Skip to main content

Advertisement

SpringerLink
Log in

Exosomes in perspective: a potential surrogate for stem cell therapy

  • Review Article
  • Published:
Odontology Aims and scope Submit manuscript

Abstract

Exosomes as a unique subtype of small extracellular vesicles (sEVs) have attracted increasing interest in recent years in the fields of mesenchymal stromal cell (MSC) research. Studies have confirmed that exosomes derived from MSCs preserve immunosuppressive phenotype and can mimic therapeutic benefits of their parent cells. This review briefly summarizes most recent findings on the potential of exosomes as an alternative of therapeutic MSCs, focusing on the role of MSCs and their secreted exosomes in regulation of immune cells, preclinical and clinical evidence of therapeutic outcomes of MSC exosomes, and the biodistribution and pharmacokinetic profile of systemically administered exosomes. It is appreciated that exosomes from MSCs of different sources have variable contents including inflammatory mediators, tropic factors, signaling molecules, and nucleic acids (DNA, mRNA, microRNA and long non-coding RNA). Diverse functions of exosomes derived from different sources are expected. More importantly, exosomes isolated in vitro may not mirror that from in vivo, where donor MSCs are exposed to specific disease or injury-related conditions. Simulating in vivo microenvironment by pretreatment of MSCs with relevant chemical mediators may lead to their secretion of therapeutically more efficient exosomes/sEVs. However, we know very little about the key molecules involved and the differences between exosomes released under different conditions. These issues would be of tremendous interest to preclinical research that pursues exosome biology-underlain therapeutic mechanisms of MSCs. Further studies are expected to demonstrate the superiority of MSC-derived exsomes/sEVs as a pharmaceutical entity with regard to efficacy, safety, and practicability.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Harding C, Heuser J, Stahl P. Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. J Cell Biol. 1983;97:329–39.

    Article  PubMed  Google Scholar 

  2. Johnstone RM, Adam M, Hammond JR, Orr L, Turbide C. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem. 1987;262:9412–20.

    PubMed  Google Scholar 

  3. Trams EG, Lauter CJ, Salem N Jr, Heine U. Exfoliation of membrane ecto-enzymes in the form of micro-vesicles. Biochim Biophys Acta. 1981;645:63–70.

    Article  PubMed  Google Scholar 

  4. Huang GT, Gronthos S, Shi S. Mesenchymal stem cells derived from dental tissues vs. those from other sources: their biology and role in regenerative medicine. J Dent Res. 2009;88:792–806.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Yildirim S, Zibandeh N, Genc D, Ozcan EM, Goker K, Akkoc T. The comparison of the immunologic properties of stem cells isolated from human exfoliated deciduous teeth, dental pulp, and dental follicles. Stem Cells Int. 2016; 2016:4682875.

    Article  PubMed  Google Scholar 

  6. Nakajima K, Kunimatsu R, Ando K, Ando T, Hayashi Y, Kihara T, Hiraki T, Tsuka Y, Abe T, Kaku M, Nikawa H, Takata T, Tanne K, Tanimoto K. Comparison of the bone regeneration ability between stem cells from human exfoliated deciduous teeth, human dental pulp stem cells and human bone marrow mesenchymal stem cells. Biochem Biophys Res Commun. 2018;497(3):876–82. https://doi.org/10.1016/j.bbrc.2018.02.156.

    Article  PubMed  Google Scholar 

  7. Stanko P, Altanerova U, Jakubechova J, Repiska V, Altaner C. Dental Mesenchymal Stem/Stromal Cells and Their Exosomes. Stem Cells Int. 2018; 2018:8973613.

  8. Guo W, Wang H, Zou S, Gu M, Watanabe M, Wei F, Dubner R, Huang GT, Ren K. Bone marrow stromal cells produce long-term pain relief in rat models of persistent pain. Stem Cells. 2011;29(8):1294–303.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Guo W, Chu YX, Imai S, Yang JL, Zou S, Mohammad Z, Wei F, Dubner R, Ren K. Further observations on the behavioral and neural effects of bone marrow stromal cells in rodent pain models. Mol Pain 12: 1744806916658043. https://doi.org/10.1177/1744806916658043.

  10. Kou X, Xu X, Chen C, Sanmillan ML, Cai T, Zhou Y, Giraudo C, Le A, Shi S. The Fas/Fap-1/Cav-1 complex regulates IL-1RA secretion in mesenchymal stem cells to accelerate wound healing. Sci Transl Med. 2018; 10(432):eaai8524. https://doi.org/10.1126/scitranslmed.aai8524.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Guo W, Imai S, Yang JL, Zou S, Watanabe M, Chu YX, Mohammad Z, Xu H, Moudgil KD, Wei F, Dubner R, Ren K. In vivo immune interactions of multipotent stromal cells underlie their long-lasting pain-relieving effect. Sci Rep. 2017;7:10107.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Timmers L, Lim SK, Arslan F, Armstrong JS, Hoefer IE, Doevendans PA, Piek JJ, El Oakley RM, Choo A, Lee CN, Pasterkamp G, de Kleijn DP. Reduction of myocardial infarct size by human mesenchymal stem cell conditioned medium. Stem Cell Res. 2007;1(2):129–37. https://doi.org/10.1016/j.scr.2008.02.002.

    Article  PubMed  Google Scholar 

  13. Gama KB, Santos DS, Evangelista AF, Silva DN, de Alcântara AC, Dos Santos RR, Soares MBP, Villarreal CF. Conditioned medium of bone marrow-derived mesenchymal stromal cells as a therapeutic approach to neuropathic pain: a preclinical evaluation. Stem Cells Int. 2018; 2018:8179013. https://doi.org/10.1155/2018/8179013.

