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Exosome and MiRNA in Stroke

  • Ji Bihl
  • Jinju Wang
  • Xiaotang Ma
  • Yi Yang
  • Bin Zhao
  • Yanfang Chen
Chapter
Part of the Springer Series in Translational Stroke Research book series (SSTSR)

Abstract

Stroke is one of the leading causes of death and disability worldwide. Various types of stem cells have been applied to treat stroke and have been shown promising potential. The principal mechanism of therapeutic action has been partially ascribed to their strong paracrine capacity. Exosomes are small vesicles released from all kinds of cells and mediate intercellular communication by transferring exosomal protein and microRNA (miRNA) cargoes between cells in the brain. Among these cargoes, miRNAs play a key role in mediating biological function due to their prominent roles in gene regulation. Emerging data suggest that stem cell-released exosomes have advantages over stem cells to treat stroke, because exosomes could cross the blood bran barrier and easily to be modified and handled. Here, we first review the biogenesis, cargoes, and detection of exosomes. Then, we discussed the role of miRNAs in stroke. At last, we highlight the use of stem cell-released exosomes as biomarkers and therapeutic avenues in stroke. Perspectives on the developing role of stem cell-released exosomes mediated transfer of miRNAs as a therapeutic approach will also be discussed.

Keywords

Stroke Exosomes miRNAs Brain microenvironment Biomarker Therapy 

Abbreviations

Ago2

Argonaute 2

AMPA

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

BBB

Blood-brain barrier

BDNF

Brain-derived neurotrophic factor

CD

Cluster of differentiation

CNS

Central nervous system

CSF

Cerebrospinal fluid

CSPGs

Chondroitin sulfate proteoglycans

CTGF

Connective tissue growth factor

DCs

Dendritic cells

Dll4

Delta-like 4

ECs

Endothelial cells

EpCAM

Epithelial cell adhesion molecule

EPCs

Endothelial progenitor cells

EPC-EXs

EPC-released exosomes

ESCART

Endosomal-sorting complex responsible for transport

EVs

Extracellular vesicles

EXs

Exosomes

FGF2

Fibroblast growth factor 2

GFAP

Glial fibrillary acidic protein

GFP

Green fluorescence protein

GluR2/3

Glutamate receptor AMPA R2/3

H/R

Hypoxia/reoxygenenation

HMGA2

High mobility group AT-hook 2

HSCs

Hematopoietic stem cells

IFN-γ

The interferon gamma

IGF

The insulin-like growth factor

L1CAM

Neuronal-specific protein L1 cell adhesion molecule

Lamp-2

Lysosomal-associated membrane protein 2

MAP 1b

Microtubule associated protein 1b

MCAO

Middle cerebral artery occlusion

miR-126-EPC-EXs

Exosomes released from miR-126 primed EPCs

miRNA

MicroRNA

MOR

Opioid receptor mu

mRNA

Messenger RNA

MSCs

Mesenchymal stromal cells

MVB

Multivesicular bodies

MVs

Microvesicles

NPCs

Neural progenitor cells

NPC-EXs

NPCs-released exosomes

NTA

Nanoparticle tracking analysis

PEG

Polyethyleneglycol

PTEN

Phosphatase and tensin homolog

Rab5

Ras-related protein

RARβ

Retinoic acid receptor β2

RhoA

ras Homolog family member A

RISC

RNA-induced silencing complex

RVG

Rabies virus glycoprotein

SGZ

Subgranular zone

Shh

Sonic hedgehog

STAT1

Signal transducer and activator of transcription 1

SVZ

Subventricular zone

TNFα

Tumor necrosis factor-α

VEGF

Vascular endothelial growth factor

VEGFR2

Vascular endothelial growth factor receptor 2

VPS4

Vacuolar protein sorting 4

References

  1. 1.
    SL P, GE P. The fine structure of neurons. J Biophys Biochem Cytol. 1955;1(1):69–88.CrossRefGoogle Scholar
  2. 2.
    Piper RC, Katzmann DJ. Biogenesis and function of multivesicular bodies. Annu Rev Cell Dev Biol. 2007;23:519–47.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Von Bartheld CS, Altick AL. Multivesicular bodies in neurons: distribution, protein content, and trafficking functions. Prog Neurobiol. 2011;93(3):313–40.CrossRefGoogle Scholar
  4. 4.
    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(1):63–70.PubMedCrossRefGoogle Scholar
  5. 5.
    Fleury A, Martinez MC, Le LS. Extracellular vesicles as therapeutic tools in cardiovascular diseases. Front Immunol. 2014;5:370.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Harding C, Heuser J, Stahl P. Endocytosis and intracellular processing of transferrin and colloidal gold-transferrin in rat reticulocytes: demonstration of a pathway for receptor shedding. Eur J Cell Biol. 1984;35(2):256–63.PubMedGoogle Scholar
  7. 7.
    Heijnen HF, Debili N, Vainchencker W, Breton-Gorius J, Geuze HJ, Sixma JJ. Multivesicular bodies are an intermediate stage in the formation of platelet alpha-granules. Blood. 1998;91(7):2313–25.PubMedGoogle Scholar
  8. 8.
    Heijnen HF, Schiel AE, Fijnheer R, Geuze HJ, Sixma JJ. Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules. Blood. 1999;94(11):3791–9.PubMedGoogle Scholar
  9. 9.
    Thery M, Piel M. Adhesive micropatterns for cells: a microcontact printing protocol. Cold Spring Harb Protoc. 2009;2009(7):db.CrossRefGoogle Scholar
  10. 10.
    Lazaro-Ibanez E, Sanz-Garcia A, Visakorpi T, Escobedo-Lucea C, Siljander P, Ayuso-Sacido A, et al. Different gDNA content in the subpopulations of prostate cancer extracellular vesicles: apoptotic bodies, microvesicles, and exosomes. Prostate. 2014;74(14):1379–90.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Revenfeld AL, Baek R, Nielsen MH, Stensballe A, Varming K, Jorgensen M. Diagnostic and prognostic potential of extracellular vesicles in peripheral blood. Clin Ther. 2014;36(6):830–46.PubMedCrossRefGoogle Scholar
  12. 12.
    Denzer K, Kleijmeer MJ, Heijnen HF, Stoorvogel W, Geuze HJ. Exosome: from internal vesicle of the multivesicular body to intercellular signaling device. J Cell Sci. 2000;113(Pt 19):3365–74.PubMedGoogle Scholar
  13. 13.
    Stoorvogel W, Kleijmeer MJ, Geuze HJ, Raposo G. The biogenesis and functions of exosomes. Traffic. 2002;3(5):321–30.PubMedCrossRefGoogle Scholar
  14. 14.
