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The Therapeutic Potential of Mesenchymal Stem Cell–Derived Exosomes in Treatment of Neurodegenerative Diseases

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Abstract

Neurologic complications are commonly regarded as irreversible impairments that stem from limited potential of regeneration of the central nervous system (CNS). On the other side, the regenerative potential of stem cells has been evaluated in basic research, as well as in preclinical studies. Mesenchymal stem cells (MSCs) have been regarded as candidate cell sources for therapeutic purposes of various neurological disorders, because of their self-renewal ability, plasticity in differentiation, neurotrophic characteristics, and immunomodulatory properties. Exosomes are extracellular vesicles which can deliver biological information over long distances and thereby influencing normal and abnormal processes in cells and tissues. The therapeutic capacity of exosomes relies on the type of cell, as well as on the physiological condition of a given cell. Therefore, based on tissue type and physiological condition of CNS, exosomes may function as contributors or suppressors of pathological conditions in this tissue. When it comes to the therapeutic viewpoint, the most promising cellular source of exosomes is considered to be MSCs. The aim of this review article is to discuss the current knowledge around the potential of stem cells and MSC-derived exosomes in the treatment of neurodegenerative diseases.

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References

  1. Przedborski S, Vila M, Jackson-Lewis V (2003) Series Introduction: Neurodegeneration: What is it and where are we? J Clin Invest 111(1):3–10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Skovronsky DM, Lee VM-Y, Trojanowski JQ (2006) Neurodegenerative diseases: new concepts of pathogenesis and their therapeutic implications. Annu Rev Pathol Mech Dis 1:151–170

    Article  CAS  Google Scholar 

  3. Barchet TM, Amiji MM (2009) Challenges and opportunities in CNS delivery of therapeutics for neurodegenerative diseases. Expert Opin Drug Deliv 6(3):211–225

    Article  CAS  PubMed  Google Scholar 

  4. Banks WA (2016) From blood–brain barrier to blood–brain interface: new opportunities for CNS drug delivery. Nat Rev Drug Discov 15(4):275

    Article  CAS  PubMed  Google Scholar 

  5. Andaloussi SE, Mäger I, Breakefield XO, Wood MJ (2013) Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discov 12(5):347

    Article  CAS  Google Scholar 

  6. Raposo G, Stoorvogel W (2013) Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol 200(4):373–383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Aryani A, Denecke B (2016) Exosomes as a nanodelivery system: a key to the future of neuromedicine? Mol Neurobiol 53(2):818–834

    Article  CAS  PubMed  Google Scholar 

  8. 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(4):341

    Article  CAS  PubMed  Google Scholar 

  9. Bongso A, Fong CY, Gauthaman K (2008) Taking stem cells to the clinic: major challenges. J Cell Biochem 105(6):1352–1360

    Article  CAS  PubMed  Google Scholar 

  10. Raff M (2003) Adult stem cell plasticity: fact or artifact? Annu Rev Cell Dev Biol 19(1):1–22

    Article  CAS  PubMed  Google Scholar 

  11. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA et al (2007) Induced pluripotent stem cell lines derived from human somatic cells. science 318(5858):1917–1920

    Article  CAS  PubMed  Google Scholar 

  12. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5):861–872

    Article  CAS  PubMed  Google Scholar 

  13. Menon S, Shailendra S, Renda A, Longaker M, Quarto N (2016) An overview of direct somatic reprogramming: the ins and outs of iPSCs. Int J Mol Sci 17(1):141

    Article  CAS  PubMed Central  Google Scholar 

  14. Lopez-Verrilli M, Caviedes A, Cabrera A, Sandoval S, Wyneken U, Khoury M (2016) Mesenchymal stem cell-derived exosomes from different sources selectively promote neuritic outgrowth. Neuroscience 320:129–139

    Article  CAS  PubMed  Google Scholar 

  15. Salgado AJ, Sousa JC, Costa BM, Pires AO, Mateus-Pinheiro A, Teixeira F, Pinto L, Sousa N (2015) Mesenchymal stem cells secretome as a modulator of the neurogenic niche: basic insights and therapeutic opportunities. Front Cell Neurosci 9:249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Tfilin M, Sudai E, Merenlender A, Gispan I, Yadid G, Turgeman G (2010) Mesenchymal stem cells increase hippocampal neurogenesis and counteract depressive-like behavior. Mol Psychiatry 15(12):1164