  14. Lai RC, Arslan F, Lee MM, Sze NS, Choo A, Chen TS, Salto-Tellez M, Timmers L, Lee CN, El Oakley RM, Pasterkamp G, de Kleijn DP, Lim SK. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res. 2010;4(3):214–22. https://doi.org/10.1016/j.scr.2009.12.003.

    Article  PubMed  Google Scholar 

  15. Di Trapani M, Bassi G, Midolo M, Gatti A, Kamga PT, Cassaro A, Carusone R, Adamo A, Krampera M. Differential and transferable modulatory effects of mesenchymal stromal cell-derived extracellular vesicles on T, B and NK cell functions. Sci Rep. 2016;6:24120. https://doi.org/10.1038/srep24120.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Cosenza S, Toupet K, Maumus M, Luz-Crawford P, Blanc-Brude O. Jorgensen C, Noël D. Mesenchymal stem cells-derived exosomes are more immunosuppressive than microparticles in inflammatory arthritis. Theranostics. 2018;8:1399–410. https://doi.org/10.7150/thno.21072.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Casado JG, Blázquez R, Vela FJ, Álvarez V, Tarazona R, Sánchez-Margallo FM. Mesenchymal stem cell-derived exosomes: immunomodulatory evaluation in an antigen-induced synovitis porcine model. Front Vet Sci. 2017;4:39.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Gonzalez-King H, García NA, Ontoria-Oviedo I, Ciria M, Montero JA, Sepúlveda P. Hypoxia inducible factor-1α potentiates jagged 1-mediated angiogenesis by mesenchymal stem cell-derived exosomes. Stem Cells. 2017;35:1747–59.

    Article  PubMed  Google Scholar 

  19. Yan Y, Jiang W, Tan Y, Zou S, Zhang H, Mao F, Gong A, Qian H, Xu W. hucMSC exosome-derived GPX1 is required for the recovery of hepatic oxidant injury. Mol Ther. 2017;25(2):465–79.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Phinney DG, Pittenger MF. Concise review: MSC-derived exosomes for cell-free therapy. Stem Cells. 2017;35:851–8.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  22. Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013;200(4):373–83.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Lötvall J, Hill AF, Hochberg F, Buzás EI, Di Vizio D, Gardiner C, Gho YS, Kurochkin IV, Mathivanan S, Quesenberry P, Sahoo S, Tahara H, Wauben MH, Witwer KW, Théry C. Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. J Extracell Vesicles. 2014;3:26913. https://doi.org/10.3402/jev.v3.26913. eCollection 2014.

    Article  PubMed  Google Scholar 

  24. Cocucci E, Meldolesi J. Ectosomes and exosomes: shedding the confusion between extracellular vesicles. Trends Cell Biol. 2015;25:364–72.

    Article  PubMed  Google Scholar 

  25. Meldolesi J. Exosomes and ectosomes in intercellular communication. Curr Biol. 2018;28:R435–44.

    Article  PubMed  Google Scholar 

  26. Kowal J, Arras G, Colombo M, Jouve M, Morath JP, Primdal-Bengtson B, Dingli F, Loew D, Tkach M, Théry C. Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc Natl Acad Sci U S A. 2016;113(8):E968-77.

    Article  PubMed  Google Scholar 

  27. Willms E, Johansson HJ, Mäger I, Lee Y, Blomberg KE, Sadik M, Alaarg A, Smith CI, Lehtiö J, El Andaloussi S, Wood MJ, Vader P. Cells release subpopulations of exosomes with distinct molecular and biological properties. Sci Rep. 2016;6:22519.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Bissig C, Gruenberg J. ALIX and the multivesicular endosome: ALIX in Wonderland. Trends Cell Biol. 2014;24:19–25.

    Article  PubMed  Google Scholar 

  29. Frankel EB, Audhya A. ESCRT-dependent cargo sorting at multivesicular endosomes. Semin Cell Dev Biol. 2018;74:4–10. https://doi.org/10.1016/j.semcdb.2017.08.020.

    Article  PubMed  Google Scholar 

  30. MacDonald C, Payne JA, Aboian M, Smith W, Katzmann DJ, Piper RC. A family of tetraspans organizes cargo for sorting into multivesicular bodies. Dev Cell. 2015;33(3):328–42.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Liang Y, Eng WS, Colquhoun DR, Dinglasan RR, Graham DR, Mahal LK. Complex N-linked glycans serve as a determinant for exosome/microvesicle cargo recruitment. J Biol Chem. 2014;289(47):32526–37. https://doi.org/10.1074/jbc.M114.606269.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Trajkovic K, Hsu C, Chiantia S, Rajendran L, Wenzel D, Wieland F, Schwille P, Brügger B, Simons M. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science. 2008;319:1244–7.

    Article  PubMed  Google Scholar 

  33. Baietti MF, Zhang Z, Mortier E, Melchior A, Degeest G, Geeraerts A, Ivarsson Y, Depoortere F, Coomans C, Vermeiren E, Zimmermann P, David G. Syndecan-syntenin-ALIX regulates the biogenesis of exosomes. Nat Cell Biol. 2012;14:677–85.

    Article  PubMed  Google Scholar 

  34. Hofer HR, Tuan RS. Secreted trophic factors of mesenchymal stem cells support neurovascular and musculoskeletal therapies. Stem Cell Res Ther. 2016;7:131. https://doi.org/10.1186/s13287-016-0394-0.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Lancaster GI, Febbraio MA. Exosome-dependent trafficking of HSP70: a novel secretory pathway for cellular stress proteins. J Biol Chem. 2005;280(24):23349–55.

    Article  PubMed  Google Scholar 

  36. Record M, Carayon K, Poirot M, Silvente-Poirot S. Exosomes as new vesicular lipid transporters involved in cell-cell communication and various pathophysiologies. Biochim Biophys Acta. 2014;1841:108–20.

    Article  PubMed  Google Scholar 

  37. Lai RC, Tan SS, Yeo RW, Choo AB, Reiner AT, Su Y, Shen Y, Fu Z, Alexander L, Sze SK, Lim SK. MSC secretes at least 3 EV types each with a unique permutation of membrane lipid, protein and RNA. J Extracell Vesicles. 2016;5:29828.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  39. Wubbolts R, Leckie RS, Veenhuizen PT, Schwarzmann G, Möbius W, Hoernschemeyer J, Slot JW, Geuze HJ, Stoorvogel W. Proteomic and biochemical analyses of human B cell-derived exosomes. Potential implications for their function and multivesicular body formation. J Biol Chem. 2003;278(13):10963–72.

    Article  PubMed  Google Scholar 

  40. Dragomir M, Chen B, Calin GA. Exosomal lncRNAs as new players in cell-to-cell communication. Transl Cancer Res. 2018;7(Suppl 2):243–52. https://doi.org/10.21037/tcr.2017.10.46.

    Article  Google Scholar 

  41. Momen-Heravi F, Getting SJ, Moschos SA. Extracellular vesicles and their nucleic acids for biomarker discovery. Pharmacol Ther. 2018. S0163-7258(18)30134-7. https://doi.org/10.1016/j.pharmthera.2018.08.002. [Epub ahead of print].

    Article  Google Scholar 

  42. Tsilioni I, Theoharides TC. Extracellular vesicles are increased in the serum of children with autism spectrum disorder, contain mitochondrial DNA, and stimulate human microglia to secrete IL-1β. J Neuroinflammation. 2018;15:239. https://doi.org/10.1186/s12974-018-1275-5.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Wang L, Li Y, Guan X, Zhao J, Shen L, Liu J. Exosomal double-stranded DNA as a biomarker for the diagnosis and preoperative assessment of pheochromocytoma and paraganglioma. Mol Cancer. 2018;17(1):128. https://doi.org/10.1186/s12943-018-0876-z.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Le Blanc K, Rasmusson I, Sundberg B, Götherström C, Hassan M, Uzunel M, Ringdén O. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet. 2004;363(9419):1439–41.

    Article  PubMed  Google Scholar 

  45. Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, Lanino E, Sundberg B, Bernardo ME, Remberger M, Dini G, Egeler RM, Bacigalupo A, Fibbe W, Ringdén O. Developmental Committee of the European Group for Blood and Marrow Transplantation. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 2008;371(9624):1579–86.

    Article  PubMed  Google Scholar 

  46. Trento C, Bernardo ME, Nagler A, Kuçi S, Bornhäuser M, Köhl U, Strunk D, Galleu A, Sanchez-Guijo F, Gaipa G, Introna M, Bukauskas A, Le Blanc K, Apperley J, Roelofs H, Van Campenhout A, Beguin Y, Kuball J, Lazzari L, Avanzini MA, Fibbe W, Chabannon C, Bonini C, Dazzi F. Manufacturing mesenchymal stromal cells for the treatment of graft-versus-host disease: a survey amongst centers affiliated to the European Group of Blood and Marrow Transplantation. Biol Blood Marrow Transpl. 2018. S1083-8791(18)30402-6. https://doi.org/10.1016/j.bbmt.2018.07.015. [Epub ahead of print].

    Article  Google Scholar 

  47. Pleumeekers MM, Nimeskern L, Koevoet JLM, Karperien M, Stok KS, van Osch GJVM. Trophic effects of adipose-tissue-derived and bone-marrow-derived mesenchymal stem cells enhance cartilage generation by chondrocytes in co-culture. PLoS One. 2018;13:e0190744.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Davies LC, Heldring N, Kadri N, Le Blanc K. mesenchymal stromal cell secretion of programmed death-1 ligands regulates t cell mediated immunosuppression. Stem Cells. 2017;35:766–76.

    Article  PubMed  Google Scholar 

  49. Teixeira GQ, Pereira CL, Ferreira JR, Maia AF, Gomez-Lazaro M, Barbosa MA, Neidlinger-Wilke C, Goncalves RM. Immunomodulation of human mesenchymal stem/stromal cells in intervertebral disc degeneration: insights from a proinflammatory/degenerative ex vivo model. Spine (Phila Pa 1976). 2018;43(12): E673-E682. https://doi.org/10.1097/BRS.0000000000002494.

    Article  Google Scholar 

  50. Lee RH, Pulin AA, Seo MJ, Kota DJ, Ylostalo J, Larson BL, Semprun-Prieto L, Delafontaine P, Prockop DJ. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Harting MT, Jimenez F, Xue H, Fischer UM, Baumgartner J, Dash PK, Cox CS. Intravenous mesenchymal stem cell therapy for traumatic brain injury. J Neurosurg. 2009;110:1189–97.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Dayan V, Yannarelli G, Billia F, Filomeno P, Wang XH, Davies JE, Keating A. Mesenchymal stromal cells mediate a switch to alternatively activated monocytes/macrophages after acute myocardial infarction. Basic Res Cardiol. 2011;106:1299–310.

    Article  PubMed  Google Scholar 

  53. Le Blanc K, Davies LC. Mesenchymal stromal cells and the innate immune response. Immunol Lett. 2015;168:140–6.

    Article  PubMed  Google Scholar 

  54. Neirinckx V, Agirman G, Coste C, Marquet A, Dion V, Rogister B, Franzen R, Wislet S. Adult bone marrow mesenchymal and neural crest stem cells are chemoattractive and accelerate motor recovery in a mouse model of spinal cord injury. Stem Cell Res Ther. 2015;6:211. https://doi.org/10.1186/s13287-015-0202-2.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Melief SM, Schrama E, Brugman MH, Tiemessen MM, Hoogduijn MJ, Fibbe WE, Roelofs H. Multipotent stromal cells induce human regulatory T cells through a novel pathway involving skewing of monocytes toward anti-inflammatory macrophages. Stem Cells. 2013;31(9):1980–91. https://doi.org/10.1002/stem.1432.

    Article  PubMed  Google Scholar 

  56. Blázquez R, Sánchez-Margallo FM, Álvarez V, Usón A, Casado JG. Surgical meshes coated with mesenchymal stem cells provide an anti-inflammatory environment by a M2 macrophage polarization. Acta Biomater. 2016;31:221–30.

    Article  PubMed  Google Scholar 

  57. Blázquez R, Sánchez-Margallo FM, Álvarez V, Usón A, Marinaro F, Casado JG. Fibrin glue mesh fixation combined with mesenchymal stem cells or exosomes modulates the inflammatory reaction in a murine model of incisional hernia. Acta Biomater. 2018;71:318–29. https://doi.org/10.1016/j.actbio.2018.02.014.

    Article  PubMed  Google Scholar 

  58. Park HJ, Kim J, Saima FT, Rhee KJ, Hwang S, Kim MY, Baik SK, Eom YW, Kim HS. Adipose-derived stem cells ameliorate colitis by suppression of inflammasome formation and regulation of M1-macrophage population through prostaglandin E2. Biochem Biophys Res Commun. 2018;498(4):988–95.

    Article  PubMed  Google Scholar 

  59. Siniscalco D, Giordano C, Galderisi U, Luongo L, de Novellis V, Rossi F, Maione S. Long-lasting effects of human mesenchymal stem cell systemic administration on pain-like behaviors, cellular, and biomolecular modifications in neuropathic mice. Front Integr Neurosci. 2011;5:79. https://doi.org/10.3389/fnint.2011.00079.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Németh K, Leelahavanichkul A, Yuen PS, Mayer B, Parmelee A, Doi K, Robey PG, Leelahavanichkul K, Koller BH, Brown JM, Hu X, Jelinek I, Star RA, Mezey E. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med. 2009;15:42–9.

    Article  PubMed  Google Scholar 

  61. Lankford KL, Arroyo EJ, Nazimek K, Bryniarski K, Askenase PW, Kocsis JD. Intravenously delivered mesenchymal stem cell-derived exosomes target M2-type macrophages in the injured spinal cord. PLoS One. 2018;13(1):e0190358. https://doi.org/10.1371/journal.pone.0190358. (eCollection 2018).

    Article  PubMed  PubMed Central  Google Scholar 

  62. 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  PubMed  PubMed Central  Google Scholar 

  63. Spinosa M, Lu G, Su G, Bontha SV, Gehrau R, Salmon MD, Smith JR, Weiss ML, Mas VR, Upchurch GR Jr, Sharma AK. Human mesenchymal stromal cell-derived extracellular vesicles attenuate aortic aneurysm formation and macrophage activation via microRNA-147. FASEB J. 2018; 29:fj201701138RR. https://doi.org/10.1096/fj.201701138RR. [Epub ahead of print].

    Article  Google Scholar 

  64. Geng L, Tang X, Zhou K, Wang D, Wang S, Yao G, Chen W, Gao X, Chen W, Shi S, Shen N, Feng X, Sun L. MicroRNA-663 induces immune dysregulation by inhibiting TGF-β1 production in bone marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus. Cell Mol Immunol. 2018; 26. https://doi.org/10.1038/cmi.2018.1. [Epub ahead of print].

  65. Guo W, Imai S, Zou S-P, Wei F, Dubner R, Ren K. Immune regulation and mesenchymal stromal cell-produced pain relief: 2. Role of NFkB signaling and regulatory T cells. SanDiego: Society for Neuroscience; 2016.

    Google Scholar 

  66. Mougiakakos D, Jitschin R, Johansson CC, Okita R, Kiessling R, Le Blanc K. The impact of inflammatory licensing on heme oxygenase-1-mediated induction of regulatory T cells by human mesenchymal stem cells. Blood. 2011;117(18):4826–35. https://doi.org/10.1182/blood-2010-12-324038.

    Article  PubMed  Google Scholar 

  67. Yan Z, Zhuansun Y, Chen R, Li J, Ran P. Immunomodulation of mesenchymal stromal cells on regulatory T cells and its possible mechanism. Exp Cell Res. 2014;324(1):65–74. https://doi.org/10.1016/j.yexcr.2014.03.013.

    Article  PubMed  Google Scholar 

  68. Tasso R, Ilengo C, Quarto R, Cancedda R, Caspi RR, Pennesi G. Mesenchymal stem cells induce functionally active T-regulatory lymphocytes in a paracrine fashion and ameliorate experimental autoimmune uveitis. Invest Ophthalmol Vis Sci. 2012;53(2):786–93. https://doi.org/10.1167/iovs.11-8211.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Favaro E, Carpanetto A, Lamorte S, Fusco A, Caorsi C, Deregibus MC, Bruno S, Amoroso A, Giovarelli M, Porta M, Perin PC, Tetta C, Camussi G, Zanone MM. Human mesenchymal stem cell-derived microvesicles modulate T cell response to islet antigen glutamic acid decarboxylase in patients with type 1 diabetes. Diabetologia. 2014;57:1664–73.

    Article  PubMed  Google Scholar 

  70. Mokarizadeh A, Delirezh N, Morshedi A, Mosayebi G, Farshid AA, Mardani K. Microvesicles derived from mesenchymal stem cells: potent organelles for induction of tolerogenic signaling. Immunol Lett. 2012;147(1–2):47–54. https://doi.org/10.1016/j.imlet.2012.06.001.

    Article  PubMed  Google Scholar 

  71. Zhang B, Yin Y, Lai RC, Tan SS, Choo AB, Lim SK. Mesenchymal stem cells secrete immunologically active exosomes. Stem Cells Dev. 2014;23:1233–44.

    Article  PubMed  Google Scholar 

  72. Du YM, Zhuansun YX, Chen R, Lin L, Lin Y, Li JG. Mesenchymal stem cell exosomes promote immunosuppression of regulatory T cells in asthma. Exp Cell Res. 2018;363(1):114–20.

    Article  PubMed  Google Scholar 

  73. Zhang B, Yeo RWY, Lai RC, Sim EWK, Chin KC, Lim SK. Mesenchymal stromal cell exosome-enhanced regulatory T-cell production through an antigen-presenting cell-mediated pathway. Cytotherapy. 2018;20(5):687–96.

    Article  PubMed  Google Scholar 

  74. Corcione A, Benvenuto F, Ferretti E, Giunti D, Cappiello V, Cazzanti F, Risso M, Gualandi F, Mancardi GL, Pistoia V, Uccelli A. Human mesenchymal stem cells modulate B-cell functions. Blood. 2006;107(1):367–72.

    Article  PubMed  Google Scholar 

  75. Budoni M, Fierabracci A, Luciano R, Petrini S, Di Ciommo V, Muraca M. The immunosuppressive effect of mesenchymal stromal cells on B lymphocytes is mediated by membrane vesicles. Cell Transpl. 2013;22(2):369–79. https://doi.org/10.3727/096368911X582769.

    Article  Google Scholar 

  76. Gupte KS, Vanikar AV, Trivedi HL, Patel CN, Patel JV. In-vitro generation of interleukin-10 secreting B-regulatory cells from donor adipose tissue derived mesenchymal stem cells and recipient peripheral blood mononuclear cells for potential cell therapy. Biomed J. 2017;40(1):49–54. https://doi.org/10.1016/j.bj.2017.01.003.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Cho KA, Lee JK, Kim YH, Park M, Woo SY, Ryu KH. Mesenchymal stem cells ameliorate B-cell-mediated immune responses and increase IL-10-expressing regulatory B cells in an EBI3-dependent manner. Cell Mol Immunol. 2017. https://doi.org/10.1038/cmi.2016.59.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Chen G, Park CK, Xie RG, Ji RR. Intrathecal bone marrow stromal cells inhibit neuropathic pain via TGF-β secretion. J Clin Invest. 2015;125:3226–40.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 7th ed. Amsterdam: Elsevier; 2014.

    Google Scholar 

  80. Imai S, Guo W, Zou S-P, Wei F, Dubner R, Ren K. Immune regulation and mesenchymal stromal cell-produced pain relief: 1. promotion of anti-inflammatory phenotype. In 2016 Program No. 445.16, San Diego: Society for Neuroscience.

  81. Krampera M, Cosmi L, Angeli R, Pasini A, Liotta F, Andreini A, Santarlasci V, Mazzinghi B, Pizzolo G, Vinante F, Romagnani P, Maggi E, Romagnani S, Annunziato F. Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells. 2006;24(2):386–98.

    Article  PubMed  Google Scholar 

  82. Li J, Deng G, Wang H, Yang M, Yang R, Li X, Zhang X, Yuan H. Interleukin-1β pre-treated bone marrow stromal cells alleviate neuropathic pain through CCL7-mediated inhibition of microglial activation in the spinal cord. Sci Rep. 2017;7:42260. https://doi.org/10.1038/srep42260.

    Article  PubMed  PubMed Central  Google Scholar 

  83. 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. https://doi.org/10.1038/leu.2014.41.

    Article  PubMed  Google Scholar 

  84. Del Fattore A, Luciano R, Pascucci L, Goffredo BM, Giorda E, Scapaticci M, Fierabracci A, Muraca M. Immunoregulatory effects of mesenchymal stem cell-derived extracellular vesicles on T lymphocytes. Cell Transplant. 2015;24(12):2615–27. https://doi.org/10.3727/096368915X687543.

    Article  PubMed  Google Scholar 

  85. Zhang Q, Fu L, Liang Y, Guo Z, Wang L, Ma C, Wang H. Exosomes originating from MSCs stimulated with TGF-β and IFN-γ promote Treg differentiation. J Cell Physiol. 2018;233(9):6832–40.

    Article  PubMed  Google Scholar 

  86. Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9(6):654–9.

    Article  PubMed  Google Scholar 

  87. Baglio SR, Rooijers K, Koppers-Lalic D, Verweij FJ, Pérez Lanzón M, Zini N, Naaijkens B, Perut F, Niessen HW, Baldini N, Pegtel DM. Human bone marrow- and adipose-mesenchymal stem cells secrete exosomes enriched in distinctive miRNA and tRNA species. Stem Cell Res Ther. 2015;6:127. https://doi.org/10.1186/s13287-015-0116-z.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Phinney DG, Di Giuseppe M, Njah J, Sala E, Shiva S, St Croix CM, Stolz DB, Watkins SC, Di YP, Leikauf GD, Kolls J, Riches DW, Deiuliis G, Kaminski N, Boregowda SV, McKenna DH, Ortiz LA. Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat Commun. 2015;6:8472. https://doi.org/10.1038/ncomms9472.

    Article  PubMed  Google Scholar 

  89. Wang X, Gu H, Qin D, Yang L, Huang W, Essandoh K, Wang Y, Caldwell CC, Peng T, Zingarelli B, Fan GC. Exosomal miR-223 contributes to mesenchymal stem cell-elicited cardioprotection in polymicrobial sepsis. Sci Rep. 2015;5:13721. https://doi.org/10.1038/srep13721.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Xiao C, Wang K, Xu Y, Hu H, Zhang N, Wang Y, Zhong Z, Zhao J, Li Q, Zhu D, Ke C, Zhong S, Wu X, Yu H, Zhu W, Chen J, Zhang J, Wang J, Hu X. Transplanted mesenchymal stem cells reduce autophagic flux in infarcted hearts via the exosomal transfer of mir-125b. Circ Res. 2018. https://doi.org/10.1161/CIRCRESAHA.118.312758.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Li X, Liu L, Yang J, Yu Y, Chai J, Wang L, Ma L, Yin H. Exosome derived from human umbilical cord mesenchymal stem cell mediates MiR-181c attenuating burn-induced excessive inflammation. EBioMedicine. 2016;8:72–82. https://doi.org/10.1016/j.ebiom.2016.04.030.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Bier A, Berenstein P, Kronfeld N, Morgoulis D, Ziv-Av A, Goldstein H, Kazimirsky G, Cazacu S, Meir R, Popovtzer R, Dori A, Brodie C. Placenta-derived mesenchymal stromal cells and their exosomes exert therapeutic effects in Duchenne muscular dystrophy. Biomaterials. 2018;174:67–78. https://doi.org/10.1016/j.biomaterials.2018.04.055.

    Article  PubMed  Google Scholar 

  93. Lee HK, Finniss S, Cazacu S, Xiang C, Brodie C. Mesenchymal stem cells deliver exogenous miRNAs to neural cells and induce their differentiation and glutamate transporter expression. Stem Cells Dev. 2014;23(23):2851–61. https://doi.org/10.1089/scd.2014.0146.

    Article  PubMed  Google Scholar 

  94. Ti D, Hao H, Tong C, Liu J, Dong L, Zheng J, Zhao Y, Liu H, Fu X, Han W. LPS-preconditioned mesenchymal stromal cells modify macrophage polarization for resolution of chronic inflammation via exosome-shuttled let-7b. J Transl Med. 2015;13:308. https://doi.org/10.1186/s12967-015-0642-6.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Wu G, Yang G, Zhang R, Xu G, Zhang L, Wen W, Lu J, Liu J, Yu Y. Altered microRNA expression profiles of extracellular vesicles in nasal mucus from patients with allergic rhinitis. Allergy Asthma Immunol Res. 2015;7(5):449–57. https://doi.org/10.4168/aair.2015.7.5.449.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Asano M, Umezu T, Katagiri S, Kobayashi C, Tauchi T, Gotoh M, Ando K, Okabe S, Ohyashiki JH, Ohyashiki K. Up-regulated exosomal miRNA-140-3p in CML patients with musculoskeletal pain associated with discontinuation of tyrosine kinase inhibitors. Int J Hematol. 2017;105(4):419–22. https://doi.org/10.1007/s12185-017-2199-z.

    Article  PubMed  Google Scholar 

  97. Moen A, Jacobsen D, Phuyal S, Legfeldt A, Haugen F, Røe C, Gjerstad J. MicroRNA-223 demonstrated experimentally in exosome-like vesicles is associated with decreased risk of persistent pain after lumbar disc herniation. J Transl Med. 2017;15(1):89. https://doi.org/10.1186/s12967-017-1194-8.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Bruno S, Grange C, Deregibus MC, Calogero RA, Saviozzi S, Collino F, Morando L, Busca A, Falda M, Bussolati B, Tetta C, Camussi G. Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol. 2009;20(5):1053–67. https://doi.org/10.1681/ASN.2008070798.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Tomasoni S, Longaretti L, Rota C, Morigi M, Conti S, Gotti E, Capelli C, Introna M, Remuzzi G, Benigni A. Transfer of growth factor receptor mRNA via exosomes unravels the regenerative effect of mesenchymal stem cells. Stem Cells Dev. 2013;22(5):772–80. https://doi.org/10.1089/scd.2012.0266.

    Article  PubMed  Google Scholar 

  100. Akyurekli C, Le Y, Richardson RB, Fergusson D, Tay J, Allan DS. A systematic review of preclinical studies on the therapeutic potential of mesenchymal stromal cell-derived microvesicles. Stem Cell Rev. 2015;11(1):150–60. https://doi.org/10.1007/s12015-014-9545-9.

    Article  Google Scholar 

  101. Chang YH, Wu KC, Harn HJ, Lin SZ, Ding DC. Exosomes and stem cells in degenerative disease diagnosis and therapy. Cell Transplant. 2018;27:349–63.

    Article  PubMed  PubMed Central  Google Scholar 

  102. 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. https://doi.org/10.1007/s00441-018-2871-5. [Epub ahead of print].

  103. Yan Y, Jiang W, Tan Y, Zou S, Zhang H, Mao F, Gong A, Qian H, Xu W. hucMSC exosome-derived GPX1 is required for the recovery of hepatic oxidant injury. Mol Ther. 2017;25:465–79.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Zhu YG, Feng XM, Abbott J, Fang XH, Hao Q, Monsel A, Qu JM, Matthay MA, Lee JW. Human mesenchymal stem cell microvesicles for treatment of Escherichia coli endotoxin-induced acute lung injury in mice. Stem Cells. 2014;32:116–25. https://doi.org/10.1002/stem.1504.

    Article  PubMed  PubMed Central  Google Scholar 

  105. 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(11):1711–5. https://doi.org/10.1038/jcbfm.2013.152.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Harrell CR, Simovic Markovic B, Fellabaum C, Arsenijevic A, Djonov V, Arsenijevic N, Volarevic V. Therapeutic potential of mesenchymal stem cell-derived exosomes in the treatment of eye diseases. Adv Exp Med Biol. 2018. https://doi.org/10.1007/5584_2018_219. [Epub ahead of print].

    Article  PubMed  Google Scholar 

  107. Doeppner TR, Herz J, Görgens 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(10):1131–43. https://doi.org/10.5966/sctm.2015-0078.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Burrello J, Monticone S, Gai C, Gomez Y, Kholia S, Camussi G. Stem cell-derived extracellular vesicles and immune-modulation. Front Cell Dev Biol. 2016;4:83. https://doi.org/10.3389/fcell.2016.00083.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Jung JW, Kwon M, Choi JC, Shin JW, Park IW, Choi BW, Kim JY. Familial occurrence of pulmonary embolism after intravenous, adipose tissue-derived stem cell therapy. Yonsei Med J. 2013;54:1293–6.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Lener T, Gimona M, Aigner L, Börger V, Buzas E, Camussi G, Chaput N, Chatterjee D, Court FA, Del Portillo HA, O’Driscoll L, Fais S, Falcon-Perez JM, Felderhoff-Mueser U, Fraile L, Gho YS, Görgens A, Gupta RC, Hendrix A, Hermann DM, Hill AF, Hochberg F, Horn PA, de Kleijn D, Kordelas L, Kramer BW, Krämer-Albers EM, Laner-Plamberger S, Laitinen S, Leonardi T, Lorenowicz MJ, Lim SK, Lötvall J, Maguire CA, Marcilla A, Nazarenko I, Ochiya T, Patel T, Pedersen S, Pocsfalvi G, Pluchino S, Quesenberry P, Reischl IG, Rivera FJ, Sanzenbacher R, Schallmoser K, Slaper-Cortenbach I, Strunk D, Tonn T, Vader P, van Balkom BW, Wauben M, Andaloussi SE, Théry C, Rohde E, Giebel B. Applying extracellular vesicles based therapeutics in clinical trials—an ISEV position paper. J Extracell Vesicles. 2015;4:30087. https://doi.org/10.3402/jev.v4.30087. (eCollection 2015).

    Article  PubMed  Google Scholar 

  111. Liu Y, Li D, Liu Z, Zhou Y, Chu D, Li X, Jiang X, Hou D, Chen X, Chen Y, Yang Z, Jin L, Jiang W, Tian C, Zhou G, Zen K, Zhang J, Zhang Y, Li J, Zhang CY. Targeted exosome-mediated delivery of opioid receptor Mu siRNA for the treatment of morphine relapse. Sci Rep. 2015;5:17543. https://doi.org/10.1038/srep17543.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Shao H, Chung J, Lee K, Balaj L, Min C, Carter BS, Hochberg FH, Breakefield XO, Lee H, Weissleder R. Chip-based analysis of exosomal mRNA mediating drug resistance in glioblastoma. Nat Commun. 2015;6:6999. https://doi.org/10.1038/ncomms7999.

    Article  PubMed  Google Scholar 

  113. Guo W, Imai S, Dubner R, Ren K. Multipotent stromal cells for arthritic joint pain therapy and beyond. Pain Manag. 2014;4:153–62.

    Article  PubMed  Google Scholar 

  114. Otero-Ortega L, Gómez de Frutos MC, Laso-García F, Rodríguez-Frutos B, Medina-Gutiérrez E, López JA, Vázquez J, Díez-Tejedor E, Gutiérrez-Fernández M. Exosomes promote restoration after an experimental animal model of intracerebral hemorrhage. J Cereb Blood Flow Metab. 2018;38(5):767–79. https://doi.org/10.1177/0271678X17708917.

    Article  PubMed  Google Scholar 

  115. Takahashi Y, Nishikawa M, Shinotsuka H, Matsui Y, Ohara S, Imai T, Takakura Y. Visualization and in vivo tracking of the exosomes of murine melanoma B16-BL6 cells in mice after intravenous injection. J Biotechnol. 2013;165(2):77–84. https://doi.org/10.1016/j.jbiotec.2013.03.013.

    Article  PubMed  Google Scholar 

  116. Grange C, Tapparo M, Bruno S, Chatterjee D, Quesenberry PJ, Tetta C, Camussi G. Biodistribution of mesenchymal stem cell-derived extracellular vesicles in a model of acute kidney injury monitored by optical imaging. Int J Mol Med. 2014;33(5):1055–63. https://doi.org/10.3892/ijmm.2014.1663.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Morishita M, Takahashi Y, Nishikawa M, Sano K, Kato K, Yamashita T, Imai T, Saji H, Takakura Y. Quantitative analysis of tissue distribution of the B16BL6-derived exosomes using a streptavidin-lactadherin fusion protein and iodine-125-labeled biotin derivative after intravenous injection in mice. J Pharm Sci. 2015;104(2):705–13. https://doi.org/10.1002/jps.24251.

    Article  PubMed  Google Scholar 

  118. Smyth T, Kullberg M, Malik N, Smith-Jones P, Graner MW, Anchordoquy TJ. Biodistribution and delivery efficiency of unmodified tumor-derived exosomes. J Control Release. 2015;199:145–55. https://doi.org/10.1016/j.jconrel.2014.12.013.

    Article  PubMed  Google Scholar 

  119. Wiklander OP, Nordin JZ, O’Loughlin A, Gustafsson Y, Corso G, Mäger I, Vader P, Lee Y, Sork H, Seow Y, Heldring N, Alvarez-Erviti L, Smith CI, Le Blanc K, Macchiarini P, Jungebluth P, Wood MJ, Andaloussi SE. Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. J Extracell Vesicles. 2015;4:26316. https://doi.org/10.3402/jev.v4.26316.

    Article  PubMed  Google Scholar 

  120. Di Rocco G, Baldari S, Toietta G. Towards therapeutic delivery of extracellular vesicles: strategies for in vivo tracking and biodistribution analysis. Stem Cells Int. 2016; 2016:5029619.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Lai CP, Mardini O, Ericsson M, Prabhakar S, Maguire C, Chen JW, Tannous BA, Breakefield XO. Dynamic biodistribution of extracellular vesicles in vivo using a multimodal imaging reporter. ACS Nano. 2014;8(1):483–94. https://doi.org/10.1021/nn404945r.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Danielyan L, Beer-Hammer S, Stolzing A, Schäfer R, Siegel G, Fabian C, Kahle P, Biedermann T, Lourhmati A, Buadze M, Novakovic A, Proksch B, Gleiter CH, Frey WH, Schwab M. Intranasal delivery of bone marrow-derived mesenchymal stem cells, macrophages, and microglia to the brain in mouse models of Alzheimer’s and Parkinson’s disease. Cell Transpl. 2014;23(Suppl 1):123–39. https://doi.org/10.3727/096368914X684970.

    Article  Google Scholar 

  123. Betzer O, Perets N, Angel A, Motiei M, Sadan T, Yadid G, Offen D, Popovtzer R. In vivo neuroimaging of exosomes using gold nanoparticles. ACS Nano. 2017;11(11):10883–93. https://doi.org/10.1021/acsnano.7b04495.

    Article  PubMed  Google Scholar 

  124. Ren K, Dubner R. Interactions between the immune and nervous systems in pain. Nat Med. 2010;16:1267–76.

    Article  PubMed  PubMed Central  Google Scholar 

  125. Waterman RS, Tomchuck SL, Henkle SL, Betancourt AM. A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an Immunosuppressive MSC2 phenotype. PLoS One. 2010;5(4):e10088. https://doi.org/10.1371/journal.pone.0010088.

    Article  PubMed  PubMed Central  Google Scholar 

  126. McDonald MK, Tian Y, Qureshi RA, Gormley M, Ertel A, Gao R, Aradillas Lopez E, Alexander GM, Sacan A, Fortina P, Ajit SK. Functional significance of macrophage-derived exosomes in inflammation and pain. Pain. 2014;155(8):1527–39. https://doi.org/10.1016/j.pain.2014.04.029.

    Article  PubMed  PubMed Central  Google Scholar 

  127. 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(4):991–7. https://doi.org/10.1097/TA.0000000000000186.

    Article  PubMed  Google Scholar 

  128. Crompot E, Van Damme M, Pieters K, Vermeersch M, Perez-Morga D, Mineur P, Maerevoet M, Meuleman N, Bron D, Lagneaux L, Stamatopoulos B. Extracellular vesicles of bone marrow stromal cells rescue chronic lymphocytic leukemia B cells from apoptosis, enhance their migration and induce gene expression modifications. Haematologica. 2017;102(9):1594–604. https://doi.org/10.3324/haematol.2016.163337.

    Article  PubMed  PubMed Central  Google Scholar 

  129. Kilpinen L, Impola U, Sankkila L, Ritamo I, Aatonen M, Kilpinen S, Tuimala J, Valmu L, Levijoki J, Finckenberg P, Siljander P, Kankuri E, Mervaala E, Laitinen S. 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; 2. https://doi.org/10.3402/jev.v2i0.21927.

  130. Helwa I, Cai J, Drewry MD, Zimmerman A, Dinkins MB, Khaled ML, Seremwe M, Dismuke WM, Bieberich E, Stamer WD, Hamrick MW, Liu Y. A comparative study of serum exosome isolation using differential ultracentrifugation and three commercial reagents. PLoS One. 2017;12(1):e0170628. https://doi.org/10.1371/journal.pone.0170628.

    Article  PubMed  PubMed Central  Google Scholar 

  131. Li P, Kaslan M, Lee SH, Yao J, Gao Z. Progress in exosome isolation techniques. Theranostics. 2017;7(3):789–804. https://doi.org/10.7150/thno.18133.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The author’s work was supported by the Maryland Stem Cell Foundation grant 2014-MSCRFI-0584 and National Institutes of Health grant DE025137.

Author information

Authors and Affiliations

  1. Department of Neural and Pain Sciences, School of Dentistry, & Program in Neuroscience, University of Maryland, 650 W. Baltimore St, Dental-8 South, Baltimore, MD, 21201, USA

    Ke Ren

Authors
  1. Ke Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ke Ren.

Ethics declarations

Conflict of interest

The author declares that he has no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ren, K. Exosomes in perspective: a potential surrogate for stem cell therapy. Odontology 107, 271–284 (2019). https://doi.org/10.1007/s10266-018-0395-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10266-018-0395-9

Keywords

Search

Navigation