    Fernandez-Borja M, Wubbolts R, Calafat J, Janssen H, Divecha N, Dusseljee S, et al. Multivesicular body morphogenesis requires phosphatidyl-inositol 3-kinase activity. Curr Biol. 1999;9(1):55–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013;200(4):373–83.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Mobius W, Ohno-Iwashita Y, van Donselaar EG, Oorschot VM, Shimada Y, Fujimoto T, et al. Immunoelectron microscopic localization of cholesterol using biotinylated and non-cytolytic perfringolysin O. J Histochem Cytochem. 2002;50(1):43–55.PubMedCrossRefGoogle Scholar
  17. 17.
    Trajkovic K, Hsu C, Chiantia S, Rajendran L, Wenzel D, Wieland F, et al. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science. 2008;319(5867):1244–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Simons M, Raposo G. Exosomes--vesicular carriers for intercellular communication. Curr Opin Cell Biol. 2009;21(4):575–81.PubMedCrossRefGoogle Scholar
  19. 19.
    Record M, Subra C, Silvente-Poirot S, Poirot M. Exosomes as intercellular signalosomes and pharmacological effectors. Biochem Pharmacol. 2011;81(10):1171–82.PubMedCrossRefGoogle Scholar
  20. 20.
    Thery C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol. 2009;9(8):581–93.PubMedCrossRefGoogle Scholar
  21. 21.
    Thery C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002;2(8):569–79.PubMedGoogle Scholar
  22. 22.
    Ostrowski M, Carmo NB, Krumeich S, Fanget I, Raposo G, Savina A, et al. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol. 2010;12(1):19–30.PubMedCrossRefGoogle Scholar
  23. 23.
    Lamparski HG, Metha-Damani A, Yao JY, Patel S, Hsu DH, Ruegg C, et al. Production and characterization of clinical grade exosomes derived from dendritic cells. J Immunol Methods. 2002;270(2):211–26.PubMedCrossRefGoogle Scholar
  24. 24.
    Zitvogel L, Regnault A, Lozier A, Wolfers J, Flament C, Tenza D, et al. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat Med. 1998;4(5):594–600.PubMedCrossRefGoogle Scholar
  25. 25.
    Lai RC, Yeo RW, Tan KH, Lim SK. Exosomes for drug delivery – a novel application for the mesenchymal stem cell. Biotechnol Adv. 2013;31(5):543–51.PubMedCrossRefGoogle Scholar
  26. 26.
    Vlassov AV, Magdaleno S, Setterquist R, Conrad R. Exosomes: current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials. Biochim Biophys Acta. 2012;1820(7):940–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Qin J, Xu Q. Functions and application of exosomes. Acta Pol Pharm. 2014;71(4):537–43.PubMedGoogle Scholar
  28. 28.
    Ha D, Yang N, Nadithe V. Exosomes as therapeutic drug carriers and delivery vehicles across biological membranes: current perspectives and future challenges. Acta Pharm Sin B. 2016;6(4):287–96.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Kooijmans SA, Vader P, van Dommelen SM, van Solinge WW, Schiffelers RM. Exosome mimetics: a novel class of drug delivery systems. Int J Nanomedicine. 2012;7:1525–41.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Crescitelli R, Lasser C, Szabo TG, Kittel A, Eldh M, Dianzani I, et al. Distinct RNA profiles in subpopulations of extracellular vesicles: apoptotic bodies, microvesicles and exosomes. J Extracell Vesicles. 2013;2:eCollection 2013.CrossRefGoogle Scholar
  31. 31.
    Wang J, Guo R, Yang Y, Jacobs B, Chen S, Iwuchukwu I, et al. The novel methods for analysis of exosomes released from endothelial cells and endothelial progenitor cells. Stem Cells Int. 2016;2016:2639728.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Wang J, Zhong Y, Ma X, Xiao X, Cheng C, Chen Y, et al. Analyses of endothelial cells and endothelial progenitor cells released microvesicles by using microbead and Q-dot based nanoparticle tracking analysis. Sci Rep. 2016;6:24679.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Hunter MP, Ismail N, Zhang X, Aguda BD, Lee EJ, Yu L, et al. Detection of microRNA expression in human peripheral blood microvesicles. PLoS One. 2008;3(11):e3694.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Chen TS, Lai RC, Lee MM, Choo AB, Lee CN, Lim SK. Mesenchymal stem cell secretes microparticles enriched in pre-microRNAs. Nucleic Acids Res. 2010;38(1):215–24.PubMedCrossRefGoogle Scholar
  35. 35.
    Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall 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.PubMedCrossRefGoogle Scholar
  36. 36.
    Baglio SR, Pegtel DM, Baldini N. Mesenchymal stem cell secreted vesicles provide novel opportunities in (stem) cell-free therapy. Front Physiol. 2012;3:359.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Baglio SR, Rooijers K, Koppers-Lalic D, Verweij FJ, Perez LM, Zini N, et al. Human bone marrow- and adipose-mesenchymal stem cells secrete exosomes enriched in distinctive miRNA and tRNA species. Stem Cell Res Ther. 2015;6:127.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Boon RA, Vickers KC. Intercellular transport of microRNAs. Arterioscler Thromb Vasc Biol. 2013;33(2):186–92.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Ohshima K, Inoue K, Fujiwara A, Hatakeyama K, Kanto K, Watanabe Y, et al. Let-7 microRNA family is selectively secreted into the extracellular environment via exosomes in a metastatic gastric cancer cell line. PLoS One. 2010;5(10):e13247.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Montecalvo A, Larregina AT, Shufesky WJ, Stolz DB, Sullivan ML, Karlsson JM, et al. Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. Blood. 2012;119(3):756–66.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Macfarlane LA, Murphy PR. MicroRNA: biogenesis, function and role in cancer. Curr Genomics. 2010;11(7):537–61.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Ratajczak J, Wysoczynski M, Hayek F, Janowska-Wieczorek A, Ratajczak MZ. Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication. Leukemia. 2006;20(9):1487–95.PubMedCrossRefGoogle Scholar
  43. 43.
    Palma CA, Tonna EJ, Ma DF, Lutherborrow MA. MicroRNA control of myelopoiesis and the differentiation block in acute myeloid leukaemia. J Cell Mol Med. 2012;16(5):978–87.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Bobrie A, Colombo M, Raposo G, Thery C. Exosome secretion: molecular mechanisms and roles in immune responses. Traffic. 2011;12(12):1659–68.PubMedCrossRefGoogle Scholar
  45. 45.
    Hess C, Sadallah S, Hefti A, Landmann R, Schifferli JA. Ectosomes released by human neutrophils are specialized functional units. J Immunol. 1999;163(8):4564–73.PubMedGoogle Scholar
  46. 46.
    Wang J, Chen S, Ma X, Cheng C, Xiao X, Chen J, et al. Effects of endothelial progenitor cell-derived microvesicles on hypoxia/reoxygenation-induced endothelial dysfunction and apoptosis. Oxidative Med Cell Longev. 2013;2013:572729.Google Scholar
  47. 47.
    Guescini M, Genedani S, Stocchi V, Agnati LF. Astrocytes and glioblastoma cells release exosomes carrying mtDNA. J Neural Transm (Vienna). 2010;117(1):1–4.CrossRefGoogle Scholar
  48. 48.
    Guescini M, Guidolin D, Vallorani L, Casadei L, Gioacchini AM, Tibollo P, et al. C2C12 myoblasts release micro-vesicles containing mtDNA and proteins involved in signal transduction. Exp Cell Res. 2010;316(12):1977–84.PubMedCrossRefGoogle Scholar
  49. 49.
    Street JM, Barran PE, Mackay CL, Weidt S, Balmforth C, Walsh TS, et al. Identification and proteomic profiling of exosomes in human cerebrospinal fluid. J Transl Med. 2012;10:5.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Banigan MG, Kao PF, Kozubek JA, Winslow AR, Medina J, Costa J, et al. Differential expression of exosomal microRNAs in prefrontal cortices of schizophrenia and bipolar disorder patients. PLoS One. 2013;8(1):e48814.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Regehr WG, Carey MR, Best AR. Activity-dependent regulation of synapses by retrograde messengers. Neuron. 2009;63(2):154–70.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Korkut C, Li Y, Koles K, Brewer C, Ashley J, Yoshihara M, et al. Regulation of postsynaptic retrograde signaling by presynaptic exosome release. Neuron. 2013;77(6):1039–46.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Chivet M, Javalet C, Laulagnier K, Blot B, Hemming FJ, Sadoul R. Exosomes secreted by cortical neurons upon glutamatergic synapse activation specifically interact with neurons. J Extracell Vesicles. 2014;3:24722.PubMedCrossRefGoogle Scholar
  54. 54.
    Nave KA, Trapp BD. Axon-glial signaling and the glial support of axon function. Annu Rev Neurosci. 2008;31:535–61.PubMedCrossRefGoogle Scholar
  55. 55.
    Fruhbeis C, Frohlich D, Kuo WP, Kramer-Albers EM. Extracellular vesicles as mediators of neuron-glia communication. Front Cell Neurosci. 2013;7:182.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Bahrini I, Song JH, Diez D, Hanayama R. Neuronal exosomes facilitate synaptic pruning by up-regulating complement factors in microglia. Sci Rep. 2015;5:7989.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Fitzner D, Schnaars M, van Rossum D, Krishnamoorthy G, Dibaj P, Bakhti M, et al. Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis. J Cell Sci. 2011;124(Pt 3):447–58.PubMedCrossRefGoogle Scholar
  58. 58.
    Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ. Structure and function of the blood-brain barrier. Neurobiol Dis. 2010;37(1):13–25.PubMedCrossRefGoogle Scholar
  59. 59.
    Schiera G, Bono E, Raffa MP, Gallo A, Pitarresi GL, Di L, et al. Synergistic effects of neurons and astrocytes on the differentiation of brain capillary endothelial cells in culture. J Cell Mol Med. 2003;7(2):165–70.PubMedCrossRefGoogle Scholar
  60. 60.
    Schiera G, Sala S, Gallo A, Raffa MP, Pitarresi GL, Savettieri G, et al. Permeability properties of a three-cell type in vitro model of blood-brain barrier. J Cell Mol Med. 2005;9(2):373–9.PubMedCrossRefGoogle Scholar
  61. 61.
    Zhang Z, Chopp M. Neural stem cells and ischemic brain. J Stroke. 2016;18(3):267–72.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Li L, Xie T. Stem cell niche: structure and function. Annu Rev Cell Dev Biol. 2005;21:605–31.PubMedCrossRefGoogle Scholar
  63. 63.
    Taupin P. Adult neural stem cells, neurogenic niches, and cellular therapy. Stem Cell Rev. 2006;2(3):213–9.PubMedCrossRefGoogle Scholar
  64. 64.
    Chen J, Xiao X, Chen S, Zhang C, Chen J, Yi D, et al. Angiotensin-converting enzyme 2 priming enhances the function of endothelial progenitor cells and their therapeutic efficacy. Hypertension. 2013;61(3):681–9.PubMedCrossRefGoogle Scholar
  65. 65.
    Spalding KL, Bergmann O, Alkass K, Bernard S, Salehpour M, Huttner HB, et al. Dynamics of hippocampal neurogenesis in adult humans. Cell. 2013;153(6):1219–27.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Ernst A, Alkass K, Bernard S, Salehpour M, Perl S, Tisdale J, et al. Neurogenesis in the striatum of the adult human brain. Cell. 2014;156(5):1072–83.PubMedCrossRefGoogle Scholar
  67. 67.
    von Bohlen und HO. Immunohistological markers for proliferative events, gliogenesis, and neurogenesis within the adult hippocampus. Cell Tissue Res. 2011;345(1):1–19.CrossRefGoogle Scholar
  68. 68.
    Batiz LF, Castro MA, Burgos PV, Velasquez ZD, Munoz RI, Lafourcade CA, et al. Exosomes as novel regulators of adult neurogenic niches. Front Cell Neurosci. 2015;9:501.PubMedGoogle Scholar
  69. 69.
    Agnati LF, Fuxe K. Extracellular-vesicle type of volume transmission and tunnelling-nanotube type of wiring transmission add a new dimension to brain neuro-glial networks. Philos Trans R Soc Lond Ser B Biol Sci. 2014;369(1652):pii:20130505.CrossRefGoogle Scholar
  70. 70.
    Borroto-Escuela DO, Agnati LF, Bechter K, Jansson A, Tarakanov AO, Fuxe K. The role of transmitter diffusion and flow versus extracellular vesicles in volume transmission in the brain neural-glial networks. Philos Trans R Soc Lond Ser B Biol Sci. 2015;370(1672):20140183.CrossRefGoogle Scholar
  71. 71.
    Chiasserini D, van Weering JR, Piersma SR, Pham TV, Malekzadeh A, Teunissen CE, et al. Proteomic analysis of cerebrospinal fluid extracellular vesicles: a comprehensive dataset. J Proteome. 2014;106:191–204.CrossRefGoogle Scholar
