julián S, Blázquez-Martínez A et al. Immunosuppressive properties of mesenchymal stem cells: advances and applications. Curr Mol Med 2012; 12: 574-591
    CrossrefPubMedGoogle Scholar
  • 21 Abumaree M, Al Jumah M, Pace RA et al. Immunosuppressive properties of mesenchymal stem cells. Stem Cell Rev 2012; 8: 375-392
    CrossrefPubMedGoogle Scholar
  • 22 Ghannam S, Bouffi C, Djouad F et al. Immunosuppression by mesenchymal stem cells: mechanisms and clinical applications. Stem Cell Res Ther 2010; 1: 2
    CrossrefPubMedGoogle Scholar
  • 23 Lee RH, Pulin AA, Seo MJ et al. Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell 2009; 5: 54-63
    CrossrefPubMedGoogle Scholar
  • 24 Zhu XY, Lerman A, Lerman LO. Concise review: mesenchymal stem cell treatment for ischemic kidney disease. Stem Cells 2013; 31: 1731-1736
    CrossrefPubMedGoogle Scholar
  • 25 Gutiérrez-Fernández M, Otero-Ortega L, Ramos-Cejudo J et al. Adipose tissue-derived mesenchymal stem cells as a strategy to improve recovery after stroke. Expert Opin Biol Ther 2015; 15: 873-881
    CrossrefPubMedGoogle Scholar
  • 26 Le Blanc K, Rasmusson I, Sundberg B et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 2004; 363: 1439-1441
    CrossrefPubMedGoogle Scholar
  • 27 Zuk PA, Zhu M, Mizuno H et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 2001; 7: 211-228
    CrossrefPubMedGoogle Scholar
  • 28 Erices A, Conget P, Minguell JJ. Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol 2000; 109: 235-242
    CrossrefPubMedGoogle Scholar
  • 29 Mareschi K, Biasin E, Piacibello W et al. Isolation of human mesenchymal stem cells: bone marrow versus umbilical cord blood. Haematologica 2001; 86: 1099-1100
    PubMedGoogle Scholar
  • 30 Bianco P, Robey PG, Simmons PJ. Mesenchymal stem cells: revisiting history, concepts, and assays. Cell Stem Cell 2008; 2: 313-319
    CrossrefPubMedGoogle Scholar
  • 31 Wuchter P, Bieback K, Schrezenmeier H et al. Standardization of Good Manufacturing Practice-compliant production of bone marrow-derived human mesenchymal stromal cells for immunotherapeutic applications. Cytotherapy 2015; 17: 128-139
    CrossrefPubMedGoogle Scholar
  • 32 Dominici M, Le Blanc K, Mueller I et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8: 315-317
    CrossrefPubMedGoogle Scholar
  • 33 Bühring HJ, Treml S, Cerabona F et al. Phenotypic characterization of distinct human bone marrow-derived MSC subsets. Ann N Y Acad Sci 2009; 1176: 124-134
    CrossrefPubMedGoogle Scholar
  • 34 Vogel W, Grünebach F, Messam CA et al. Heterogeneity among human bone marrow-derived mesenchymal stem cells and neural progenitor cells. Haematologica 2003; 88: 126-133
    PubMedGoogle Scholar
  • 35 Kaltz N, Ringe J, Holzwarth C et al. Novel markers of mesenchymal stem cells defined by genome-wide gene expression analysis of stromal cells from different sources. Exp Cell Res 2010; 316: 2609-2617
    CrossrefPubMedGoogle Scholar
  • 36 Baron F, Storb R. Mensenchymal stromal cells: a new tool against graft-versus-host disease?. Biol Blood Marrow Transplant 2012; 18: 822-840
    CrossrefPubMedGoogle Scholar
  • 37 Galipeau J. The mesenchymal stromal cells dilemma – does a negative phase III trial of random donor mesenchymal stromal cells in steroid-resistant graft-versus-host disease represent a death knell or a bump in the road?. Cytotherapy 2013; 15: 2-8
    CrossrefPubMedGoogle Scholar
  • 38 Zhao S, Wehner R, Bornhäuser M et al. Immunomodulatory properties of mesenchymal stromal cells and their therapeutic consequences for immune-mediated disorders. Stem Cells Dev 2010; 19: 607-614
