Skip to main content
SpringerLink
Log in

Exosome and MiRNA in Stroke

  • Chapter
  • First Online:
Cellular and Molecular Approaches to Regeneration and Repair

Part of the book series: Springer Series in Translational Stroke Research ((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 haveĀ 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.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

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-Ī³:

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

RARĪ²:

Retinoic acid receptor Ī²2

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

TNFĪ±:

Tumor necrosis factor-Ī±

VEGF:

Vascular endothelial growth factor

VEGFR2:

Vascular endothelial growth factor receptor 2

VPS4:

Vacuolar protein sorting 4

References

  1. SL P, GE P. The fine structure of neurons. J Biophys Biochem Cytol. 1955;1(1):69ā€“88.

    ArticleĀ  Google ScholarĀ 

  2. Piper RC, Katzmann DJ. Biogenesis and function of multivesicular bodies. Annu Rev Cell Dev Biol. 2007;23:519ā€“47.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  3. Von Bartheld CS, Altick AL. Multivesicular bodies in neurons: distribution, protein content, and trafficking functions. Prog Neurobiol. 2011;93(3):313ā€“40.

    ArticleĀ  Google ScholarĀ 

  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):63ā€“70.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  5. Fleury A, Martinez MC, Le LS. Extracellular vesicles as therapeutic tools in cardiovascular diseases. Front Immunol. 2014;5:370.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  CASĀ  Google ScholarĀ 

  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):256ā€“63.

    CASĀ  PubMedĀ  Google ScholarĀ 

  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):2313ā€“25.

    CASĀ  PubMedĀ  Google ScholarĀ 

  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):3791ā€“9.

    CASĀ  PubMedĀ  Google ScholarĀ 

  9. Thery M, Piel M. Adhesive micropatterns for cells: a microcontact printing protocol. Cold Spring Harb Protoc. 2009;2009(7):db.

    ArticleĀ  Google ScholarĀ 

  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):1379ā€“90.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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):830ā€“46.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  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):3365ā€“74.

    CASĀ  PubMedĀ  Google ScholarĀ 

  13. Stoorvogel W, Kleijmeer MJ, Geuze HJ, Raposo G. The biogenesis and functions of exosomes. Traffic. 2002;3(5):321ā€“30.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):55ā€“8.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

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

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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):43ā€“55.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):1244ā€“7.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  18. Simons M, Raposo G. Exosomes--vesicular carriers for intercellular communication. Curr Opin Cell Biol. 2009;21(4):575ā€“81.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  19. Record M, Subra C, Silvente-Poirot S, Poirot M. Exosomes as intercellular signalosomes and pharmacological effectors. Biochem Pharmacol. 2011;81(10):1171ā€“82.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  20. Thery C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol. 2009;9(8):581ā€“93.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  21. Thery C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002;2(8):569ā€“79.

    CASĀ  PubMedĀ  Google ScholarĀ 

  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):19ā€“30.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):211ā€“26.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):594ā€“600.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  25. Lai RC, Yeo RW, Tan KH, Lim SK. Exosomes for drug deliveryĀ ā€“ a novel application for the mesenchymal stem cell. Biotechnol Adv. 2013;31(5):543ā€“51.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):940ā€“8.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  27. Qin J, Xu Q. Functions and application of exosomes. Acta Pol Pharm. 2014;71(4):537ā€“43.

    PubMedĀ  Google ScholarĀ 

  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):287ā€“96.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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;7:1525ā€“41.

    CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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.

    ArticleĀ  CASĀ  Google ScholarĀ 

  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.

    PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  CASĀ  Google ScholarĀ 

  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):215ā€“24.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):654ā€“9.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  CASĀ  Google ScholarĀ 

  38. Boon RA, Vickers KC. Intercellular transport of microRNAs. Arterioscler Thromb Vasc Biol. 2013;33(2):186ā€“92.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  CASĀ  Google ScholarĀ 

  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):756ā€“66.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  41. Macfarlane LA, Murphy PR. MicroRNA: biogenesis, function and role in cancer. Curr Genomics. 2010;11(7):537ā€“61.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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):1487ā€“95.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):978ā€“87.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  44. Bobrie A, Colombo M, Raposo G, Thery C. Exosome secretion: molecular mechanisms and roles in immune responses. Traffic. 2011;12(12):1659ā€“68.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):4564ā€“73.

    CASĀ  PubMedĀ  Google ScholarĀ 

  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 ScholarĀ 

  47. Guescini M, Genedani S, Stocchi V, Agnati LF. Astrocytes and glioblastoma cells release exosomes carrying mtDNA. J Neural Transm (Vienna). 2010;117(1):1ā€“4.

    ArticleĀ  CASĀ  Google ScholarĀ 

  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):1977ā€“84.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  51. Regehr WG, Carey MR, Best AR. Activity-dependent regulation of synapses by retrograde messengers. Neuron. 2009;63(2):154ā€“70.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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):1039ā€“46.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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.

    ArticleĀ  PubMedĀ  CASĀ  Google ScholarĀ 

  54. Nave KA, Trapp BD. Axon-glial signaling and the glial support of axon function. Annu Rev Neurosci. 2008;31:535ā€“61.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  55. Fruhbeis C, Frohlich D, Kuo WP, Kramer-Albers EM. Extracellular vesicles as mediators of neuron-glia communication. Front Cell Neurosci. 2013;7:182.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  CASĀ  Google ScholarĀ 

  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.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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):447ā€“58.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  58. Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ. Structure and function of the blood-brain barrier. Neurobiol Dis. 2010;37(1):13ā€“25.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):165ā€“70.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  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):373ā€“9.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  61. Zhang Z, Chopp M. Neural stem cells and ischemic brain. J Stroke. 2016;18(3):267ā€“72.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  62. Li L, Xie T. Stem cell niche: structure and function. Annu Rev Cell Dev Biol. 2005;21:605ā€“31.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  63. Taupin P. Adult neural stem cells, neurogenic niches, and cellular therapy. Stem Cell Rev. 2006;2(3):213ā€“9.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  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):681ā€“9.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):1219ā€“27.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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):1072ā€“83.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  67. von Bohlen und HO. Immunohistological markers for proliferative events, gliogenesis, and neurogenesis within the adult hippocampus. Cell Tissue Res. 2011;345(1):1ā€“19.

    ArticleĀ  CASĀ  Google ScholarĀ 

  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.

    PubMedĀ  Google ScholarĀ 

  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.

    ArticleĀ  CASĀ  Google ScholarĀ 

  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.

    ArticleĀ  CASĀ  Google ScholarĀ 

  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;106:191ā€“204.

    ArticleĀ  CASĀ  Google ScholarĀ 

  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.

    ArticleĀ  PubMedĀ  CASĀ  Google ScholarĀ 

  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.

    ArticleĀ  CASĀ  Google ScholarĀ 

  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.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  CASĀ  Google ScholarĀ 

  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):355ā€“69.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  76. Elijovich L, Patel PV, Hemphill JC III. Intracerebral hemorrhage. Semin Neurol. 2008;28(5):657ā€“67.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  77. Sierra C, Coca A, Schiffrin EL. Vascular mechanisms in the pathogenesis of stroke. Curr Hypertens Rep. 2011;13(3):200ā€“7.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):959ā€“66.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):92ā€“101.

    ArticleĀ  PubMedĀ  CASĀ  Google ScholarĀ 

  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.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  CASĀ  Google ScholarĀ 

  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):675ā€“87.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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):774ā€“8.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):213ā€“9.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):6398ā€“408.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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):17ā€“26.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  86. Lee ST, Chu K, Jung KH, Yoon HJ, Jeon D, Kang KM, et al. MicroRNAs induced during ischemic preconditioning. Stroke. 2010;41(8):1646ā€“51.

    ArticleĀ  PubMedĀ  CASĀ  Google ScholarĀ 

  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;3:1265ā€“72.

    Google ScholarĀ 

  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):4299ā€“307.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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):753ā€“60.

    CASĀ  PubMedĀ  Google ScholarĀ 

  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):E828ā€“37.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  91. Gyorgy B, Hung ME, Breakefield XO, Leonard JN. Therapeutic applications of extracellular vesicles: clinical promise and open questions. Annu Rev Pharmacol Toxicol. 2015;55:439ā€“64.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  92. Ouyang YB, Stary CM, Yang GY, Giffard R. microRNAs: innovative targets for cerebral ischemia and stroke. Curr Drug Targets. 2013;14(1):90ā€“101.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  93. Yin KJ, Hamblin M, Chen YE. Angiogenesis-regulating microRNAs and ischemic stroke. Curr Vasc Pharmacol. 2015;13(3):352ā€“65.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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):764ā€“71.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):1055ā€“66.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):1906ā€“14.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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):202ā€“12.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  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):1402ā€“19.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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):6885ā€“94.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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):963ā€“6.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  101. He X, Yu Y, Awatramani R, Lu QR. Unwrapping myelination by microRNAs. Neuroscientist. 2012;18(1):45ā€“55.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):208ā€“20.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  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):3032ā€“9.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  104. Ohab JJ, Fleming S, Blesch A, Carmichael ST. A neurovascular niche for neurogenesis after stroke. J Neurosci. 2006;26(50):13007ā€“16.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  105. Zhang ZG, Chopp M. Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic. Lancet Neurol. 2009;8(5):491ā€“500.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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):1305ā€“20.

    Google ScholarĀ 

  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):2440ā€“8.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):1470ā€“6.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  111. Winkler EA, Bell RD, Zlokovic BV. Central nervous system pericytes in health and disease. Nat Neurosci. 2011;14(11):1398ā€“405.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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):1337ā€“43.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  CASĀ  Google ScholarĀ 

  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):2385ā€“94.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):656ā€“60.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):372ā€“83.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):674ā€“86.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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):193ā€“204.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  119. Famakin BM. The immune response to acute focal cerebral ischemia and associated post-stroke immunodepression: a focused review. Aging Dis. 2014;5(5):307ā€“26.

    PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  120. Zhang ZG, Chopp M. Exosomes in stroke pathogenesis and therapy. J Clin Invest. 2016;126(4):1190ā€“7.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  121. Higa GS, de SE, Walter LT, Kinjo ER, Resende RR, Kihara AH. MicroRNAs in neuronal communication. Mol Neurobiol. 2014;49(3):1309ā€“26.

    CASĀ  PubMedĀ  Google ScholarĀ 

  122. Kawikova I, Askenase PW. Diagnostic and therapeutic potentials of exosomes in CNS diseases. Brain Res. 2015;1617:63ā€“71.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):642ā€“8.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):409ā€“18.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):9195ā€“208.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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):15731ā€“45.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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):7105ā€“16.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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. 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):3766ā€“75.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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):1747ā€“54.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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.

    ArticleĀ  CASĀ  Google ScholarĀ 

  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;54:457ā€“81.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):48ā€“56.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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;1545:139ā€“51.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  135. Wang Y, Sheng G, Juranek S, Tuschl T, Patel DJ. Structure of the guide-strand-containing argonaute silencing complex. Nature. 2008;456(7219):209ā€“13.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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.

    ArticleĀ  CASĀ  Google ScholarĀ 

  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.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  CASĀ  Google ScholarĀ 

  139. Pritchard CC, Cheng HH, Tewari M. MicroRNA profiling: approaches and considerations. Nat Rev Genet. 2012;13(5):358ā€“69.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  CASĀ  Google ScholarĀ 

  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;28:3ā€“13.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  142. Chaput N, Thery C. Exosomes: immune properties and potential clinical implementations. Semin Immunopathol. 2011;33(5):419ā€“40.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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.

    ArticleĀ  CASĀ  Google ScholarĀ 

  144. Kanninen KM, Bister N, Koistinaho J, Malm T. Exosomes as new diagnostic tools in CNS diseases. Biochim Biophys Acta. 2016;1862(3):403ā€“10.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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 ScholarĀ 

  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.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  CASĀ  Google ScholarĀ 

  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):993ā€“1003.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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. Cordeiro MF, Horn AP. Stem cell therapy in intracerebral hemorrhage rat model. World J Stem Cells. 2015;7(3):618ā€“29.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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):5269ā€“77.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):1311ā€“7.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  152. Moskowitz MA, Lo EH, Iadecola C. The science of stroke: mechanisms in search of treatments. Neuron. 2010;67(2):181ā€“98.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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):2694ā€“700.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  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):1099ā€“106.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  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:28059661:1ā€“10.

    Google ScholarĀ 

  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.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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.

    PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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):2034ā€“43.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  159. Banerjee S, Bhat MA. Neuron-glial interactions in blood-brain barrier formation. Annu Rev Neurosci. 2007;30:235ā€“58.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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):1606ā€“14.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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):4491ā€“9.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  162. Pardridge WM. Drug transport across the blood-brain barrier. J Cereb Blood Flow Metab. 2012;32(11):1959ā€“72.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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):8521ā€“30.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):587ā€“606.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):865ā€“9.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):2003ā€“14.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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):1769ā€“79.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  CASĀ  Google ScholarĀ 

  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):341ā€“5.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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):185ā€“91.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):336ā€“41.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):1131ā€“43.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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):170ā€“5.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):1556ā€“64.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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):1711ā€“5.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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):2737ā€“46.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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):856ā€“67.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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):14ā€“21.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):4953ā€“67.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  181. Jones EV, Bouvier DS. Astrocyte-secreted matricellular proteins in CNS remodelling during development and disease. Neural Plast. 2014;2014:321209.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  CASĀ  Google ScholarĀ 

  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):312ā€“21.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  183. Altaba A, Sanchez P, Dahmane N. Gli and hedgehog in cancer: tumours, embryos and stem cells. Nat Rev Cancer. 2002;2(5):361ā€“72.

    ArticleĀ  CASĀ  Google ScholarĀ 

  184. Goetz JA, Suber LM, Zeng X, Robbins DJ. Sonic Hedgehog as a mediator of long-range signaling. BioEssays. 2002;24(2):157ā€“65.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):3163ā€“74.

    CASĀ  PubMedĀ  Google ScholarĀ 

  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):823ā€“6.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):12478ā€“88.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  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):335ā€“44.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):32462ā€“70.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):221ā€“8.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):967ā€“72.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):284ā€“8.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):103ā€“9.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  CASĀ  Google ScholarĀ 

  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):412ā€“27.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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):75ā€“85.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  197. Sluijter JP, Verhage V, Deddens JC, van den Akker F, Doevendans PA. Microvesicles and exosomes for intracardiac communication. Cardiovasc Res. 2014;102(2):302ā€“11.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  198. Xin H, Li Y, Chopp M. Exosomes/miRNAs as mediating cell-based therapy of stroke. Front Cell Neurosci. 2014;8:377.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  CASĀ  Google ScholarĀ 

  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):279ā€“88.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  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.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  CASĀ  Google ScholarĀ 

  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):623ā€“38.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Wright State University, Dayton, OH, 45435, USA

    Ji Bihl,Ā Jinju WangĀ &Ā Yanfang Chen

  2. Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Guangdong Medical University, Zhanjiang, 524001, China

    Xiaotang MaĀ &Ā Bin Zhao

  3. College of Health Science, Wuhan Sports University, Wuhan, Hubei, 430000, China

    Yi Yang

Authors
  1. Ji Bihl
    View author publications

    You can also search for this author in PubMedĀ Google Scholar

  2. Jinju Wang
    View author publications

    You can also search for this author in PubMedĀ Google Scholar

  3. Xiaotang Ma
    View author publications

    You can also search for this author in PubMedĀ Google Scholar

  4. Yi Yang
    View author publications

    You can also search for this author in PubMedĀ Google Scholar

  5. Bin Zhao
    View author publications

    You can also search for this author in PubMedĀ Google Scholar

  6. Yanfang Chen
    View author publications

    You can also search for this author in PubMedĀ Google Scholar

Corresponding author

Correspondence to Yanfang Chen .

Editor information

Editors and Affiliations

  1. Department of Neurology & Neurosurgery, Cedars-Sinai Medical Center, AHSP, Los Angeles, California, USA

    Paul A. Lapchak

  2. Department of Physiology, Loma Linda University, Loma Linda, California, USA

    John H. Zhang

Rights and permissions

Reprints and permissions

Copyright information

Ā© 2018 Springer International Publishing AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Bihl, J., Wang, J., Ma, X., Yang, Y., Zhao, B., Chen, Y. (2018). Exosome and MiRNA in Stroke. In: Lapchak, P., Zhang, J. (eds) Cellular and Molecular Approaches to Regeneration and Repair. Springer Series in Translational Stroke Research. Springer, Cham. https://doi.org/10.1007/978-3-319-66679-2_17

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-66679-2_17

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-66678-5

  • Online ISBN: 978-3-319-66679-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation