Skip to main content
Top
Published in: Odontology 3/2019

01-07-2019 | Review Article

Exosomes in perspective: a potential surrogate for stem cell therapy

Author: Ke Ren

Published in: Odontology | Issue 3/2019

Login to get access

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.
Literature
1.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
2.
go back to reference 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 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
3.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
4.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
5.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
6.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
7.
go back to reference Stanko P, Altanerova U, Jakubechova J, Repiska V, Altaner C. Dental Mesenchymal Stem/Stromal Cells and Their Exosomes. Stem Cells Int. 2018; 2018:8973613. 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.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
11.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
13.
go back to reference 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. 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.
17.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
18.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
19.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
20.
go back to reference Phinney DG, Pittenger MF. Concise review: MSC-derived exosomes for cell-free therapy. Stem Cells. 2017;35:851–8.CrossRefPubMed Phinney DG, Pittenger MF. Concise review: MSC-derived exosomes for cell-free therapy. Stem Cells. 2017;35:851–8.CrossRefPubMed
21.
go back to reference Théry C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol. 2009;9:581–93.CrossRefPubMed Théry C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol. 2009;9:581–93.CrossRefPubMed
23.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
24.
go back to reference Cocucci E, Meldolesi J. Ectosomes and exosomes: shedding the confusion between extracellular vesicles. Trends Cell Biol. 2015;25:364–72.CrossRefPubMed Cocucci E, Meldolesi J. Ectosomes and exosomes: shedding the confusion between extracellular vesicles. Trends Cell Biol. 2015;25:364–72.CrossRefPubMed
25.
26.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
27.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
28.
go back to reference Bissig C, Gruenberg J. ALIX and the multivesicular endosome: ALIX in Wonderland. Trends Cell Biol. 2014;24:19–25.CrossRefPubMed Bissig C, Gruenberg J. ALIX and the multivesicular endosome: ALIX in Wonderland. Trends Cell Biol. 2014;24:19–25.CrossRefPubMed
30.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
32.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
33.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
35.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
36.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
37.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
38.
go back to reference Mathivanan S, Ji H, Simpson RJ. Exosomes: extracellular organelles important in intercellular communication. J Proteomics. 2010;73:1907–20.CrossRefPubMed Mathivanan S, Ji H, Simpson RJ. Exosomes: extracellular organelles important in intercellular communication. J Proteomics. 2010;73:1907–20.CrossRefPubMed
39.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
44.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
45.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
46.
go back to reference 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].CrossRef 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].CrossRef
47.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
48.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
49.
go back to reference 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.CrossRef 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​.CrossRef
50.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
51.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
52.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
53.
go back to reference Le Blanc K, Davies LC. Mesenchymal stromal cells and the innate immune response. Immunol Lett. 2015;168:140–6.CrossRefPubMed Le Blanc K, Davies LC. Mesenchymal stromal cells and the innate immune response. Immunol Lett. 2015;168:140–6.CrossRefPubMed
55.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
56.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
58.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
60.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
62.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
63.
go back to reference 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].CrossRef 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].CrossRef
64.
go back to reference 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]. 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.
go back to reference 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. 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.
69.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
71.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
72.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
73.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
74.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
78.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
79.
go back to reference Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 7th ed. Amsterdam: Elsevier; 2014. Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 7th ed. Amsterdam: Elsevier; 2014.
80.
go back to reference 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. 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.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
85.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
86.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
88.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
96.
101.
102.
103.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
109.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
110.
go back to reference 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).CrossRefPubMed 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).CrossRefPubMed
113.
go back to reference Guo W, Imai S, Dubner R, Ren K. Multipotent stromal cells for arthritic joint pain therapy and beyond. Pain Manag. 2014;4:153–62.CrossRefPubMed Guo W, Imai S, Dubner R, Ren K. Multipotent stromal cells for arthritic joint pain therapy and beyond. Pain Manag. 2014;4:153–62.CrossRefPubMed
114.
go back to reference 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.CrossRefPubMed 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​.CrossRefPubMed
117.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
119.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
120.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
122.
go back to reference 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.CrossRef 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​.CrossRef
128.
129.
go back to reference 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. 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.
Metadata
Title
Exosomes in perspective: a potential surrogate for stem cell therapy
Author
Ke Ren
Publication date
01-07-2019
Publisher
Springer Japan
Published in
Odontology / Issue 3/2019
Print ISSN: 1618-1247
Electronic ISSN: 1618-1255
DOI
https://doi.org/10.1007/s10266-018-0395-9

Other articles of this Issue 3/2019

Odontology 3/2019 Go to the issue