    CrossrefPubMedGoogle Scholar
  • 39 Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood 2007; 110: 3499-3506
    CrossrefPubMedGoogle Scholar
  • 40 Otto Beitnes J, Oie E, Shahdadfar A et al. Intramyocardial injections of human mesenchymal stem cells following acute myocardial infarction modulate scar formation and improve left ventricular function. Cell Transplant 2012; 21: 1697-1709
    CrossrefPubMedGoogle Scholar
  • 41 Waszak P, Alphonse R, Vadivel A et al. Preconditioning enhances the paracrine effect of mesenchymal stem cells in preventing oxygen-induced neonatal lung injury in rats. Stem Cells Dev 2012; 21: 2789-2797
    CrossrefPubMedGoogle Scholar
  • 42 Gao J, Dennis JE, Muzic RF et al. The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion. Cells Tissues Organs 2001; 169: 12-20
    CrossrefPubMedGoogle Scholar
  • 43 Schrepfer S, Deuse T, Reichenspurner H et al. Stem cell transplantation: the lung barrier. Transplant Proc 2007; 39: 573-576
    CrossrefPubMedGoogle Scholar
  • 44 Gnecchi M, He H, Noiseux N et al. Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J 2006; 20: 661-669
    CrossrefPubMedGoogle Scholar
  • 45 Gnecchi M, He H, Liang OD et al. Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med 2005; 11: 367-368
    CrossrefPubMedGoogle Scholar
  • 46 Timmers L, Lim SK, Arslan F et al. Reduction of myocardial infarct size by human mesenchymal stem cell conditioned medium. Stem Cell Res 2007; 1: 129-137
    PubMedGoogle Scholar
  • 47 Timmers L, Lim SK, Hoefer IE et al. Human mesenchymal stem cell-conditioned medium improves cardiac function following myocardial infarction. Stem Cell Res 2011; 6: 206-214
    CrossrefPubMedGoogle Scholar
  • 48 Ionescu L, Byrne RN, van Haaften T et al. Stem cell conditioned medium improves acute lung injury in mice: in vivo evidence for stem cell paracrine action. Am J Physiol Lung Cell Mol Physiol 2012; 303: L967-L977
    CrossrefPubMedGoogle Scholar
  • 49 Fouraschen SM, Pan Q, de Ruiter PE et al. Secreted factors of human liver-derived mesenchymal stem cells promote liver regeneration early after partial hepatectomy. Stem Cells Dev 2012; 21: 2410-2419
    CrossrefPubMedGoogle Scholar
  • 50 Bruno S, Grange C, Deregibus MC et al. Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol 2009; 20: 1053-1067
    CrossrefPubMedGoogle Scholar
  • 51 Crawford N. The presence of contractile proteins in platelet microparticles isolated from human and animal platelet-free plasma. Br J Haematol 1971; 21: 53-69
    CrossrefPubMedGoogle Scholar
  • 52 Stegmayr B, Ronquist G. Promotive effect on human sperm progressive motility by prostasomes. Urol Res 1982; 10: 253-257
    PubMedGoogle Scholar
  • 53 Anderson HC. Vesicles associated with calcification in the matrix of epiphyseal cartilage. J Cell Biol 1969; 41: 59-72
    CrossrefPubMedGoogle Scholar
  • 54 Valadi H, Ekström K, Bossios A et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 2007; 9: 654-659
    CrossrefPubMedGoogle Scholar
  • 55 Deregibus MC, Cantaluppi V, Calogero R et al. Endothelial progenitor cell derived microvesicles activate an angiogenic program in endothelial cells by a horizontal transfer of mRNA. Blood 2007; 110: 2440-2448
    CrossrefPubMedGoogle Scholar
  • 56 Ratajczak J, Miekus K, Kucia M et al. Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia 2006; 20: 847-856
    CrossrefPubMedGoogle Scholar
  • 57 Théry C, Amigorena S, Raposo G, Clayton A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol 2006; Chapter 3: Unit 3.22.