    Article  CAS  PubMed  Google Scholar 

  17. Levy Y, Bahat-Stroomza M, Levy Y, Bahat-Stroomza M, Barzilay R, Burshtein A, Bulvik S, Barhum Y et al (2008) Regenerative effect of neural-induced human mesenchymal stromal cells in rat models of Parkinson’s disease. Cytotherapy 10(4):340–352

    Article  CAS  PubMed  Google Scholar 

  18. Somoza R, Juri C, Baes M, Wyneken U, Rubio FJ (2010) Intranigral transplantation of epigenetically induced BDNF-secreting human mesenchymal stem cells: implications for cell-based therapies in Parkinson’s disease. Biol Blood Marrow Transplant 16(11):1530–1540

    Article  CAS  PubMed  Google Scholar 

  19. Zhu J, Liu Q, Jiang Y, Wu L, Xu G, Liu X (2015) Enhanced angiogenesis promoted by human umbilical mesenchymal stem cell transplantation in stroked mouse is Notch1 signaling associated. Neuroscience 290:288–299

    Article  CAS  PubMed  Google Scholar 

  20. Marconi S, Bonaconsa M, Scambi I, Squintani G, Rui W, Turano E, Ungaro D, D’Agostino S et al (2013) Systemic treatment with adipose-derived mesenchymal stem cells ameliorates clinical and pathological features in the amyotrophic lateral sclerosis murine model. Neuroscience 248:333–343

    Article  CAS  PubMed  Google Scholar 

  21. Baez-Jurado E, Hidalgo-Lanussa O, Guio-Vega G, Ashraf GM, Echeverria V, Aliev G, Barreto GE (2018) Conditioned medium of human adipose mesenchymal stem cells increases wound closure and protects human astrocytes following scratch assay in vitro. Mol Neurobiol 55(6):5377–5392. https://doi.org/10.1007/s12035-017-0771-4

    Article  CAS  PubMed  Google Scholar 

  22. Torrente D, Avila MF, Cabezas R, Morales L, Gonzalez J, Samudio I, Barreto GE (2014) Paracrine factors of human mesenchymal stem cells increase wound closure and reduce reactive oxygen species production in a traumatic brain injury in vitro model. Hum Exp Toxicol 33(7):673–684. https://doi.org/10.1177/0960327113509659

    Article  CAS  PubMed  Google Scholar 

  23. Cabezas R, Baez-Jurado E, Hidalgo-Lanussa O, Echeverria V, Ashrad GM, Sahebkar A, Barreto GE (2018) Growth factors and neuroglobin in astrocyte protection against neurodegeneration and oxidative stress. Mol Neurobiol. https://doi.org/10.1007/s12035-018-1203-9

  24. Baez E, Echeverria V, Cabezas R, Avila-Rodriguez M, Garcia-Segura LM, Barreto GE (2016) Protection by neuroglobin expression in brain pathologies. Front Neurol 7:146. https://doi.org/10.3389/fneur.2016.00146

    Article  PubMed  PubMed Central  Google Scholar 

  25. Baez-Jurado E, Vega GG, Aliev G, Tarasov VV, Esquinas P, Echeverria V, Barreto GE (2018) Blockade of neuroglobin reduces protection of conditioned medium from human mesenchymal stem cells in human astrocyte model (T98G) under a scratch assay. Mol Neurobiol 55(3):2285–2300. https://doi.org/10.1007/s12035-017-0481-y

    Article  CAS  PubMed  Google Scholar 

  26. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW et al (1999) Multilineage potential of adult human mesenchymal stem cells. science 284(5411):143–147

    Article  CAS  PubMed  Google Scholar 

  27. Bianco P (2014) “Mesenchymal” stem cells. Annu Rev Cell Dev Biol 30:677–704

    Article  CAS  PubMed  Google Scholar 

  28. Bianco P, Cao X, Frenette PS, Mao JJ, Robey PG, Simmons PJ, Wang C-Y (2013) The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine. Nat Med 19(1):35

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kuznetsov SA, Krebsbach PH, Satomura K, Kerr J, Riminucci M, Benayahu D, Robey PG (1997) Single-colony derived strains of human marrow stromal fibroblasts form bone after transplantation in vivo. J Bone Miner Res 12(9):1335–1347

    Article  CAS  PubMed  Google Scholar 

  30. Batouli S, Miura M, Brahim J, Tsutsui T, Fisher L, Gronthos S, Robey PG, Shi S (2003) Comparison of stem-cell-mediated osteogenesis and dentinogenesis. J Dent Res 82(12):976–981

    Article  CAS  PubMed  Google Scholar 

  31. Cocucci E, Meldolesi J (2015) Ectosomes and exosomes: shedding the confusion between extracellular vesicles. Trends Cell Biol 25(6):364–372

    Article  CAS  PubMed  Google Scholar 

  32. Cocucci E, Racchetti G, Meldolesi J (2009) Shedding microvesicles: artefacts no more. Trends Cell Biol 19(2):43–51

    Article  CAS  PubMed  Google Scholar 

  33. Wideman JG, Leung KF, Field MC, Dacks JB (2014) The cell biology of the endocytic system from an evolutionary perspective. Cold Spring Harb Perspect Biol 6(4):a016998

  34. Lopez-Verrilli MA (2013) Exosomes: mediators of communication in eukaryotes. Biol Res 46(1):5–11

    Article  CAS  PubMed  Google Scholar 

  35. Colombo M, Raposo G, Théry C (2014) Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol 30:255–289

    Article  CAS  PubMed  Google Scholar 

  36. Pan B-T, Teng K, Wu C, Adam M, Johnstone RM (1985) Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes. J Cell Biol 101(3):942–948

    Article  CAS  PubMed  Google Scholar 

  37. Harding C, Heuser J, Stahl P (1983) Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. J Cell Biol 97(2):329–339

    Article  CAS  PubMed  Google Scholar 

  38. Hanson PI, Cashikar A (2012) Multivesicular body morphogenesis. Annu Rev Cell Dev Biol 28:337–362

    Article  CAS  PubMed  Google Scholar 

  39. Savina A, Furlán M, Vidal M, Colombo MI (2003) Exosome release is regulated by a calcium-dependent mechanism in K562 cells. J Biol Chem 278(22):20083–90

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

    Article  CAS  PubMed  Google Scholar 

  41. Kosaka N, Iguchi H, Hagiwara K, Yoshioka Y, Takeshita F, Ochiya T (2013) Neutral sphingomyelinase 2 (nSMase2)-dependent exosomal transfer of angiogenic microRNAs regulate cancer cell metastasis. J Biol Chem 288(15):10849–59

  42. Baietti MF, Zhang Z, Mortier E, Melchior A, Degeest G, Geeraerts A, Ivarsson Y, Depoortere F et al (2012) Syndecan–syntenin–ALIX regulates the biogenesis of exosomes. Nat Cell Biol 14(7):677

    Article  CAS  PubMed  Google Scholar 

  43. Hurley JH, Odorizzi G (2012) Get on the exosome bus with ALIX. Nat Cell Biol 14(7):654

    Article  CAS  PubMed  Google Scholar 

  44. Villarroya-Beltri C, Gutiérrez-Vázquez C, Sánchez-Cabo F, Pérez-Hernández D, Vázquez J, Martin-Cofreces N, Martinez-Herrera DJ, Pascual-Montano A et al (2013) Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat Commun 4:2980

    Article  CAS  PubMed  Google Scholar 

  45. Simons M, Raposo G (2009) Exosomes–vesicular carriers for intercellular communication. Curr Opin Cell Biol 21(4):575–581

    Article  CAS  PubMed  Google Scholar 

  46. Taylor AR, Robinson MB, Gifondorwa DJ, Tytell M, Milligan CE (2007) Regulation of heat shock protein 70 release in astrocytes: role of signaling kinases. Dev Neurobiol 67(13):1815–1829

    Article  CAS  PubMed  Google Scholar 

  47. Chaput N, Théry C (2011) Exosomes: immune properties and potential clinical implementations. Semin Immunopathol 33(5):419–40

  48. Sahu R, Kaushik S, Clement CC, Cannizzo ES, Scharf B, Follenzi A, Potolicchio I, Nieves E et al (2011) Microautophagy of cytosolic proteins by late endosomes. Dev Cell 20(1):131–139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Pols MS, Klumperman J (2009) Trafficking and function of the tetraspanin CD63. Exp Cell Res 315(9):1584–1592

    Article  CAS  PubMed  Google Scholar 

  50. Kleijmeer MJ, Stoorvogel W, Griffith JM, Yoshie O, Geuze HJ (1998) Selective enrichment of tetraspan proteins on the internal vesicles of multivesicular endosomes and on exosomes secreted by human B-lymphocytes. J Biol Chem 273(32):20121–20127

    Article  PubMed  Google Scholar 

  51. Théry C, Amigorena S, Raposo G, Clayton A (2006) Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol 30(1):3.22.21–23.22.29

    Article  Google Scholar 

  52. Strauss K, Goebel C, Runz H, Möbius W, Weiss S, Feussner I, Simons M, Schneider A (2010) Exosome secretion ameliorates lysosomal storage of cholesterol in Niemann-Pick type C disease. J Biol Chem 285(34):26279–88

  53. Grapp M, Wrede A, Schweizer M, Hüwel S, Galla H-J, Snaidero N, Simons M, Bückers J et al (2013) Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma. Nat Commun 4:2123

    Article  CAS  PubMed  Google Scholar 

  54. Lötvall J, Hill AF, Hochberg F, Buzás EI, Di Vizio D, Gardiner C, Gho YS, Kurochkin IV et al (2014) 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:https://doi.org/10.3402/jev.v3.26913

  55. Kowal J, Tkach M, Thery C (2014) Biogenesis and secretion of exosomes. Curr Opin Cell Biol 29:116–125

    Article  CAS  PubMed  Google Scholar 

  56. Montecalvo A, Larregina AT, Shufesky WJ, Stolz DB, Sullivan ML, Karlsson JM, Baty CJ, Gibson GA et al (2012) Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. Blood 119(3):756–766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Christianson HC, Svensson KJ, van Kuppevelt TH, Li J-P, Belting M (2013) Cancer cell exosomes depend on cell-surface heparan sulfate proteoglycans for their internalization and functional activity. Proc Natl Acad Sci 110(43):17380–5

  58. 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(6):654

    Article  CAS  PubMed  Google Scholar 

  59. Tian T, Zhu Y-L, Zhou Y-Y, Liang G-F, Wang Y-Y, Hu F-H, Xiao Z-D (2014) Exosome uptake through clathrin-mediated endocytosis and macropinocytosis and mediating miR-21 delivery. J Biol Chem 289(32):22258–67

  60. Feng D, Zhao WL, Ye YY, Bai XC, Liu RQ, Chang LF, Zhou Q, Sui SF (2010) Cellular internalization of exosomes occurs through phagocytosis. Traffic 11(5):675–687

    Article  CAS  PubMed  Google Scholar 

  61. Fitzner D, Schnaars M, van Rossum D, Krishnamoorthy G, Dibaj P, Bakhti M, Regen T, Hanisch U-K et al (2011) Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis. J Cell Sci 124(3):447–458

    Article  CAS  PubMed  Google Scholar 

  62. Svensson KJ, Christianson HC, Wittrup A, Bourseau-Guilmain E, Lindqvist E, Svensson LM, Morgelin M, Belting M (2013) Exosome uptake depends on ERK1/2-heat shock protein 27 signalling and lipid raft-mediated endocytosis negatively regulated by caveolin-1. J Biol Chem 288(24):17713-24

  63. Tian T, Zhu YL, Hu FH, Wang YY, Huang NP, Xiao ZD (2013) Dynamics of exosome internalization and trafficking. J Cell Physiol 228(7):1487–1495

    Article  CAS  PubMed  Google Scholar 

  64. Mulcahy LA, Pink RC, Carter DRF (2014) Routes and mechanisms of extracellular vesicle uptake. J Extracell Vesicles 3(1):24641

    Article  CAS  Google Scholar 

  65. Parolini I, Federici C, Raggi C, Lugini L, Palleschi S, De Milito A, Coscia C, Iessi E et al (2009) Microenvironmental pH is a key factor for exosome traffic in tumor cells. J Biol Chem 284(49):34211-22

  66. Gibbings DJ, Ciaudo C, Erhardt M, Voinnet O (2009) Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity. Nat Cell Biol 11(9):1143

    Article  CAS  PubMed  Google Scholar 

  67. Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief C, Geuze HJ (1996) B lymphocytes secrete antigen-presenting vesicles. J Exp Med 183(3):1161–1172

    Article  CAS  PubMed  Google Scholar 

  68. Zitvogel L, Regnault A, Lozier A, Wolfers J, Flament C, Tenza D, Ricciardi-Castagnoli P, Raposo G et al (1998) Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell derived exosomes. Nat Med 4(5):594

    Article  CAS  PubMed  Google Scholar 

  69. Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, Jacobs AH, Wyss-Coray T et al (2015) Neuroinflammation in Alzheimer’s disease. Lancet Neurol 14(4):388–405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Zhuang X, Xiang X, Grizzle W, Sun D, Zhang S, Axtell RC, Ju S, Mu J et al (2011) Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. Mol Ther 19(10):1769–1779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Haney MJ, Klyachko NL, Zhao Y, Gupta R, Plotnikova EG, He Z, Patel T, Piroyan A et al (2015) Exosomes as drug delivery vehicles for Parkinson’s disease therapy. J Control Release 207:18–30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Pusic AD, Pusic KM, Clayton BL, Kraig RP (2014) IFNγ-stimulated dendritic cell exosomes as a potential therapeutic for remyelination. J Neuroimmunol 266(1–2):12–23

    Article  CAS  PubMed  Google Scholar 

  73. Record M, Subra C, Silvente-Poirot S, Poirot M (2011) Exosomes as intercellular signalosomes and pharmacological effectors. Biochem Pharmacol 81(10):1171–1182

    Article  CAS  PubMed  Google Scholar 

  74. Zhou W, Fong MY, Min Y, Somlo G, Liu L, Palomares MR, Yu Y, Chow A et al (2014) Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell 25(4):501–515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Tominaga N, Kosaka N, Ono M, Katsuda T, Yoshioka Y, Tamura K, Lötvall J, Nakagama H et al (2015) Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood–brain barrier. Nat Commun 6:6716

    Article  CAS  PubMed  Google Scholar 

  76. Pivoraitė U, Jarmalavičiūtė A, Tunaitis V, Ramanauskaitė G, Vaitkuvienė A, Kašėta V, Biziulevičienė G, Venalis A et al (2015) Exosomes from human dental pulp stem cells suppress carrageenan-induced acute inflammation in mice. Inflammation 38(5):1933–1941

    Article  CAS  PubMed  Google Scholar 

  77. S-i O, Takanashi M, Sudo K, Ueda S, Ishikawa A, Matsuyama N, Fujita K, Mizutani T et al (2013) Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells. Mol Ther 21(1):185–191

    Article  CAS  Google Scholar 

  78. Liu Y, Li D, Liu Z, Zhou Y, Chu D, Li X, Jiang X, Hou D et al (2015) Targeted exosome-mediated delivery of opioid receptor Mu siRNA for the treatment of morphine relapse. Sci Rep 5:17543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Lee C, Hu J, Ralls S, Kitamura T, Loh YP, Yang Y, Mukouyama Y-s, Ahn S (2012) The molecular profiles of neural stem cell niche in the adult subventricular zone. PLoS One 7(11):e50501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Chever O, Pannasch U, Ezan P, Rouach N (2014) Astroglial connexin 43 sustains glutamatergic synaptic efficacy. Philos Trans R Soc B 369(1654):20130596

    Article  CAS  Google Scholar 

  81. Mercier F, Hatton GI (2001) Connexin 26 and basic fibroblast growth factor are expressed primarily in the subpial and subependymal layers in adult brain parenchyma: roles in stem cell proliferation and morphological plasticity? J Comp Neurol 431(1):88–104

    Article  CAS  PubMed  Google Scholar 

  82. Soares AR, Martins-Marques T, Ribeiro-Rodrigues T, Ferreira JV, Catarino S, Pinho MJ, Zuzarte M, Anjo SI et al (2015) Gap junctional protein Cx43 is involved in the communication between extracellular vesicles and mammalian cells. Sci Rep 5:13243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Evans WH, Leybaert L (2007) Mimetic peptides as blockers of connexin channel-facilitated intercellular communication. Cell Commun Adhes 14(6):265–273

    Article  CAS  PubMed  Google Scholar 

  84. Evans W, Boitano S (2001) Connexin mimetic peptides: specific inhibitors of gap-junctional intercellular communication. Biochem Soc Trans 2001;29(Pt 4):606-12

  85. Garcion E, Halilagic A, Faissner A (2004) Generation of an environmental niche for neural stem cell development by the extracellular matrix molecule tenascin C. Development 131(14):3423–3432

    Article  CAS  PubMed  Google Scholar 

  86. Chiquet-Ehrismann R, Orend G, Chiquet M, Tucker RP, Midwood KS (2014) Tenascins in stem cell niches. Matrix Biol 37:112–123

    Article  CAS  PubMed  Google Scholar 

  87. Ferhat L, Chevassus-Au-Louis N, Khrestchatisky M, Ben-Ari Y, Represa A (1996) Seizures induce tenascin-C mRNA expression in neurons. J Neurocytol 25(1):535–546

    Article  CAS  PubMed  Google Scholar 

  88. Kim MY, Kim OR, Choi YS, Lee H, Park K, Lee C-T, Kang KW, Jeong S (2012) Selection and characterization of tenascin C targeting peptide. Mol Cell 33(1):71–77

    Article  CAS  Google Scholar 

  89. Schwarz JM (2015) Using fluorescence activated cell sorting to examine cell-type-specific gene expression in rat brain tissue. J Vis Exp 99:e52537

  90. Okaty BW, Sugino K, Nelson SB (2011) A quantitative comparison of cell-type-specific microarray gene expression profiling methods in the mouse brain. PLoS One 6(1):e16493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Pastrana E, Cheng L-C, Doetsch F (2009) Simultaneous prospective purification of adult subventricular zone neural stem cells and their progeny. Proc Natl Acad Sci 106(15):6387–6392

    Article  PubMed  PubMed Central  Google Scholar 

  92. Bonaguidi MA, Peng C-Y, McGuire T, Falciglia G, Gobeske KT, Czeisler C, Kessler JA (2008) Noggin expands neural stem cells in the adult hippocampus. J Neurosci 28(37):9194–9204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Heng YHE, Zhou B, Harris L, Harvey T, Smith A, Horne E, Martynoga B, Andersen J et al (2014) NFIX regulates proliferation and migration within the murine SVZ neurogenic niche. Cereb Cortex 25(10):3758–3778

    Article  PubMed  PubMed Central  Google Scholar 

  94. Fuentealba LC, Rompani SB, Parraguez JI, Obernier K, Romero R, Cepko CL, Alvarez-Buylla A (2015) Embryonic origin of postnatal neural stem cells. Cell 161(7):1644–1655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Alvarez-Buylla A, García-Verdugo JM, Tramontin AD (2001) A unified hypothesis on the lineage of neural stem cells. Nat Rev Neurosci 2(4):287

    Article  CAS  PubMed  Google Scholar 

  96. Shen Q, Temple S (2009) Fine control: microRNA regulation of adult neurogenesis. Nat Neurosci 12(4):369

    Article  CAS  PubMed  Google Scholar 

  97. Zheng K, Li H, Zhu Y, Zhu Q, Qiu M (2010) MicroRNAs are essential for the developmental switch from neurogenesis to gliogenesis in the developing spinal cord. J Neurosci 30(24):8245–8250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Zhang Z, Yan R, Zhang Q, Li J, Kang X, Wang H, Huan L, Zhang L et al (2014) Hes1, a Notch signaling downstream target, regulates adult hippocampal neurogenesis following traumatic brain injury. Brain Res 1583:65–78

    Article  CAS  PubMed  Google Scholar 

  99. Coolen M, Katz S, Bally-Cuif L (2013) miR-9: a versatile regulator of neurogenesis. Front Cell Neurosci 7:220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Wang C, Yao N, Lu C-L, Li D, Ma X (2010) Mouse microRNA-124 regulates the expression of Hes1 in P19 cells. Front Biosci (Elite Ed) 2:127–132

    Google Scholar 

  101. Liu XS, Chopp M, Zhang RL, Tao T, Wang XL, Kassis H, Hozeska-Solgot A, Zhang L et al (2011) MicroRNA profiling in subventricular zone after stroke: miR-124a regulates proliferation of neural progenitor cells through Notch signaling pathway. PLoS One 6(8):e23461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Patterson M, Gaeta X, Loo K, Edwards M, Smale S, Cinkornpumin J, Xie Y, Listgarten J et al (2014) let-7 miRNAs can act through notch to regulate human gliogenesis. Stem Cell Rep 3(5):758–773

    Article  CAS  Google Scholar 

  103. Rafalski VA, Ho PP, Brett JO, Ucar D, Dugas JC, Pollina EA, Chow LM, Ibrahim A et al (2013) Expansion of oligodendrocyte progenitor cells following SIRT1 inactivation in the adult brain. Nat Cell Biol 15(6):614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Zhang L, Wang X, Chen P (2013) MiR-204 down regulates SIRT1 and reverts SIRT1-induced epithelial-mesenchymal transition, anoikis resistance and invasion in gastric cancer cells. BMC Cancer 13(1):290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Lee HK, Finniss S, Cazacu S, Xiang C, Brodie C (2014) Mesenchymal stem cells deliver exogenous miRNAs to neural cells and induce their differentiation and glutamate transporter expression. Stem Cells Dev 23(23):2851–2861

    Article  CAS  PubMed  Google Scholar 

  106. Huang G-J, Gronthos S, Shi S (2009) Mesenchymal stem cells derived from dental tissues vs. those from other sources: their biology and role in regenerative medicine. J Dent Res 88(9):792–806

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Kaukua N, Shahidi MK, Konstantinidou C, Dyachuk V, Kaucka M, Furlan A, An Z, Wang L et al (2014) Glial origin of mesenchymal stem cells in a tooth model system. Nature 513(7519):551

    Article  CAS  PubMed  Google Scholar 

  108. Jarmalavičiūtė A, Tunaitis V, Strainienė E, Aldonytė R, Ramanavičius A, Venalis A, Magnusson K-E, Pivoriūnas A (2013) A new experimental model for neuronal and glial differentiation using stem cells derived from human exfoliated deciduous teeth. J Mol Neurosci 51(2):307–317

    Article  CAS  Google Scholar 

  109. Kiraly M, Porcsalmy B, Pataki A, Kadar K, Jelitai M, Molnar B, Hermann P, Gera I et al (2009) Simultaneous PKC and cAMP activation induces differentiation of human dental pulp stem cells into functionally active neurons. Neurochem Int 55(5):323–332

    Article  CAS  PubMed  Google Scholar 

  110. Arthur A, Rychkov G, Shi S, Koblar SA, Gronthos S (2008) Adult human dental pulp stem cells differentiate toward functionally active neurons under appropriate environmental cues. Stem Cells 26(7):1787–1795

    Article  CAS  PubMed  Google Scholar 

  111. Sakai K, Yamamoto A, Matsubara K, Nakamura S, Naruse M, Yamagata M, Sakamoto K, Tauchi R et al (2012) Human dental pulp-derived stem cells promote locomotor recovery after complete transection of the rat spinal cord by multiple neuro-regenerative mechanisms. J Clin Invest 122(1):80–90

    CAS  PubMed  Google Scholar 

  112. Nosrat IV, Widenfalk J, Olson L, Nosrat CA (2001) Dental pulp cells produce neurotrophic factors, interact with trigeminal neurons in vitro, and rescue motoneurons after spinal cord injury. Dev Biol 238(1):120–132

    Article  CAS  PubMed  Google Scholar 

  113. Jarmalavičiūtė A, Tunaitis V, Pivoraitė U, Venalis A, Pivoriūnas A (2015) Exosomes from dental pulp stem cells rescue human dopaminergic neurons from 6-hydroxy-dopamine–induced apoptosis. Cytotherapy 17(7):932–939

    Article  CAS  PubMed  Google Scholar 

  114. Mazzio EA, Reams RR, Soliman KF (2004) The role of oxidative stress, impaired glycolysis and mitochondrial respiratory redox failure in the cytotoxic effects of 6-hydroxydopamine in vitro. Brain Res 1004(1–2):29–44

    Article  CAS  PubMed  Google Scholar 

  115. Zhou Y, Xu H, Xu W, Wang B, Wu H, Tao Y, Zhang B, Wang M et al (2013) Exosomes released by human umbilical cord mesenchymal stem cells protect against cisplatin-induced renal oxidative stress and apoptosis in vivo and in vitro. Stem Cell Res Ther 4(2):34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Sreekumar PG, Kannan R, Kitamura M, Spee C, Barron E, Ryan SJ, Hinton DR (2010) αB crystallin is apically secreted within exosomes by polarized human retinal pigment epithelium and provides neuroprotection to adjacent cells. PLoS One 5(10):e12578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Katsuda T, Tsuchiya R, Kosaka N, Yoshioka Y, Takagaki K, Oki K, Takeshita F, Sakai Y et al (2013) Human adipose tissue-derived mesenchymal stem cells secrete functional neprilysin-bound exosomes. Sci Rep 3:1197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Miners JS, Barua N, Kehoe PG, Gill S, Love S (2011) Aβ-degrading enzymes: potential for treatment of Alzheimer disease. J Neuropathol Exp Neurol 70(11):944–959

    Article  CAS  PubMed  Google Scholar 

  119. Farinazzo A, Turano E, Marconi S, Bistaffa E, Bazzoli E, Bonetti B (2015) Murine adipose-derived mesenchymal stromal cell vesicles: in vitro clues for neuroprotective and neuroregenerative approaches. Cytotherapy 17(5):571–578

    Article  CAS  PubMed  Google Scholar 

  120. Bonafede R, Scambi I, Peroni D, Potrich V, Boschi F, Benati D, Bonetti B, Mariotti R (2016) Exosome derived from murine adipose-derived stromal cells: neuroprotective effect on in vitro model of amyotrophic lateral sclerosis. Exp Cell Res 340(1):150–158

    Article  CAS  PubMed  Google Scholar 

  121. Kordelas L, Rebmann V, Ludwig A, Radtke S, Ruesing J, Doeppner T, Epple M, Horn P et al (2014) MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease. Leukemia 28(4):970

    Article  CAS  PubMed  Google Scholar 

  122. Doeppner TR, Herz J, Görgens A, Schlechter J, Ludwig A-K, Radtke S, de Miroschedji K, Horn PA et al (2015) Extracellular vesicles improve post-stroke neuroregeneration and prevent postischemic immunosuppression. Stem Cells Transl Med 4(10):1131–1143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Xin H, Li Y, Cui Y, Yang JJ, Zhang ZG, Chopp M (2013) Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J Cereb Blood Flow Metab 33(11):1711–1715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Zhang Y, Chopp M, Meng Y, Katakowski M, Xin H, Mahmood A, Xiong Y (2015) Effect of exosomes derived from multipluripotent mesenchymal stromal cells on functional recovery and neurovascular plasticity in rats after traumatic brain injury. J Neurosurg 122(4):856–867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Xin H, Li Y, Buller B, Katakowski M, Zhang Y, Wang X, Shang X, Zhang ZG et al (2012) Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells 30(7):1556–1564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Kim J, Inoue K, Ishii J, Vanti WB, Voronov SV, Murchison E, Hannon G, Abeliovich A (2007) A microRNA feedback circuit in midbrain dopamine neurons. Science 317(5842):1220–1224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Li T, Yan Y, Wang B, Qian H, Zhang X, Shen L, Wang M, Zhou Y et al (2012) Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis. Stem Cells Dev 22(6):845–854

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Bernardo ME, Fibbe WE (2013) Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell 13(4):392–402

    Article  CAS  PubMed  Google Scholar 

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Designed and conceived the idea: AMG, NK, HAT, AS

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Gorabi, A.M., Kiaie, N., Barreto, G.E. et al. The Therapeutic Potential of Mesenchymal Stem Cell–Derived Exosomes in Treatment of Neurodegenerative Diseases. Mol Neurobiol 56, 8157–8167 (2019). https://doi.org/10.1007/s12035-019-01663-0

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