  72. 72.
    Grapp M, Wrede A, Schweizer M, Huwel S, Galla HJ, Snaidero N, et al. Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma. Nat Commun. 2013;4:2123.PubMedCrossRefGoogle Scholar
  73. 73.
    Pegtel DM, Peferoen L, Amor S. Extracellular vesicles as modulators of cell-to-cell communication in the healthy and diseased brain. Philos Trans R Soc Lond Ser B Biol Sci. 2014;369(1652):20130516.CrossRefGoogle Scholar
  74. 74.
    Feliciano DM, Zhang S, Nasrallah CM, Lisgo SN, Bordey A. Embryonic cerebrospinal fluid nanovesicles carry evolutionarily conserved molecules and promote neural stem cell amplification. PLoS One. 2014;9(2):e88810.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Feigin VL, Lawes CM, Bennett DA, Barker-Collo SL, Parag V. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol. 2009;8(4):355–69.PubMedCrossRefGoogle Scholar
  76. 76.
    Elijovich L, Patel PV, Hemphill JC III. Intracerebral hemorrhage. Semin Neurol. 2008;28(5):657–67.PubMedCrossRefGoogle Scholar
  77. 77.
    Sierra C, Coca A, Schiffrin EL. Vascular mechanisms in the pathogenesis of stroke. Curr Hypertens Rep. 2011;13(3):200–7.PubMedCrossRefGoogle Scholar
  78. 78.
    Jeyaseelan K, Lim KY, Armugam A. MicroRNA expression in the blood and brain of rats subjected to transient focal ischemia by middle cerebral artery occlusion. Stroke. 2008;39(3):959–66.PubMedCrossRefGoogle Scholar
  79. 79.
    Liu DZ, Tian Y, Ander BP, Xu H, Stamova BS, Zhan X, et al. Brain and blood microRNA expression profiling of ischemic stroke, intracerebral hemorrhage, and kainate seizures. J Cereb Blood Flow Metab. 2010;30(1):92–101.PubMedCrossRefGoogle Scholar
  80. 80.
    Tan KS, Armugam A, Sepramaniam S, Lim KY, Setyowati KD, Wang CW, et al. Expression profile of MicroRNAs in young stroke patients. PLoS One. 2009;4(11):e7689.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Dharap A, Bowen K, Place R, Li LC, Vemuganti R. Transient focal ischemia induces extensive temporal changes in rat cerebral microRNAome. J Cereb Blood Flow Metab. 2009;29(4):675–87.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Yuan Y, Wang JY, Xu LY, Cai R, Chen Z, Luo BY. MicroRNA expression changes in the hippocampi of rats subjected to global ischemia. J Clin Neurosci. 2010;17(6):774–8.PubMedCrossRefGoogle Scholar
  83. 83.
    Ouyang YB, Lu Y, Yue S, Giffard RG. miR-181 targets multiple Bcl-2 family members and influences apoptosis and mitochondrial function in astrocytes. Mitochondrion. 2012;12(2):213–9.PubMedCrossRefGoogle Scholar
  84. 84.
    Yin KJ, Deng Z, Hamblin M, Xiang Y, Huang H, Zhang J, et al. Peroxisome proliferator-activated receptor delta regulation of miR-15a in ischemia-induced cerebral vascular endothelial injury. J Neurosci. 2010;30(18):6398–408.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Yin KJ, Deng Z, Huang H, Hamblin M, Xie C, Zhang J, et al. miR-497 regulates neuronal death in mouse brain after transient focal cerebral ischemia. Neurobiol Dis. 2010;38(1):17–26.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Lee ST, Chu K, Jung KH, Yoon HJ, Jeon D, Kang KM, et al. MicroRNAs induced during ischemic preconditioning. Stroke. 2010;41(8):1646–51.PubMedCrossRefGoogle Scholar
  87. 87.
    Zeng L, Liu J, Wang Y, Wang L, Weng S, Tang Y, et al. MicroRNA-210 as a novel blood biomarker in acute cerebral ischemia. Front Biosci (Elite Ed). 2011;3:1265–72.Google Scholar
  88. 88.
    Buller B, Liu X, Wang X, Zhang RL, Zhang L, Hozeska-Solgot A, et al. MicroRNA-21 protects neurons from ischemic death. FEBS J. 2010;277(20):4299–307.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Liu L, Yu X, Guo X, Tian Z, Su M, Long Y, et al. miR-143 is downregulated in cervical cancer and promotes apoptosis and inhibits tumor formation by targeting Bcl-2. Mol Med Rep. 2012;5(3):753–60.PubMedGoogle Scholar
  90. 90.
    Wu K, Yang Y, Zhong Y, Ammar HM, Zhang P, Guo R, et al. The effects of microvesicles on endothelial progenitor cells are compromised in type 2 diabetic patients via downregulation of the miR-126/VEGFR2 pathway. Am J Physiol Endocrinol Metab. 2016;310(10):E828–37.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Gyorgy B, Hung ME, Breakefield XO, Leonard JN. Therapeutic applications of extracellular vesicles: clinical promise and open questions. Annu Rev Pharmacol Toxicol. 2015;55:439–64.PubMedCrossRefGoogle Scholar
  92. 92.
    Ouyang YB, Stary CM, Yang GY, Giffard R. microRNAs: innovative targets for cerebral ischemia and stroke. Curr Drug Targets. 2013;14(1):90–101.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Yin KJ, Hamblin M, Chen YE. Angiogenesis-regulating microRNAs and ischemic stroke. Curr Vasc Pharmacol. 2015;13(3):352–65.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Teng H, Zhang ZG, Wang L, Zhang RL, Zhang L, Morris D, et al. Coupling of angiogenesis and neurogenesis in cultured endothelial cells and neural progenitor cells after stroke. J Cereb Blood Flow Metab. 2008;28(4):764–71.PubMedCrossRefGoogle Scholar
  95. 95.
    Miyamoto N, Pham LD, Seo JH, Kim KW, Lo EH, Arai K. Crosstalk between cerebral endothelium and oligodendrocyte. Cell Mol Life Sci. 2014;71(6):1055–66.PubMedCrossRefGoogle Scholar
  96. 96.
    Buller B, Chopp M, Ueno Y, Zhang L, Zhang RL, Morris D, et al. Regulation of serum response factor by miRNA-200 and miRNA-9 modulates oligodendrocyte progenitor cell differentiation. Glia. 2012;60(12):1906–14.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Gherardini L, Gennaro M, Pizzorusso T. Perilesional treatment with chondroitinase ABC and motor training promote functional recovery after stroke in rats. Cereb Cortex. 2015;25(1):202–12.PubMedCrossRefGoogle Scholar
  98. 98.