    PubMedGoogle Scholar
  • 58 György B, Szabó TG, Pásztói M et al. Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cell Mol Life Sci 2011; 68: 2667-2688
    CrossrefPubMedGoogle Scholar
  • 59 Pan BT, Teng K, Wu C et al. Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes. J Cell Biol 1985; 101: 942-948
    CrossrefPubMedGoogle Scholar
  • 60 Harding C, Heuser J, Stahl P. Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. J Cell Biol 1983; 97: 329-339
    CrossrefPubMedGoogle Scholar
  • 61 Johnstone RM, Adam M, Hammond JR et al. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem 1987; 262: 9412-9420
    PubMedGoogle Scholar
  • 62 Pan BT, Johnstone RM. Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell 1983; 33: 967-978
    CrossrefPubMedGoogle Scholar
  • 63 Sokolova V, Ludwig AK, Hornung S et al. Characterisation of exosomes derived from human cells by nanoparticle tracking analysis and scanning electron microscopy. Colloids Surf B Biointerfaces 2011; 87: 146-150
    CrossrefPubMedGoogle Scholar
  • 64 Dragovic RA, Gardiner C, Brooks AS et al. Sizing and phenotyping of cellulars vesicles using Nanoparticle Tracking Analysis. Nanomedicine 2011; 7: 780-788
    CrossrefPubMedGoogle Scholar
  • 65 Ludwig AK, Giebel B. Exosomes: small vesicles participating in intercellular communication. Int J Biochem Cell Biol 2012; 44: 11-15
    CrossrefPubMedGoogle Scholar
  • 66 Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol 2013; 200: 373-383
    CrossrefPubMedGoogle Scholar
  • 67 Kim DK, Lee J, Kim SR et al. EVpedia: a community web portal for extracellular vesicles research. Bioinformatics 2015; 31: 933-939
    CrossrefPubMedGoogle Scholar
  • 68 Gould SJ, Raposo G. As we wait: coping with an imperfect nomenclature for extracellular vesicles. J Extracell Vesicles 2013; DOI: 10.3402/jev.v2i0.20389.
    PubMedGoogle Scholar
  • 69 Lai RC, Arslan F, Lee MM et al. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res 2010; 4: 214-222
    CrossrefPubMedGoogle Scholar
  • 70 Théry C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 2009; 9: 581-593
    CrossrefPubMedGoogle Scholar
  • 71 Simons M, Raposo G. Exosomes – vesicular carriers for intercellular communication. Curr Opin Cell Biol 2009; 21: 575-581
    CrossrefPubMedGoogle Scholar
  • 72 Mathivanan S, Ji H, Simpson RJ. Exosomes: extracellular organelles important in intercellular communication. J Proteomics 2010; 73: 1907-1920
    CrossrefPubMedGoogle Scholar
  • 73 Nazarenko I, Rana S, Baumann A et al. Cell surface tetraspanin Tspan8 contributes to molecular pathways of exosome-induced endothelial cell activation. Cancer Res 2010; 70: 1668-1678
    CrossrefPubMedGoogle Scholar
  • 74 Raposo G, Nijman HW, Stoorvogel W et al. B lymphocytes secrete antigen-presenting vesicles. J Exp Med 1996; 183: 1161-1172
    CrossrefPubMedGoogle Scholar
  • 75 Zitvogel L, Regnault A, Lozier A et al. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat Med 1998; 4: 594-600
    CrossrefPubMedGoogle Scholar
  • 76 Escudier B, Dorval T, Chaput N et al. Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of thefirst phase I clinical trial. J Transl Med 2005; 3: 10
    CrossrefPubMedGoogle Scholar
  • 77 Morse MA, Garst J, Osada T et al. A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer. J Transl Med 2005; 3: 9
    CrossrefPubMedGoogle Scholar
  • 78 Viaud S, Ploix S, Lapierre V et al. Updated technology to produce highly immunogenic dendritic cell-derived exosomes of clinical grade: a critical role of interferon-gamma. J Immunother 2011; 34: 65-75
    CrossrefPubMedGoogle Scholar
  • 79 Yáñez-Mó M, Siljander PR, Andreu Z et al. Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles 2015; 4: 27066
    PubMedGoogle Scholar
  • 80 Kordelas L, Rebmann V, Ludwig AK et al. MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease. Leukemia 2014; 28: 970-973
    PubMedGoogle Scholar
  • 81 Forslöw U, Blennow O, LeBlanc K et al. Treatment with mesenchymal stromal cells is a risk factor for pneumonia-related death after allogeneic hematopoietic stem cell transplantation. Eur J Haematol 2012; 89: 220-227
    CrossrefPubMedGoogle Scholar
  • 82 Del Fattore A, Luciano R, Pascucci L et al. Immunoregulatory effects of mesenchymal stem cell-derived extracellular vesicles on T lymphocytes. Cell Transplant 2015; DOI: 10.3727/096368915X687543.
