Exosomes in stroke pathogenesis and therapy

Journal of Clinical Investigation

Volumn 126, Issue 4, 2016, Pages 1190-1197

  Zhang, Zheng Gang ^a   Chopp, Michael ^a,b  

^a HENRY FORD HOSPITAL   (United States)

^b OAKLAND UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

MICRORNA 126; MICRORNA 15A; MICRORNA 9; NERVE PROTEIN; RNA;

ANGIOGENESIS; BRAIN ISCHEMIA; COGNITIVE DEFECT; ENDOTHELIUM CELL; EXOSOME; GLIA; HUMAN; MESENCHYMAL STEM CELL; NERVE CELL PLASTICITY; NERVOUS SYSTEM DEVELOPMENT; NEURAL STEM CELL; NONHUMAN; OCCLUSIVE CEREBROVASCULAR DISEASE; OLIGODENDROGLIA; PATHOGENESIS; PATHOPHYSIOLOGY; PRIORITY JOURNAL; REVIEW; ANIMAL; BRAIN; METABOLISM; STROKE;

ANIMALS; BRAIN; EXOSOMES; HUMANS; NERVE TISSUE PROTEINS; NEURAL STEM CELLS; RNA; STROKE;

EID: 84964688291     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI81133     Document Type: Review

References (141)

1. Lackland DT, et al. Factors influencing the decline in stroke mortality: A statement from the American Heart Association/American Stroke Association. Stroke. 2014;45(1):315-353.
2. [No authors listed]. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333(24):1581-1587.
3. Hacke W, et al. Thrombolysis with alteplase 3 to 4. N Engl J Med. 2008;359(13):1317-1329.
4. Adeoye O, Hornung R, Khatri P, Kleindorfer D. Recombinant tissue-type plasminogen activator use for ischemic stroke in the United States: A doubling of treatment rates over the course of 5 years. Stroke. 2011;42(7):1952-1955.
5. Zivin JA. Acute stroke therapy with tissue plasminogen activator (tPA) since it was approved by the U. Ann Neurol. 2009;66(1):6-10.
6. Goyal M, et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015;372(11):1019-1030.
7. Campbell BC, et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med. 2015;372(11):1009-1018.
8. Berkhemer OA, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372(1):11-20.
9. Lo EH, Dalkara T, Moskowitz MA. Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci. 2003;4(5):399-415.
10. Zhang ZG, Chopp M. Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic. Lancet Neurol. 2009;8(5):491-500.
11. Li Y, Liu Z, Xin H, Chopp M. The role of astrocytes in mediating exogenous cell-based restorative therapy for stroke. Glia. 2014;62(1):1-16.
12. Lai CP, Breakefield XO. Role of exosomes/microvesicles in the nervous system and use in emerging therapies. Front Physiol. 2012;3:228.
13. Gyorgy B, Hung ME, Breakefield XO, Leonard JN. Therapeutic applications of extracellular vesicles: clinical promise and open questions. Annu Rev Pharmacol Toxicol. 2015;55:439-464.
14. Zhang ZG, et al. Dynamic platelet accumulation at the site of the occluded middle cerebral artery and in downstream microvessels is associated with loss of microvascular integrity after embolic middle cerebral artery occlusion. Brain Res. 2001;912(2):181-194.
15. Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med. 2008;359(9):938-949.
16. Garcia JH, et al. Progression from ischemic injury to infarct following middle cerebral artery occlusion in the rat. Am J Pathol. 1993;142(2):623-635.
17. Zhang ZG, et al. Cerebral microvascular obstruction by fibrin is associated with upregulation of PAI-1 acutely after onset of focal embolic ischemia in rats. J Neurosci. 1999;19(24):10898-10907.
18. Moskowitz MA, Lo EH, Iadecola C. The science of stroke: mechanisms in search of treatments. Neuron. 2010;67(2):181-198.
19. Rosenberg GA. Neurological diseases in relation to the blood-brain barrier. J Cereb Blood Flow Metab. 2012;32(7):1139-1151.
20. Ginsberg MD. Current status of neuroprotection for cerebral ischemia: synoptic overview. Stroke. 2009;40(3 suppl):S111-S114.
21. Nudo RJ. Postinfarct cortical plasticity and behavioral recovery. Stroke. 2007;38(2 suppl):840-845.
22. Krupinski J, Kaluza J, Kumar P, Kumar S, Wang JM. Role of angiogenesis in patients with cerebral ischemic stroke. Stroke. 1994;25(9):1794-1798.
23. Zhang ZG, et al. VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. J Clin Invest. 2000;106(7):829-838.
24. Risau W. Mechanisms of angiogenesis. Nature. 1997;386(6626):671-674.
25. Carmeliet P. VEGF gene therapy: stimulating angiogenesis or angioma-genesis? Nat Med. 2000;6(10):1102-1103.
26. 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):284-288.
27. Zhang RL, et al. Stroke increases neural stem cells and angiogenesis in the neurogenic niche of the adult mouse. PLoS One. 2014;9(12):e113972.
28. Plate KH. Mechanisms of angiogenesis in the brain. J Neuropathol Exp Neurol. 1999;58(4):313-320.
29. Miller FD, Gauthier-Fisher A. Home at last: neural stem cell niches defined. Cell Stem Cell. 2009;4(6):507-510.
30. Iwai M, et al. Temporal profile of stem cell division, migration, and differentiation from subventricular zone to olfactory bulb after transient forebrain ischemia in gerbils. J Cereb Blood Flow Metab. 2003;23(3):331-341.
31. Ohab JJ, Fleming S, Blesch A, Carmichael ST. A neurovascular niche for neurogenesis after stroke. J Neurosci. 2006;26(50):13007-13016.
32. Yamashita T, et al. Subventricular zone-derived neuroblasts migrate and differentiate into mature neurons in the post-stroke adult striatum. J Neurosci. 2006;26(24):6627-6636.
33. Felling RJ, et al. Neural stem/progenitor cells participate in the regenerative response to perinatal hypoxia/ischemia. J Neurosci. 2006;26(16):4359-4369.
34. Jin K, et al. Evidence for stroke-induced neurogenesis in the human brain. Proc Natl Acad Sci U S A. 2006;103(35):13198-13202.
35. Macas J, Nern C, Plate KH, Momma S. Increased generation of neuronal progenitors after ischemic injury in the aged adult human forebrain. J Neurosci. 2006;26(50):13114-13119.
36. Minger SL, Ekonomou A, Carta EM, Chinoy A, Perry RH, Ballard CG. Endogenous neurogenesis in the human brain following cerebral infarction. Regen Med. 2007;2(1):69-74.
37. Curtis MA, Kam M, Faull RL. Neurogenesis in humans. Eur J Neurosci. 2011;33(6):1170-1174.
38. Marti-Fabregas J, et al. Proliferation in the human ipsilateral subventricular zone after ischemic stroke. Neurology. 2010;74(5):357-365.
39. Silva-Vargas V, Crouch EE, Doetsch F. Adult neural stem cells and their niche: A dynamic duo during homeostasis, regeneration, and aging. Curr Opin Neurobiol. 2013;23(6):935-942.
40. Tran PB, Ren D, Veldhouse TJ, Miller RJ. Chemokine receptors are expressed widely by embryonic and adult neural progenitor cells. J Neurosci Res. 2004;76(1):20-34.
41. Robin AM, et al. Stromal cell-derived factor 1α mediates neural progenitor cell motility after focal cerebral ischemia. J Cereb Blood Flow Metab. 2006;26(1):125-134.
42. Zhang RL, et al. Patterns and dynamics of subven-tricular zone neuroblast migration in the ischemic striatum of the adult mouse. J Cereb Blood Flow Metab. 2009;29(7):1240-1250.
43. Zhang RL, et al. Neuroblast division during migration toward the ischemic striatum: A study of dynamic migratory and proliferative characteristics of neuroblasts from the subventricular zone. J Neurosci. 2007;27(12):3157-3162.
44. Wang X, Mao X, Xie L, Sun F, Greenberg DA, Jin K. Conditional depletion of neurogenesis inhibits long-term recovery after experimental stroke in mice. PLoS One. 2012;7(6):e38932.
45. Young KM, et al. Oligodendrocyte dynamics in the healthy adult CNS: evidence for myelin remodeling. Neuron. 2013;77(5):873-885.
46. Fields RD. White matter in learning, cognition and psychiatric disorders. Trends Neurosci. 2008;31(7):361-370.
47. Zatorre RJ, Fields RD, Johansen-Berg H. Plasticity in gray and white: neuroimaging changes in brain structure during learning. Nat Neurosci. 2012;15(4):528-536.
48. Zhang RL, et al. Sildenafil enhances neurogenesis and oligodendrogenesis in ischemic brain of middle-aged mouse. PLoS One. 2012;7(10):e48141.
49. Zhang RL, et al. Ascl1 lineage cells contribute to ischemia-induced neurogenesis and oligodendrogenesis. J Cereb Blood Flow Metab. 2011;31(2):614-625.
50. Ueno Y, et al. Axonal outgrowth and dendritic plasticity in the cortical peri-infarct area after experimental stroke. Stroke. 2012;43(8):2221-2228.
51. Gregersen R, Christensen T, Lehrmann E, Diemer NH, Finsen B. Focal cerebral ischemia induces increased myelin basic protein and growthassociated protein-43 gene transcription in peri-infarct areas in the rat brain. Exp Brain Res. 2001;138(3):384-392.
52. 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):1055-1066.
53. Yin KJ, Hamblin M, Chen YE. Angiogenesisregulating microRNAs and Ischemic Stroke. Curr Vasc Pharmacol. 2015;13(3):352-365.
54. Teng H, 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):764-771.
55. Buller B, et al. Regulation of serum response factor by miRNA-200 and miRNA-9 modulates oligodendrocyte progenitor cell differentiation. Glia. 2012;60(12):1906-1914.
56. 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):202-212.
57. Zhang Y, et al. MicroRNAs in the axon locally mediate the effects of chondroitin sulfate proteoglycans and cGMP on axonal growth. Dev Neurobiol. 2015;75(12):1402-1419.
58. Zhang Y, et al. The MicroRNA-17-92 cluster enhances axonal outgrowth in embryonic cortical neurons. J Neurosci. 2013;33(16):6885-6894.
59. Park KK, et al. Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science. 2008;322(5903):963-966.
60. He X, Yu Y, Awatramani R, Lu QR. Unwrapping myelination by microRNAs. Neuroscientist. 2012;18(1):45-55.
61. Fruhbeis C, Frohlich D, Kuo WP, Kramer-Albers EM. Extracellular vesicles as mediators of neuron-glia communication. Front Cell Neurosci. 2013;7:182.
62. Perez-Gonzalez R, Gauthier SA, Kumar A, Levy E. The exosome secretory pathway transports amyloid precursor protein carboxyl-terminal fragments from the cell into the brain extracellular space. J Biol Chem. 2012;287(51):43108-43115.
63. Banigan MG, et al. Differential expression of exosomal microRNAs in prefrontal cortices of schizophrenia and bipolar disorder patients. PLoS One. 2013;8(1):e48814.
64. Rajendran L, et al. Alzheimer's disease β-amyloid peptides are released in association with exosomes. Proc Natl Acad Sci U S A. 2006;103(30):11172-11177.
65. Dinkins MB, Dasgupta S, Wang G, Zhu G, Bieberich E. Exosome reduction in vivo is associated with lower amyloid plaque load in the 5XFAD mouse model of Alzheimer's disease. Neurobiol Aging. 2014;35(8):1792-1800.
66. Cantaluppi V, et al. Microvesicles derived from endothelial progenitor cells enhance neoangiogenesis of human pancreatic islets. Cell Transplant. 2012;21(6):1305-1320.
67. Deregibus MC, et al. Endothelial progenitor cell derived microvesicles activate an angiogenic program in endothelial cells by a horizontal transfer of mRNA. Blood. 2007;110(7):2440-2448.
68. Skog J, et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol. 2008;10(12):1470-1476.
69. 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.
70. Yamamoto S, et al. Inflammation-induced endothelial cell-derived extracellular vesicles modulate the cellular status of pericytes. Sci Rep. 2015;5:8505.
71. Takahashi H, Shibuya M. The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions. Clin Sci (Lond). 2005;109(3):227-241.
72. Winkler EA, Bell RD, Zlokovic BV. Central nervous system pericytes in health and disease. Nat Neurosci. 2011;14(11):1398-1405.
73. Schulz GB, et al. Cerebral cavernous malformation-1 protein controls DLL4-Notch3 signaling between the endothelium and pericytes. Stroke. 2015;46(5):1337-1343.
74. Sheldon H, et al. New mechanism for Notch signaling to endothelium at a distance by Δ-like 4 incorporation into exosomes. Blood. 2010;116(13):2385-2394.
75. 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.
76. Tammela T, et al. Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature. 2008;454(7204):656-660.
77. 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):372-383.
78. Pan W, et al. Exosomes derived from ischemic cerebral endothelial cells and neural progenitor cells enhance neurogenesis and angiogenesis. Stroke. 2016;47(suppl 1):AWMP39.
79. Ihrie RA, Alvarez-Buylla A. Lake-front property: A unique germinal niche by the lateral ventricles of the adult brain. Neuron. 2011;70(4):674-686.
80. 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.
81. Cossetti C, 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.
82. Famakin BM. The immune response to acute focal cerebral ischemia and associated poststroke immunodepression: A focused review. Aging Dis. 2014;5(5):307-326.
83. Higa GS, de Sousa E, Walter LT, Kinjo ER, Resende RR, Kihara AH. MicroRNAs in neuronal communication. Mol Neurobiol. 2014;49(3):1309-1326.
84. Kawikova I, Askenase PW. Diagnostic and therapeutic potentials of exosomes in CNS diseases. Brain Res. 2015;1617:63-71.
85. Faure J, et al. Exosomes are released by cultured cortical neurones. Mol Cell Neurosci. 2006;31(4):642-648.
86. Lachenal G, et al. Release of exosomes from differentiated neurons and its regulation by synaptic glutamatergic activity. Mol Cell Neurosci. 2011;46(2):409-418.
87. Goldie BJ, et al. Activity-associated miRNA are packaged in Map1b-enriched exosomes released from depolarized neurons. Nucleic Acids Res. 2014;42(14):9195-9208.
88. Goncalves MB, et al. Neuronal RARβ 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):15731-15745.
89. Morel L, et al. Neuronal exosomal miRNAdependent translational regulation of astroglial glutamate transporter GLT1. J Biol Chem. 2013;288(10):7105-7116.
90. Dajas-Bailador F, Bonev B, Garcez P, Stanley P, Guillemot F, Papalopulu N. microRNA-9 regulates axon extension and branching by targeting Map1b in mouse cortical neurons [published online ahead of print April 8, 2012]. Nat Neurosci. doi:10.1038/nn.3082.
91. 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):3766-3775.
92. 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):1747-1754.
93. Edelstein L, Smythies J. The role of epigeneticrelated codes in neurocomputation: dynamic hardware in the brain. Philos Trans R Soc Lond B Biol Sci. 2014;369(1652):20130519.
94. Taylor AR, Robinson MB, Gifondorwa DJ, Tytell M, Milligan CE. Regulation of heat shock protein 70 release in astrocytes: role of signaling kinases. Dev Neurobiol. 2007;67(13):1815-1829.
95. Wang S, et al. Synapsin I is an oligomannose-carrying glycoprotein, acts as an oligomannose-binding lectin, and promotes neurite outgrowth and neuronal survival when released via glia-derived exosomes. J Neurosci. 2011;31(20):7275-7290.
96. Lauritzen M, Dreier JP, Fabricius M, Hartings JA, Graf R, Strong AJ. Clinical relevance of cortical spreading depression in neurological disorders: migraine, malignant stroke, subarachnoid and intracranial hemorrhage, and traumatic brain injury. J Cereb Blood Flow Metab. 2011;31(1):17-35.
97. Kramer-Albers EM, et al. Oligodendrocytes secrete exosomes containing major myelin and stressprotective proteins: Trophic support for axons? Proteomics Clin Appl. 2007;1(11):1446-1461.
98. Fruhbeis C, et al. Neurotransmitter-triggered transfer of exosomes mediates oligodendrocyte-neuron communication. PLoS Biol. 2013;11(7):e1001604.
99. Bakhti M, Winter C, Simons M. Inhibition of myelin membrane sheath formation by oligodendrocyte-derived exosome-like vesicles. J Biol Chem. 2011;286(1):787-796.
100. Frohlich D, et al. Multifaceted effects of oligodendroglial exosomes on neurons: impact on neuronal firing rate, signal transduction and gene regulation. Philos Trans R Soc Lond B Biol Sci. 2014;369(1652):2013510.
101. Potolicchio I, et al. Proteomic analysis of microglia-derived exosomes: metabolic role of the aminopeptidase CD13 in neuropeptide catabolism. J Immunol. 2005;175(4):2237-2243.
102. Fitzner D, et al. Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis. J Cell Sci. 2011;124(pt 3):447-458.
103. Sato K. Effects of Microglia on Neurogenesis. Glia. 2015;63(8):1394-1405.
104. Ribeiro Xavier AL, Kress BT, Goldman SA, Lacerda de Menezes JR, Nedergaard M. A distinct population of microglia supports adult neurogenesis in the subventricular zone. J Neurosci. 2015;35(34):11848-11861.
105. Butovsky O, et al. Microglia activated by IL-4 or IFN-γ differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol Cell Neurosci. 2006;31(1):149-160.
106. Querfurth HW, LaFerla FM. Alzheimer's disease. N Engl J Med. 2010;362(4):329-344.
107. Yuyama K, Sun H, Mitsutake S, Igarashi Y. Sphingolipid-modulated exosome secretion promotes clearance of amyloid-β by microglia. J Biol Chem. 2012;287(14):10977-10989.
108. Tamboli IY, et al. Statins promote the degradation of extracellular amyloid β-peptide by microglia via stimulation of exosome-associated insulindegrading enzyme (IDE) secretion. J Biol Chem. 2010;285(48):37405-37414.
109. Darwish H, Mahmood A, Schallert T, Chopp M, Therrien B. Simvastatin and environmental enrichment effect on recognition and temporal order memory after mild-to-moderate traumatic brain injury. Brain Inj. 2014;28(2):211-226.
110. Chen J, et al. Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke. Ann Neurol. 2003;53(6):743-751.
111. Basso M, et al. Mutant copper-zinc superoxide dismutase (SOD1) induces protein secretion pathway alterations and exosome release in astrocytes: implications for disease spreading and motor neuron pathology in amyotrophic lateral sclerosis. J Biol Chem. 2013;288(22):15699-15711.
112. Wang G, et al. Astrocytes secrete exosomes enriched with proapoptotic ceramide and prostate apoptosis response 4 (PAR-4): potential mechanism of apoptosis induction in Alzheimer disease (AD). J Biol Chem. 2012;287(25):21384-21395.
113. Yeo RW, et al. Mesenchymal stem cell: an efficient mass producer of exosomes for drug delivery. Adv Drug Deliv Rev. 2013;65(3):336-341.
114. Doeppner TR, et al. Extracellular vesicles improve post-stroke neuroregeneration and prevent postischemic immunosuppression. Stem Cells Transl Med. 2015;4(10):1131-1143.
115. 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):170-175.
116. Zhang Y, 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):856-867.
117. 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):1711-1715.
118. Xin H, 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):1556-1564.
119. Xin H, 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):2737-2746.
120. 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.
121. