Skip to main content

Role of Extracellular Vesicles in Tissue/Organ Regeneration

  • Chapter
  • First Online:
Adult Stem Cell Therapies: Alternatives to Plasticity

Part of the book series: Stem Cell Biology and Regenerative Medicine ((STEMCELL))

Abstract

There is substantial evidence to support the hypothesis that stem cells exert a regenerative effect on damaged tissues/organs by paracrine mechanisms. Stem cells may favor self-tissue/organ repair by means of soluble factor production as well as by release of small vesicles into the extracellular space. Since microvesicles are a heterogeneous population which includes cell surface-shed vesicles and exosomes, herein we call them collectively extracellular vesicles (EVs). EVs enable stem/progenitor cells to transfer information that may change the phenotype of recipient cells. EVs contain selected patterns of proteins, messenger ribonucleic acid (mRNA), long noncoding RNA, and microRNA (miRNA) characteristic of stem/progenitor cells. The transfer of these functional transcripts to injured cells changes their phenotype and activates self-regenerative programs. In this chapter, we discuss studies indicating that EVs derived from different stem cell sources retain the biological activity of stem cells and can mimic their therapeutic effects.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Ratajczak MZ, Kucia M, Jadczyk T, Greco NJ, Wojakowski W, Tendera M et al (2012) Pivotal role of paracrine effects in stem cell therapies in regenerative medicine: can we translate stem cell-secreted paracrine factors and microvesicles into better therapeutic strategies? Leukemia 26:1166–1173

    Article  PubMed  CAS  Google Scholar 

  2. Gnecchi M, Danieli P, Cervio E (2012) Mesenchymal stem cell therapy for heart disease. Vascul Pharmacol 57:48–55

    Article  PubMed  CAS  Google Scholar 

  3. Sanges D, Lluis F, Cosma MP (2011) Cell-fusion-mediated reprogramming: pluripotency or transdifferentiation? Implications for regenerative medicine. Adv Exp Med Biol 713:137–159

    Article  PubMed  CAS  Google Scholar 

  4. Gnecchi M, He H, Noiseux N, Liang OD, Zhang L, Morello F et al (2006) Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J 20:661–669

    Article  PubMed  CAS  Google Scholar 

  5. Timmers L, Lim SK, Arslan F, Armstrong JS, Hoefer IE, Doevendans PA et al (2007) Reduction of myocardial infarct size by human mesenchymal stem cell conditioned medium. Stem Cell Res 1:129–137

    Article  PubMed  CAS  Google Scholar 

  6. Bi B, Schmitt R, Israilova M, Nishio H, Cantley LG (2007) Stromal cells protect against acute tubular injury via an endocrine effect. J Am Soc Nephrol 18:2486–2496

    Article  PubMed  Google Scholar 

  7. Majka M, Janowska-Wieczorek A, Ratajczak J, Ehrenman K, Pietrzkowski Z, Kowalska MA et al (2001) Numerous growth factors, cytokines, and chemokines are secreted by human CD34(+) cells, myeloblasts, erythroblasts, and megakaryoblasts and regulate normal hematopoiesis in an autocrine/paracrine manner. Blood 97:3075–3085

    Article  PubMed  CAS  Google Scholar 

  8. Janowska-Wieczorek A, Majka M, Ratajczak J, Ratajczak MZ (2001) Autocrine/paracrine mechanisms in human hematopoiesis. Stem Cells 19:99–107

    Article  PubMed  CAS  Google Scholar 

  9. Sahoo S, Klychko E, Thorne T, Misener S, Schults KM, Millay M et al (2011) Exosomes from human CD34 + stem cells mediate their proangiopoietic paracrine activity. Circ Res 109:724–728

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  10. Lataillade JJ, Clay D, Bourin P, Hérodin F, Dupuy C, Jasmin C et al (2002) Stromal cell-derived factor 1 regulates primitive hematopoiesis by suppressing apoptosis and by promoting G(0)/G(1) transition in CD34(+) cells: evidence for an autocrine/paracrine mechanism. Blood 99:1117–1129

    Article  PubMed  CAS  Google Scholar 

  11. Ratajczak J, Wysoczynski M, Hayek F, Janowska-Wieczorek A, Ratajczak MZ (2006) Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication. Leukemia 20:1487–1495