    PubMedGoogle Scholar
  • 83 Favaro E, Carpanetto A, Lamorte S et al. Human mesenchymal stem cell-derived microvesicles modulate T cell response to islet antigen glutamic acid decarboxylase in patients with type 1 diabetes. Diabetologia 2014; 57: 1664-1673
    CrossrefPubMedGoogle Scholar
  • 84 Blazquez R, Sanchez-Margallo FM, de la Rosa O et al. Immunomodulatory potential of human adipose mesenchymal stem cells derived exosomes on in vitro stimulated T cells. Front Immunol 2014; 5: 556
    PubMedGoogle Scholar
  • 85 Zhang B, Yin Y, Lai RC et al. Mesenchymal stem cells secrete immunologically active exosomes. Stem Cells Dev 2014; 23: 1233-1244
    CrossrefPubMedGoogle Scholar
  • 86 Budoni M, Fierabracci A, Luciano R et al. The immunosuppressive effect of mesenchymal stromal cells on B lymphocytes is mediated by membrane vesicles. Cell Transplant 2013; 22: 369-379
    PubMedGoogle Scholar
  • 87 Zhang B, Wu X, Zhang X et al. Human umbilical cord mesenchymal stem cell exosomes enhance angiogenesis through the Wnt4/beta-catenin pathway. Stem Cells Transl Med 2015; 4: 513-522
    CrossrefPubMedGoogle Scholar
  • 88 Bian S, Zhang L, Duan L et al. Extracellular vesicles derived from human bone marrow mesenchymal stem cells promote angiogenesis in a rat myocardial infarction model. J Mol Med (Berl) 2014; 92: 387-397
    CrossrefPubMedGoogle Scholar
  • 89 Salomon C, Ryan J, Sobrevia L et al. Exosomal signaling during hypoxia mediates microvascular endothelial cell migration and vasculogenesis. PLoS One 2013; 8: e68451
    CrossrefPubMedGoogle Scholar
  • 90 Chen J, Liu Z, Hong MM et al. Proangiogenic compositions of microvesicles derived from human umbilical cord mesenchymal stem cells. PLoS One 2014; 9: e115316
    CrossrefPubMedGoogle Scholar
  • 91 Shabbir A, Cox A, Rodriguez-Menocal L et al. Mesenchymal stem cell exosomes induce the proliferation and migration of normal and chronic wound fibroblasts, and enhance angiogenesis in vitro. Stem Cells Dev 2015; 24: 1635-1647
    CrossrefPubMedGoogle Scholar
  • 92 Zhu W, Huang L, Li Y et al. Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth in vivo. Cancer Lett 2012; 315: 28-37
    CrossrefPubMedGoogle Scholar
  • 93 Roccaro AM, Sacco A, Maiso P et al. BM mesenchymal stromal cell-derived exosomes facilitate multiple myeloma progression. J Clin Invest 2013; 123: 1542-1555
    CrossrefPubMedGoogle Scholar
  • 94 Bruno S, Collino F, Iavello A, Camussi G. Effects of mesenchymal stromal cell-derived extracellular vesicles on tumor growth. Front Immunol 2014; 5: 382
    PubMedGoogle Scholar
  • 95 Katakowski M, Buller B, Zheng X et al. Exosomes from marrow stromal cells expressing miR-146b inhibit glioma growth. Cancer Lett 2013; 335: 201-204
    CrossrefPubMedGoogle Scholar
  • 96 Ono M, Kosaka N, Tominaga N et al. Exosomes from bone marrow mesenchymal stem cells contain a microRNA that promotes dormancy in metastatic breast cancer cells. Sci Signal 2014; 7: ra63
    CrossrefPubMedGoogle Scholar
  • 97 Gatti S, Bruno S, Deregibus MC et al. Microvesicles derived from human adult mesenchymal stem cells protect against ischaemia-reperfusion-induced acute and chronic kidney injury. Nephrol Dial Transplant 2011; 26: 1474-1483
    CrossrefPubMedGoogle Scholar
  • 98 Bruno S, Grange C, Collino F et al. Microvesicles derived from mesenchymal stem cells enhance survival in a lethal model of acute kidney injury. PLoS ONE 2012; 7: e33115
    CrossrefPubMedGoogle Scholar
  • 99 He J, Wang Y, Sun S et al. Bone marrow stem cells-derived microvesicles protect against renal injury in the mouse remnant kidney model. Nephrology 2012; 17: 493-500
    CrossrefPubMedGoogle Scholar
  • 100 Zhou Y, Xu H, Xu W et al. Exosomes released by human umbilical cord mesenchymal stem cells protect against cisplatin-induced renal oxidative stress and apoptosis in vivo and in vitro. Stem Cell Res Ther 2013; 4: 34
    CrossrefPubMedGoogle Scholar
  • 101 Kilpinen L, Impola U, Sankkila L et al. Extracellular membrane vesicles from umbilical cord blood-derived MSC protect against ischemic acute kidney injury, a feature that is lost after inflammatory conditioning. J Extracell Vesicles 2013; DOI: 10.3402/jev.v2i0.21927.
    PubMedGoogle Scholar
  • 102 Reis LA, Borges FT, Simões MJ et al. 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
    CrossrefPubMedGoogle Scholar
  • 103 Zhou Y, Xu H, Xu W et al. Microvesicles derived from human Whartonʼs Jelly mesenchymal stromal cells ameliorate renal ischemia-reperfusion injury in rats by suppressing CX3CL1. Stem Cell Res Ther 2013; 4: 34
    CrossrefPubMedGoogle Scholar
  • 104 Li T, Yan Y, Wang B et al. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis. Stem Cells Dev 2013; 22: 845-854
    CrossrefPubMedGoogle Scholar
  • 105 Tan CY, Lai RC, Wong W et al. Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models. Stem Cell Res Ther 2014; 5: 76
    CrossrefPubMedGoogle Scholar
  • 106 Lee C, Mitsialis SA, Aslam M et al. Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia-induced pulmonary hypertension. Circulation 2012; 126: 2601-2611
    CrossrefPubMedGoogle Scholar
  • 107 Zhu YG, Feng XM, Abbott J et al. Human mesenchymal stem cell microvesicles for treatment of Escherichia coli endotoxin-induced acute lung injury in mice. Stem Cells 2014; 32: 116-125
    CrossrefPubMedGoogle Scholar
  • 108 Nakamura Y, Miyaki S, Ishitobi H et al. Mesenchymal-stem-cell-derived exosomes accelerate skeletal muscle regeneration. FEBS Lett 2015; 589: 1257-1265
    CrossrefPubMedGoogle Scholar
  • 109 Zhang HC, Liu XB, Huang S et al. Microvesicles derived from human umbilical cord mesenchymal stem cells stimulated by hypoxia promote angiogenesis both in vitro and in vivo. Stem Cells Dev 2012; 21: 3289-3297
    CrossrefPubMedGoogle Scholar
  • 110 Zhang B, Wang M, Gong A et al. HucMSC-exosome Mediated-Wnt4 Signaling Is Required for Cutaneous Wound Healing. Stem Cells 2015; 33: 2158-2168
    CrossrefPubMedGoogle Scholar
  • 111 Zhang B, Yin Y, Lai RC et al. Mesenchymal stem cell secrete immunologically active exosomes. Stem Cells Dev 2014; 23: 1233-1244
    CrossrefPubMedGoogle Scholar
  • 112 Xin H, Li Y, Cui Y et al. 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: 1711-1715
    CrossrefPubMedGoogle Scholar
  • 113 Doeppner TR, Herz J, Görgens A et al. Extracellular vesicles improve post-stroke neuroregeneration and prevent post-ischemic immunosuppression. Stem Cells Transl Med in press
    PubMedGoogle Scholar
  • 114 Raisi A, Azizi S, Delirezh N et al. 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: 991-997
    CrossrefPubMedGoogle Scholar
  • 115 van der Meel R, Fens MH, Vader P et al. Extracellular vesicles as drug delivery systems: lessons from the liposome field. J Control Release 2014; 195: 72-85
    CrossrefPubMedGoogle Scholar
  • 116 Hosseini HM, Fooladi AA, Nourani MR et al. The role of exosomes in infectious diseases. Inflamm Allergy Drug Targets 2013; 12: 29-37
    CrossrefPubMedGoogle Scholar
  • 117 Boukouris S, Mathivanan S. Exosomes in bodily fluids are a highly stable resource of disease biomarkers. Proteomics Clin Appl 2015; 9: 358-367
    CrossrefPubMedGoogle Scholar
  • 118 Salido-Guadarrama I, Romero-Cordoba S, Peralta-Zaragoza O et al. MicroRNAs transported by exosomes in body fluids as mediators of intercellular communication in cancer. Onco Targets Ther 2014; 7: 1327-1338
    PubMedGoogle Scholar
  • 119 EudraLex – Volume 4 Good manufacturing practice (GMP) Guidelines. Annex 2, Manufacture of Biological active substances and Medicinal Products for Human Use. 2015.. Im Internet: http://ec.europa.eu/health/documents/eudralex/vol-4/index_en.htm Stand: 07/2015
    PubMedGoogle Scholar
  • 120 EudraLex – Volume 10 Clinical trials guidelines. Chapter III Good manufacturing practices for manufacture of investigational medicinal products. 2015.. Im Internet: http://ec.europa.eu/health/documents/eudralex/vol-10/index_en.htm Stand: 07/2015
    PubMedGoogle Scholar
  • 121 Directive 2004/23/EC of the European Parliament and of the Council of 31 March 2004 on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells.. Im Internet: http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=URISERV:c11573 Stand: 07/2015
    PubMedGoogle Scholar
  • 122 Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004. Im Internet: http://eur-lex.europa.eu/legal-content/EN/ALL/?uri=CELEX:32007R1394 Stand: 07/2015
    PubMedGoogle Scholar