    Zhang Y, Chopp M, Liu XS, Kassis H, Wang X, Li C, et al. MicroRNAs in the axon locally mediate the effects of chondroitin sulfate proteoglycans and cGMP on axonal growth. Dev Neurobiol. 2015;75(12):1402–19.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Zhang Y, Ueno Y, Liu XS, Buller B, Wang X, Chopp M, et al. The microRNA-17-92 cluster enhances axonal outgrowth in embryonic cortical neurons. J Neurosci. 2013;33(16):6885–94.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Park KK, Liu K, Hu Y, Smith PD, Wang C, Cai B, et al. Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science. 2008;322(5903):963–6.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    He X, Yu Y, Awatramani R, Lu QR. Unwrapping myelination by microRNAs. Neuroscientist. 2012;18(1):45–55.PubMedCrossRefGoogle Scholar
  102. 102.
    Moubarik C, Guillet B, Youssef B, Codaccioni JL, Piercecchi MD, Sabatier F, et al. Transplanted late outgrowth endothelial progenitor cells as cell therapy product for stroke. Stem Cell Rev. 2011;7(1):208–20.PubMedCrossRefGoogle Scholar
  103. 103.
    Thored P, Wood J, Arvidsson A, Cammenga J, Kokaia Z, Lindvall O. Long-term neuroblast migration along blood vessels in an area with transient angiogenesis and increased vascularization after stroke. Stroke. 2007;38(11):3032–9.PubMedCrossRefGoogle Scholar
  104. 104.
    Ohab JJ, Fleming S, Blesch A, Carmichael ST. A neurovascular niche for neurogenesis after stroke. J Neurosci. 2006;26(50):13007–16.PubMedCrossRefGoogle Scholar
  105. 105.
    Zhang ZG, Chopp M. Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic. Lancet Neurol. 2009;8(5):491–500.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Cantaluppi V, Biancone L, vliolini F, Beltramo S, Medica D, Deregibus MC, et al. Microvesicles derived from endothelial progenitor cells enhance neoangiogenesis of human pancreatic islets. Cell Transplant. 2012;21(6):1305–20.Google Scholar
  107. 107.
    Deregibus MC, Cantaluppi V, Calogero R, Lo IM, Tetta C, Biancone L, et al. Endothelial progenitor cell derived microvesicles activate an angiogenic program in endothelial cells by a horizontal transfer of mRNA. Blood. 2007;110(7):2440–8.PubMedCrossRefGoogle Scholar
  108. 108.
    Skog J, Wurdinger T, van RS, Meijer DH, Gainche L, Sena-Esteves M, et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol. 2008;10(12):1470–6.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Haqqani AS, Delaney CE, Tremblay TL, Sodja C, Sandhu JK, Stanimirovic DB. Method for isolation and molecular characterization of extracellular microvesicles released from brain endothelial cells. Fluids Barriers CNS. 2013;10(1):4.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Yamamoto S, Niida S, Azuma E, Yanagibashi T, Muramatsu M, Huang TT, et al. Inflammation-induced endothelial cell-derived extracellular vesicles modulate the cellular status of pericytes. Sci Rep. 2015;5:8505.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Winkler EA, Bell RD, Zlokovic BV. Central nervous system pericytes in health and disease. Nat Neurosci. 2011;14(11):1398–405.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Schulz GB, Wieland E, Wustehube-Lausch J, Boulday G, Moll I, Tournier-Lasserve E, et al. Cerebral cavernous malformation-1 protein controls DLL4-notch3 signaling between the endothelium and pericytes. Stroke. 2015;46(5):1337–43.PubMedCrossRefGoogle Scholar
  113. 113.
    Sharghi-Namini S, Tan E, Ong LL, Ge R, Asada HH. Dll4-containing exosomes induce capillary sprout retraction in a 3D microenvironment. Sci Rep. 2014;4:4031.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Sheldon H, Heikamp E, Turley H, Dragovic R, Thomas P, Oon CE, et al. New mechanism for Notch signaling to endothelium at a distance by delta-like 4 incorporation into exosomes. Blood. 2010;116(13):2385–94.PubMedCrossRefGoogle Scholar
  115. 115.
    Tammela T, Zarkada G, Wallgard E, Murtomaki A, Suchting S, Wirzenius M, et al. Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature. 2008;454(7204):656–60.PubMedCrossRefGoogle Scholar
  116. 116.
    Taylor KL, Henderson AM, Hughes CC. Notch activation during endothelial cell network formation in vitro targets the basic HLH transcription factor HESR-1 and downregulates VEGFR-2/KDR expression. Microvasc Res. 2002;64(3):372–83.PubMedCrossRefGoogle Scholar
  117. 117.
    Ihrie RA, Alvarez-Buylla A. Lake-front property: a unique germinal niche by the lateral ventricles of the adult brain. Neuron. 2011;70(4):674–86.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Cossetti C, Iraci N, Mercer TR, Leonardi T, Alpi E, Drago D, et al. Extracellular vesicles from neural stem cells transfer IFN-gamma via Ifngr1 to activate Stat1 signaling in target cells. Mol Cell. 2014;56(2):193–204.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Famakin BM. The immune response to acute focal cerebral ischemia and associated post-stroke immunodepression: a focused review. Aging Dis. 2014;5(5):307–26.PubMedPubMedCentralGoogle Scholar
  120. 120.
    Zhang ZG, Chopp M. Exosomes in stroke pathogenesis and therapy. J Clin Invest. 2016;126(4):1190–7.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Higa GS, de SE, Walter LT, Kinjo ER, Resende RR, Kihara AH. MicroRNAs in neuronal communication. Mol Neurobiol. 2014;49(3):1309–26.PubMedGoogle Scholar
  122. 122.
    Kawikova I, Askenase PW. Diagnostic and therapeutic potentials of exosomes in CNS diseases. Brain Res. 2015;1617:63–71.PubMedCrossRefGoogle Scholar
  123. 123.
    Faure J, Lachenal G, Court M, Hirrlinger J, Chatellard-Causse C, Blot B, et al. Exosomes are released by cultured cortical neurones. Mol Cell Neurosci. 2006;31(4):642–8.PubMedCrossRefGoogle Scholar
  124. 124.
    Lachenal G, Pernet-Gallay K, Chivet M, Hemming FJ, Belly A, Bodon G, et al. Release of exosomes from differentiated neurons and its regulation by synaptic glutamatergic activity. Mol Cell Neurosci. 2011;46(2):409–18.PubMedCrossRefGoogle Scholar
  125. 125.
    Goldie BJ, Dun MD, Lin M, Smith ND, Verrills NM, Dayas CV, et al. Activity-associated miRNA are packaged in Map1b-enriched exosomes released from depolarized neurons. Nucleic Acids Res. 2014;42(14):9195–208.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Goncalves MB, Malmqvist T, Clarke E, Hubens CJ, Grist J, Hobbs C, et al. Neuronal RARbeta signaling modulates PTEN activity directly in neurons and via exosome transfer in astrocytes to prevent glial scar formation and induce spinal cord regeneration. J Neurosci. 2015;35(47):15731–45.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Morel L, Regan M, Higashimori H, Ng SK, Esau C, Vidensky S, et al. Neuronal exosomal miRNA-dependent translational regulation of astroglial glutamate transporter GLT1. J Biol Chem. 2013;288(10):7105–16.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Dajas-Bailador F, Bonev B, Garcez P, Stanley P, Guillemot F, Papalopulu N. MicroRNA-9 regulates axon extension and branching by targeting Map 1b in mouse cortical neurons. Nat Neurosci. 2012.  https://doi.org/10.1038/nn.3082.
  129. 129.
    Clarkson AN, Overman JJ, Zhong S, Mueller R, Lynch G, Carmichael ST. AMPA receptor-induced local brain-derived neurotrophic factor signaling mediates motor recovery after stroke. J Neurosci. 2011;31(10):3766–75.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Shen LH, Li Y, Gao Q, Savant-Bhonsale S, Chopp M. Down-regulation of neurocan expression in reactive astrocytes promotes axonal regeneration and facilitates the neurorestorative effects of bone marrow stromal cells in the ischemic rat brain. Glia. 2008;56(16):1747–54.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Edelstein L, Smythies J. The role of epigenetic-related codes in neurocomputation: dynamic hardware in the brain. Philos Trans R Soc Lond Ser B Biol Sci. 2014;369(1652):20130519.CrossRefGoogle Scholar
  132. 132.
    Lausted C, Lee I, Zhou Y, Qin S, Sung J, Price ND, et al. Systems approach to neurodegenerative disease biomarker discovery. Annu Rev Pharmacol Toxicol. 2014;54:457–81.PubMedCrossRefGoogle Scholar
  133. 133.
    Nedaeinia R, Manian M, Jazayeri MH, Ranjbar M, Salehi R, Sharifi M, et al. Circulating exosomes and exosomal microRNAs as biomarkers in gastrointestinal cancer. Cancer Gene Ther. 2017;24(2):48–56.PubMedCrossRefGoogle Scholar
  134. 134.
    Perez-Gonzalez R, Gauthier SA, Kumar A, Saito M, Saito M, Levy E. A method for isolation of extracellular vesicles and characterization of exosomes from brain extracellular space. Methods Mol Biol. 2017;1545:139–51.PubMedCrossRefGoogle Scholar
  135. 135.
    Wang Y, Sheng G, Juranek S, Tuschl T, Patel DJ. Structure of the guide-strand-containing argonaute silencing complex. Nature. 2008;456(7219):209–13.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Li M, Zeringer E, Barta T, Schageman J, Cheng A, Vlassov AV. Analysis of the RNA content of the exosomes derived from blood serum and urine and its potential as biomarkers. Philos Trans R Soc Lond Ser B Biol Sci. 2014;369(1652):20130502.CrossRefGoogle Scholar
  137. 137.
    Chen Y, Song Y, Huang J, Qu M, Zhang Y, Geng J, et al. Increased circulating exosomal miRNA-223 is associated with acute ischemic stroke. Front Neurol. 2017;8:57.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Rice J, Roberts H, Burton J, Pan J, States V, Rai SN, et al. Assay reproducibility in clinical studies of plasma miRNA. PLoS One. 2015;10(4):e0121948.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Pritchard CC, Cheng HH, Tewari M. MicroRNA profiling: approaches and considerations. Nat Rev Genet. 2012;13(5):358–69.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Goodall EF, Heath PR, Bandmann O, Kirby J, Shaw PJ. Neuronal dark matter: the emerging role of microRNAs in neurodegeneration. Front Cell Neurosci. 2013;7:178.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Villarroya-Beltri C, Baixauli F, Gutierrez-Vazquez C, Sanchez-Madrid F, Mittelbrunn M. Sorting it out: regulation of exosome loading. Semin Cancer Biol. 2014;28:3–13.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Chaput N, Thery C. Exosomes: immune properties and potential clinical implementations. Semin Immunopathol. 2011;33(5):419–40.PubMedCrossRefGoogle Scholar
  143. 143.
    Frohlich D, Kuo WP, Fruhbeis C, Sun JJ, Zehendner CM, Luhmann HJ, et al. Multifaceted effects of oligodendroglial exosomes on neurons: impact on neuronal firing rate, signal transduction and gene regulation. Philos Trans R Soc Lond Ser B Biol Sci. 2014;369(1652):20130510.CrossRefGoogle Scholar
  144. 144.
    Kanninen KM, Bister N, Koistinaho J, Malm T. Exosomes as new diagnostic tools in CNS diseases. Biochim Biophys Acta. 2016;1862(3):403–10.PubMedCrossRefGoogle Scholar
  145. 145.
    de Jong OG, Verhaar MC, Chen Y, Vader P, Gremmels H, Posthuma G, et al. Cellular stress conditions are reflected in the protein and RNA content of endothelial cell-derived exosomes. J Extracell Vesicles. 2012;1:eCollection.2012.Google Scholar
  146. 146.
    Ji Q, Ji Y, Peng J, Zhou X, Chen X, Zhao H, et al. Increased brain-specific MiR-9 and MiR-124 in the serum exosomes of acute ischemic stroke patients. PLoS One. 2016;11(9):e0163645.PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Chimowitz MI, Lynn MJ, Derdeyn CP, Turan TN, Fiorella D, Lane BF, et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med. 2011;365(11):993–1003.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Wei L, Wei ZZ, Jiang MQ, Mohamad O, Yu SP. Stem cell transplantation therapy for multifaceted therapeutic benefits after stroke. Prog Neurobiol. 2017.  https://doi.org/10.1016/j.pneurobio.2017.03.003.
  149. 149.
    Cordeiro MF, Horn AP. Stem cell therapy in intracerebral hemorrhage rat model. World J Stem Cells. 2015;7(3):618–29.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Hu Y, Liu N, Zhang P, Pan C, Zhang Y, Tang Y, et al. Preclinical studies of stem cell transplantation in intracerebral hemorrhage: a systemic review and meta-analysis. Mol Neurobiol. 2016;53(8):5269–77.PubMedCrossRefGoogle Scholar
  151. 151.
    Ma X, Qin J, Song B, Shi C, Zhang R, Liu X, et al. Stem cell-based therapies for intracerebral hemorrhage in animal model: a meta-analysis. Neurol Sci. 2015;36(8):1311–7.PubMedCrossRefGoogle Scholar
  152. 152.
    Moskowitz MA, Lo EH, Iadecola C. The science of stroke: mechanisms in search of treatments. Neuron. 2010;67(2):181–98.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Diez-Tejedor E, Gutierrez-Fernandez M, Martinez-Sanchez P, Rodriguez-Frutos B, Ruiz-Ares G, Lara ML, et al. Reparative therapy for acute ischemic stroke with allogeneic mesenchymal stem cells from adipose tissue: a safety assessment: a phase II randomized, double-blind, placebo-controlled, single-center, pilot clinical trial. J Stroke Cerebrovasc Dis. 2014;23(10):2694–700.PubMedCrossRefGoogle Scholar
  154. 154.
    Lee JS, Hong JM, Moon GJ, Lee PH, Ahn YH, Bang OY. A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells. 2010;28(6):1099–106.PubMedCrossRefGoogle Scholar
  155. 155.
    Nakazaki M, Sasaki M, Kataoka-Sasaki Y, Oka S, Namioka T, Namioka A, et al. Intravenous infusion of mesenchymal stem cells inhibits intracranial hemorrhage after recombinant tissue plasminogen activator therapy for transient middle cerebral artery occlusion in rats. J Neurosurg. 2017;PMID:28059661:1–10.Google Scholar
  156. 156.
    Chen J, Chen J, Chen S, Zhang C, Zhang L, Xiao X, et al. Transfusion of CXCR4-primed endothelial progenitor cells reduces cerebral ischemic damage and promotes repair in db/db diabetic mice. PLoS One. 2012;7(11):e50105.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Doeppner TR, Kaltwasser B, Bahr M, Hermann DM. Effects of neural progenitor cells on post-stroke neurological impairment-a detailed and comprehensive analysis of behavioral tests. Front Cell Neurosci. 2014;8:338.PubMedPubMedCentralGoogle Scholar
  158. 158.
    Zhang R, Zhang Z, Chopp M. Function of neural stem cells in ischemic brain repair processes. J Cereb Blood Flow Metab. 2016;36(12):2034–43.PubMedCrossRefGoogle Scholar
  159. 159.
    Banerjee S, Bhat MA. Neuron-glial interactions in blood-brain barrier formation. Annu Rev Neurosci. 2007;30:235–58.PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Sun D, Zhuang X, Xiang X, Liu Y, Zhang S, Liu C, et al. A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol Ther. 2010;18(9):1606–14.PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Dhillon N, Aggarwal BB, Newman RA, Wolff RA, Kunnumakkara AB, Abbruzzese JL, et al. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res. 2008;14(14):4491–9.PubMedCrossRefGoogle Scholar
  162. 162.
    Pardridge WM. Drug transport across the blood-brain barrier. J Cereb Blood Flow Metab. 2012;32(11):1959–72.PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Peng Q, Zhang S, Yang Q, Zhang T, Wei XQ, Jiang L, et al. Preformed albumin corona, a protective coating for nanoparticles based drug delivery system. Biomaterials. 2013;34(33):8521–30.PubMedCrossRefGoogle Scholar
  164. 164.
    Veronese FM, Caliceti P, Schiavon O, Sergi M. Polyethylene glycol-superoxide dismutase, a conjugate in search of exploitation. Adv Drug Deliv Rev. 2002;54(4):587–606.PubMedCrossRefGoogle Scholar
  165. 165.
    Yoshida K, Burton GF, McKinney JS, Young H, Ellis EF. Brain and tissue distribution of polyethylene glycol-conjugated superoxide dismutase in rats. Stroke. 1992;23(6):865–9.PubMedCrossRefGoogle Scholar
  166. 166.
    Yang T, Martin P, Fogarty B, Brown A, Schurman K, Phipps R, et al. Exosome delivered anticancer drugs across the blood-brain barrier for brain cancer therapy in Danio rerio. Pharm Res. 2015;32(6):2003–14.PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Zhuang X, Xiang X, Grizzle W, Sun D, Zhang S, Axtell RC, et al. Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. Mol Ther. 2011;19(10):1769–79.PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Fruhbeis C, Frohlich D, Kuo WP, Amphornrat J, Thilemann S, Saab AS, et al. Neurotransmitter-triggered transfer of exosomes mediates oligodendrocyte-neuron communication. PLoS Biol. 2013;11(7):e1001604.PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol. 2011;29(4):341–5.PubMedCrossRefGoogle Scholar
  170. 170.
    Liu Y, Li D, Liu Z, Zhou Y, Chu D, Li X, et al. Targeted exosome-mediated delivery of opioid receptor Mu siRNA for the treatment of morphine relapse. Sci Rep. 2015;5:17543.PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Ohno S, Takanashi M, Sudo K, Ueda S, Ishikawa A, Matsuyama N, et al. Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells. Mol Ther. 2013;21(1):185–91.PubMedCrossRefGoogle Scholar
  172. 172.
    Yeo RW, Lai RC, Zhang B, Tan SS, Yin Y, Teh BJ, et al. Mesenchymal stem cell: an efficient mass producer of exosomes for drug delivery. Adv Drug Deliv Rev. 2013;65(3):336–41.PubMedCrossRefGoogle Scholar
  173. 173.
    Doeppner TR, Herz J, Gorgens A, Schlechter J, Ludwig AK, Radtke S, et al. Extracellular vesicles improve post-stroke neuroregeneration and prevent postischemic immunosuppression. Stem Cells Transl Med. 2015;4(10):1131–43.PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Kim DK, Nishida H, An SY, Shetty AK, Bartosh TJ, Prockop DJ. Chromatographically isolated CD63+CD81+ extracellular vesicles from mesenchymal stromal cells rescue cognitive impairments after TBI. Proc Natl Acad Sci U S A. 2016;113(1):170–5.PubMedCrossRefGoogle Scholar
  175. 175.
    Xin H, Li Y, Buller B, Katakowski M, Zhang Y, Wang X, et al. Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells. 2012;30(7):1556–64.PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Xin H, Li Y, Liu Z, Wang X, Shang X, Cui Y, et al. MiR-133b promotes neural plasticity and functional recovery after treatment of stroke with multipotent mesenchymal stromal cells in rats via transfer of exosome-enriched extracellular particles. Stem Cells. 2013;31(12):2737–46.PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Zhang Y, Chopp M, Meng Y, Katakowski M, Xin H, Mahmood A, et al. Effect of exosomes derived from multipluripotent mesenchymal stromal cells on functional recovery and neurovascular plasticity in rats after traumatic brain injury. J Neurosurg. 2015;122(4):856–67.PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Penfornis P, Vallabhaneni KC, Whitt J, Pochampally R. Extracellular vesicles as carriers of microRNA, proteins and lipids in tumor microenvironment. Int J Cancer. 2016;138(1):14–21.PubMedCrossRefGoogle Scholar