    Article  PubMed  CAS  Google Scholar 

  12. Lee Y, El Andaloussi S, Wood MJ (2012) Exosomes and microvesicles: extracellular vesicles for genetic information transfer and gene therapy. Hum Mol Genet 21(R1):R125–R134

    Article  PubMed  CAS  Google Scholar 

  13. Cocucci E, Racchetti G, Meldolesi J (2009) Shedding microvesicles: artefacts no more. Trends Cell Biol 19:43–51

    Article  PubMed  CAS  Google Scholar 

  14. Théry C, Ostrowski M, Segura E (2009) Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 9:581–593

    Article  PubMed  Google Scholar 

  15. Mathivanan S, Ji H, Simpson RJ (2010) Exosomes: extracellular organelles important in intercellular communication. J Proteomics 73:1907–1920

    Article  PubMed  CAS  Google Scholar 

  16. György B, Szabó TG, Pásztói M, Pál Z, Misják P, Aradi B et al (2011) Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cell Mol Life Sci 68:2667–2688

    Article  PubMed  PubMed Central  Google Scholar 

  17. Ratajczak J, Miekus K, Kucia M, Zhang J, Reca R, Dvorak P et al (2006) Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia 20:847–856

    Article  PubMed  CAS  Google Scholar 

  18. Deregibus MC, Cantaluppi V, Calogero R, Lo Iacono M, Tetta C, Biancone L et al (2007) Endothelial progenitor cell derived microvesicles activate an angiogenic program in endothelial cells by a horizontal transfer of mRNA. Blood 110:2440–2448

    Article  PubMed  CAS  Google Scholar 

  19. Quesenberry PJ, Dooner MS, Aliotta JM (2010) Stem cell plasticity revisited: the continuum marrow model and phenotypic changes mediated by microvesicles. Exp Hematol 38:581–592

    Article  PubMed  PubMed Central  Google Scholar 

  20. Caby MP, Lankar D, Vincendeau-Scherrer C, Raposo G, Bonnerot C (2005) Exosomal-like vesicles are present in human blood plasma. Int Immunol 17:879–887

    Article  PubMed  CAS  Google Scholar 

  21. Pisitkun T, Shen RF, Knepper MA (2004) Identification and proteomic profiling of exosomes in human urine. Proc Natl Acad Sci U S A 101:13368–13373

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  22. Xiao H, Wong DT (2012) Proteomic analysis of microvesicles in human saliva by gel electrophoresis with liquid chromatography-mass spectrometry. Anal Chim Acta 723:61–67

    Article  PubMed  CAS  Google Scholar 

  23. Lässer C, Alikhani VS, Ekström K, Eldh M, Paredes PT, Bossios A et al (2011) Human saliva, plasma and breast milk exosomes contain RNA: uptake by macrophages. J Transl Med 9:9

    Article  PubMed  PubMed Central  Google Scholar 

  24. Admyre C, Grunewald J, Thyberg J, Gripenback S, Tornling G, Eklund A et al (2003) Exosomes with major histocompatibility complex class II and co-stimulatory molecules are present in human BAL fluid. Eur Respir J 22:578–583

    Article  PubMed  CAS  Google Scholar 

  25. Admyre C, Johansson SM, Qazi KR, Filen JJ, Lahesmaa R, Norman M et al (2007) Exosomes with immune modulatory features are present in human breast milk. J Immunol 179:1969–1978

    Article  PubMed  CAS  Google Scholar 

  26. Street JM, Barran PE, Mackay CL, Weidt S, Balmforth C, Walsh TS et al (2012) Identification and proteomic profiling of exosomes in human cerebrospinal fluid. J Transl Med 10:5

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  27. Bard MP, Hegmans JP, Hemmes A, Luider TM, Willemsen R, Severijnen LA et al (2004) Proteomic analysis of exosomes isolated from human malignant pleural effusions. Am J Respir Cell Mol Biol 31:114–121

    Article  PubMed  CAS  Google Scholar 

  28. Schara K, Jansa V, Sustar V, Dolinar D, Pavlic JI, Lokar M et al (2009) Mechanisms for the formation of membranous nanostructures in cell-to-cell communication. Cell Mol Biol Let 14:636–656

    Article  CAS  Google Scholar 

  29. Bianco F, Perrotta C, Novellino L, Francolini M, Riganti L, Menna E et al (2009) Acid Sphingomyelinase activity triggers microparticle release from glial cells. EMBO J 28:1043–1054

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. George JN, Thoi LL, McManus LM, Reimann TA (1982) Isolation of human platelet membrane microparticles from plasma and serum. Blood 60:834–840

    PubMed  CAS  Google Scholar 

  31. Martínez MC, Tesse A, Zobairi F, Andriantsitohaina R (2005) Shed membrane microparticles from circulating and vascular cells in regulating vascular function. Am J Physiol Heart Circ Physiol 288:H1004–H1009

    Article  PubMed  Google Scholar 

  32. Henne WM, Buchkovich NJ, Emr SD (2011) The ESCRT pathway. Dev Cell 21:77–91

    Article  PubMed  CAS  Google Scholar 

  33. Ostrowski M, Carmo NB, Krumeich S, Fanget I, Raposo G, Savina A et al (2010) Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol 12:19–30

    Article  PubMed  CAS  Google Scholar 

  34. Trajkovic K, Hsu C, Chiantia S, Rajendran L, Wenzel D, Wieland F et al (2008) Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 319(5867):1244–1247

    Article  PubMed  CAS  Google Scholar 

  35. van Niel GC, Saftig P et al (2011) The tetraspanin CD63 regulates ESCRT-independent and -dependent endosomal sorting during melanogenesis. Dev Cell 21:708–721

    Article  PubMed  PubMed Central  Google Scholar 

  36. Verweij FJ, Van Eijndhoven MA, Hopmans ES, Vendrig T, Wurdinger T, Cahir-Mc Farland E et al (2011) LMP1 association with CD63 in endosomes and secretion via exosomes limits constitutive NF-kB activation. EMBO J 30:2115–2129

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  37. Shen B, Fang Y, Wu N, Gould SJ (2011) Biogenesis of the posterior pole is mediated by the exosome/microvesicle protein-sorting pathway. J Biol Chem 286:44162–44176

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  38. Fang Y, Wu N, Gan X, Yan W, Morrell JC, Gould SJ (2007) Higher-order oligomerization targets plasma membrane proteins and HIV gag to exosomes. PLoS Biol 5:e158

    Article  PubMed  PubMed Central  Google Scholar 

  39. Baietti MF, Zhang Z, Mortier E, Melchior A, Degeest G, Geeraerts A et al (2012) Syndecan-syntenin-ALIX regulates the biogenesis of exosomes. Nat Cell Biol 14:677–685

    Article  PubMed  CAS  Google Scholar 

  40. Mathivanan S, Fahner CJ, Reid GE, Simpson RJ (2012) ExoCarta 2012: database of exosomal proteins, RNA and lipids. Nucleic Acids Res 40(Database issue):D1241–D1244

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  41. Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9:654–659

    Article  PubMed  CAS  Google Scholar 

  42. Collino F, Deregibus MC, Bruno S, Sterpone L, Aghemo G, Viltono L et al (2010) Microvesicles derived from adult human bone marrow and tissue specific mesenchymal stem cells shuttle selected pattern of miRNAs. PLoS ONE 5:e11803

    Article  PubMed  PubMed Central  Google Scholar 

  43. Del Tatto MN, Berz D et al (2011) Marrow cell genetic phenotype change induced by human lung cancer cells. Exp Hematol 39:1072–1080

    Article  PubMed  CAS  Google Scholar 

  44. Quesenberry PJ, Aliotta JM (2010) Cellular phenotype switching and microvesicles. Adv Drug Deliv Rev 62:1141–1148

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  45. Quesenberry PJ, Dooner MS, Goldberg LR, Aliotta JM, Pereira M, Amaral A et al (2012) A new stem cell biology: the continuum and microvesicles. Trans Am Clin Climatol Assoc 123:152–166

    PubMed  PubMed Central  Google Scholar 

  46. Chen X, Liang H, Zhang J, Zen K, Zhang CY (2012) Secreted microRNAs: a new form of intercellular communication. Trends Cell Biol 22:125–132

    Article  PubMed  CAS  Google Scholar 

  47. Gallo A, Tandon M, Alevizos I, Illei GG (2012) The majority of microRNAs detectable in serum and saliva is concentrated in exosomes. PLoS ONE 7:e30679

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  48. Wang K, Zhang S, Weber J, Baxter D, Galas DJ (2010) Export of microRNAs and microRNA-protective protein by mammalian cells. Nucleic Acids Res 38:7248–7259

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  49. Arroyo JD, Chevillet JR, Kroh EM, Ruf IK, Pritchard CC, Gibson DF et al (2011) Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc Natl Acad Sci U S A 108:5003–5008

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  50. Vickers KC, Palmisano BT, Shoucri BM, Shamburek RD, Remaley AT (2011) MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat Cell Biol 13:423–433

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  51. Whitehead J, Pandey GK, Kanduri C (2009) Regulation of the mammalian epigenome by long noncoding RNAs. Biochim Biophys Acta 1790:936–947

    Article  PubMed  CAS  Google Scholar 

  52. Yuan A, Farber EL, Rapoport AL, Tejada D, Deniskin R, Akhmedov NB et al (2009) Transfer of microRNAs by embryonic stem cell microvesicles. PLoS ONE 4:e4722

    Article  PubMed  PubMed Central  Google Scholar 

  53. Bruno S, Grange C, Deregibus MC, Calogero RA, Saviozzi S, Collino F et al (2009) Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol 20:1053–1067

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  54. Herrera MB, Fonsato V, Gatti S, Deregibus MC, Sordi A, Cantarella D et al (2010) Human liver stem cell-derived microvesicles accelerate hepatic regeneration in hepatectomized rats. J Cell Mol Med 14:1605–1618

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  55. Aliotta JM, Pereira M, Johnson KW, de Paz N, Dooner MS, Puente N et al (2010) Microvesicle entry into marrow cells mediates tissue-specific changes in mRNA by direct delivery of mRNA and induction of transcription. Exp Hematol 38:233–245

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  56. Krol J, Loedige I, Filipowicz W (2010) The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet 11:597–610

    PubMed  CAS  Google Scholar 

  57. Höck J, Meister G (2008) The Argonaute protein family. Genome Biol 9:210

    Article  PubMed  PubMed Central  Google Scholar 

  58. Eulalio A, Behm-Ansmant I, Izaurralde E (2007) P bodies: at the crossroads of post-transcriptional pathways. Nat Rev Mol Cell Biol 8:9–22

    Article  PubMed  CAS  Google Scholar 

  59. Ranghino A, Cantaluppi V, Grange C, Vitillo L, Fop F, Biancone L et al (2012) Endothelial progenitor cell-derived microvesicles improve neovascularization in a murine model of hindlimb ischemia. Int J Immunopathol Pharmacol 25:75–85

    PubMed  CAS  Google Scholar 

  60. Cantaluppi V, Gatti S, Medica D, Figliolini F, Bruno S, Deregibus MC et al (2012) Microvesicles derived from endothelial progenitor cells protect the kidney from ischemia-reperfusion injury by microRNA-dependent reprogramming of resident renal cells. Kidney Int 82:412–427

    Article  PubMed  CAS  Google Scholar 

  61. Bruno S, Grange C, Collino F, Deregibus MC, Cantaluppi V, Biancone L et al (2012) Microvesicles derived from mesenchymal stem cells enhance survival in a lethal model of acute kidney injury. PLoS ONE 7:e33115

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  62. Tomasoni S, Longaretti L, Rota C, Morigi M, Conti S, Gotti E et al (2013) Transfer of growth factor receptor mRNA via exosomes unravels the regenerative effect of mesenchymal stem cells. Stem Cells Dev 22:772–780

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  63. Fonsato V, Collino F, Herrera MB, Cavallari C, Deregibus MC, Cisterna B et al (2012) Human liver stem cell-derived microvesicles inhibit hepatoma growth in SCID mice by delivering antitumor microRNAs. Stem Cells 30:1985–1998

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  64. Bruno S, Collino F, Deregibus MC, Grange C, Tetta C, Camussi G (2013) Microvesicles derived from human bone marrow mesenchymal stem cells inhibit tumor growth. Stem Cells Dev 22:758–771

    Article  PubMed  CAS  Google Scholar 

  65. Li T, Yan Y, Wang B, Qian H, Zhang X, Shen L et al (2013) Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis. Stem Cells Dev 22:845–854

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  66. Lai RC, Arslan F, Lee MM, Sze NS, Choo A, Chen TS et al (2010) Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res 4:214–222

    Article  PubMed  CAS  Google Scholar 

  67. Lai RC, Arslan F, Tan SS, Tan B, Choo A, Lee MM et al (2010) Derivation and characterization of human fetal MSCs: an alternative cell source for large-scale production of cardioprotective microparticles. J Mol Cell Cardiol 48:1215–1224

    Article  PubMed  CAS  Google Scholar 

  68. Chen L, Wang Y, Pan Y, Zhang L, Shen C, Qin G et al (2013) Cardiac progenitor-derived exosomes protect ischemic myocardium from acute ischemia/reperfusion injury. Biochem Biophys Res Commun 431:566–571

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  69. Iglesias DM, El-Kares R, Taranta A, Bellomo F, Emma F, Besouw M et al (2012) Stem cell microvesicles transfer cystinosin to human cystinotic cells and reduce cystine accumulation in vitro. PLoS ONE 7:e42840

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  70. Kooijmans SA, Vader P, van Dommelen SM, van Solinge WW, Schiffelers RM (2012) Exosome mimetics: a novel class of drug delivery systems. Int J Nanomed 7:1525–1541

    CAS  Google Scholar 

  71. Shen B, Wu N, Yang JM, Gould SJ (2011) Protein targeting to exosomes/microvesicles by plasma membrane anchors. J Biol Chem 286:14383–14395

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  72. El Andaloussi S, Lakhal S, Mäger I, Wood MJ (2013) Exosomes for targeted siRNA delivery across biological barriers. Adv Drug Deliv Rev 65:391–397

    Article  PubMed  CAS  Google Scholar 

  73. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ (2011) Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 29:341–345

    Article  PubMed  CAS  Google Scholar 

  74. Akao Y, Iio A, Itoh T, Noguchi S, Itoh Y, Ohtsuki Y et al (2011) Microvesicle-mediated RNA molecule delivery system using monocytes/macrophages. Mol Ther 19:395–399

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  75. van den Boorn JG, Schlee M, Coch C, Hartmann G (2011) SiRNA delivery with exosomes nanoparticles. Nat Biotechnol 29:325–326

    Article  PubMed  CAS  Google Scholar 

  76. Chen TS, Arslan F, Yin Y, Tan SS, Lai RC, Choo AB et al (2011) Enabling a robust scalable manufacturing process for therapeutic exosomes through oncogenic immortalization of human ESC-derived MSCs. J Transl Med 9:47

    Article  PubMed  CAS  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Giovanni Camussi .

Editor information

Editors and Affiliations

Conclusions

Conclusions

Taken together, these studies suggest that EVs derived from different stem cell sources retain the biological activity of stem cells and can mimic the therapeutic effects of the cell of origin. However, it is evident that an EV-based therapy does not replace the injured tissue, but may rather coordinate tissue self-repair and limit the injury. By exploiting membrane receptors expressed by the stem cell of origin, EVs were able to home into the site of injury. In addition, EVs have the potential to interfere with multiple cellular pathways involved in different physiological and pathological processes because they contain a complex array of constituents. Identification of the molecular components accountable for the beneficial action of EVs in different pathologies, along with a better understanding of homing processes and of exRNA containment within EVs may prompt new strategies for producing engineered EVs for therapeutic purposes. The use of EVs instead of stem cells may bypass problems such as maldifferentiation and tumorigenesis that can result from the injection of replicating cells into the host organism. Other potential advantages from using EVs include the possibility of extensive expansion in vitro and of cryopreservation and, regarding the stem cell-derived EVs, the absence of immunogenicity. However, before a clinical application can be envisaged, many problems need to be solved. Firstly, the definition of GMP protocols for large-scale EV production and the evaluation of bio-distribution, pharmacokinetics, biosafety, and effectiveness in different pathological conditions.

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

Deregibus, M., Iavello, A., Tetta, C., Camussi, G. (2014). Role of Extracellular Vesicles in Tissue/Organ Regeneration. In: Ratajczak, M. (eds) Adult Stem Cell Therapies: Alternatives to Plasticity. Stem Cell Biology and Regenerative Medicine. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-1001-4_13

Download citation

Publish with us

Policies and ethics