  180. 180.
    Vallabhaneni KC, Penfornis P, Dhule S, Guillonneau F, Adams KV, Mo YY, et al. Extracellular vesicles from bone marrow mesenchymal stem/stromal cells transport tumor regulatory microRNA, proteins, and metabolites. Oncotarget. 2015;6(7):4953–67.PubMedCrossRefGoogle Scholar
  181. 181.
    Jones EV, Bouvier DS. Astrocyte-secreted matricellular proteins in CNS remodelling during development and disease. Neural Plast. 2014;2014:321209.PubMedPubMedCentralCrossRefGoogle Scholar
  182. 182.
    Mackie AR, Klyachko E, Thorne T, Schultz KM, Millay M, Ito A, et al. Sonic hedgehog-modified human CD34+ cells preserve cardiac function after acute myocardial infarction. Circ Res. 2012;111(3):312–21.PubMedPubMedCentralCrossRefGoogle Scholar
  183. 183.
    Altaba A, Sanchez P, Dahmane N. Gli and hedgehog in cancer: tumours, embryos and stem cells. Nat Rev Cancer. 2002;2(5):361–72.CrossRefGoogle Scholar
  184. 184.
    Goetz JA, Suber LM, Zeng X, Robbins DJ. Sonic Hedgehog as a mediator of long-range signaling. BioEssays. 2002;24(2):157–65.PubMedCrossRefGoogle Scholar
  185. 185.
    Roberts DJ, Johnson RL, Burke AC, Nelson CE, Morgan BA, Tabin C. Sonic hedgehog is an endodermal signal inducing Bmp-4 and Hox genes during induction and regionalization of the chick hindgut. Development. 1995;121(10):3163–74.PubMedGoogle Scholar
  186. 186.
    Androutsellis-Theotokis A, Leker RR, Soldner F, Hoeppner DJ, Ravin R, Poser SW, et al. Notch signalling regulates stem cell numbers in vitro and in vivo. Nature. 2006;442(7104):823–6.PubMedCrossRefGoogle Scholar
  187. 187.
    Liu XS, Chopp M, Wang XL, Zhang L, Hozeska-Solgot A, Tang T, et al. MicroRNA-17-92 cluster mediates the proliferation and survival of neural progenitor cells after stroke. J Biol Chem. 2013;288(18):12478–88.PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Palma V, Lim DA, Dahmane N, Sanchez P, Brionne TC, Herzberg CD, et al. Sonic hedgehog controls stem cell behavior in the postnatal and adult brain. Development. 2005;132(2):335–44.PubMedCrossRefGoogle Scholar
  189. 189.
    Wang L, Zhang ZG, Gregg SR, Zhang RL, Jiao Z, LeTourneau Y, et al. The Sonic hedgehog pathway mediates carbamylated erythropoietin-enhanced proliferation and differentiation of adult neural progenitor cells. J Biol Chem. 2007;282(44):32462–70.PubMedCrossRefGoogle Scholar
  190. 190.
    Asahara T, Masuda H, Takahashi T, Kalka C, Pastore C, Silver M, et al. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res. 1999;85(3):221–8.PubMedCrossRefGoogle Scholar
  191. 191.
    Murayama T, Tepper OM, Silver M, Ma H, Losordo DW, Isner JM, et al. Determination of bone marrow-derived endothelial progenitor cell significance in angiogenic growth factor-induced neovascularization in vivo. Exp Hematol. 2002;30(8):967–72.PubMedCrossRefGoogle Scholar
  192. 192.
    Zhang ZG, Zhang L, Jiang Q, Chopp M. Bone marrow-derived endothelial progenitor cells participate in cerebral neovascularization after focal cerebral ischemia in the adult mouse. Circ Res. 2002;90(3):284–8.PubMedCrossRefGoogle Scholar
  193. 193.
    Yang Z, von Ballmoos MW, Faessler D, Voelzmann J, Ortmann J, Diehm N, et al. Paracrine factors secreted by endothelial progenitor cells prevent oxidative stress-induced apoptosis of mature endothelial cells. Atherosclerosis. 2010;211(1):103–9.PubMedCrossRefGoogle Scholar
  194. 194.
    Gu S, Zhang W, Chen J, Ma R, Xiao X, Ma X, et al. EPC-derived microvesicles protect cardiomyocytes from Ang II-induced hypertrophy and apoptosis. PLoS One. 2014;9(1):e85396.PubMedPubMedCentralCrossRefGoogle Scholar
  195. 195.
    Cantaluppi V, Gatti S, Medica D, Figliolini F, Bruno S, Deregibus MC, et al. Microvesicles derived from endothelial progenitor cells protect the kidney from ischemia-reperfusion injury by microRNA-dependent reprogramming of resident renal cells. Kidney Int. 2012;82(4):412–27.PubMedCrossRefGoogle Scholar
  196. 196.
    Ranghino A, Cantaluppi V, Grange C, Vitillo L, Fop F, Biancone L, et al. Endothelial progenitor cell-derived microvesicles improve neovascularization in a murine model of hindlimb ischemia. Int J Immunopathol Pharmacol. 2012;25(1):75–85.PubMedCrossRefGoogle Scholar
  197. 197.
    Sluijter JP, Verhage V, Deddens JC, van den Akker F, Doevendans PA. Microvesicles and exosomes for intracardiac communication. Cardiovasc Res. 2014;102(2):302–11.PubMedCrossRefGoogle Scholar
  198. 198.
    Xin H, Li Y, Chopp M. Exosomes/miRNAs as mediating cell-based therapy of stroke. Front Cell Neurosci. 2014;8:377.PubMedPubMedCentralCrossRefGoogle Scholar
  199. 199.
    Tavazoie M, Van d V, Silva-Vargas V, Louissaint M, Colonna L, Zaidi B, et al. A specialized vascular niche for adult neural stem cells. Cell Stem Cell. 2008;3(3):279–88.PubMedCrossRefGoogle Scholar
  200. 200.
    Wang J, Chen Y, Yang Y, Xiao X, Chen S, Zhang C, et al. Endothelial progenitor cells and neural progenitor cells synergistically protect cerebral endothelial cells from Hypoxia/reoxygenation-induced injury via activating the PI3K/Akt pathway. Mol Brain. 2016;9:12.PubMedPubMedCentralCrossRefGoogle Scholar
  201. 201.
    Talaveron R, Matarredona ER, de la Cruz RR, Macias D, Galvez V, Pastor AM. Implanted neural progenitor cells regulate glial reaction to brain injury and establish gap junctions with host glial cells. Glia. 2014;62(4):623–38.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Ji Bihl
    • 1
  • Jinju Wang
    • 1
  • Xiaotang Ma
    • 2
  • Yi Yang
    • 3
  • Bin Zhao
    • 2
  • Yanfang Chen
    • 1
  1. 1.Department of Pharmacology and ToxicologyWright State UniversityDaytonUSA
  2. 2.Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of NeurologyGuangdong Medical UniversityZhanjiangChina
  3. 3.College of Health ScienceWuhan Sports UniversityWuhanChina

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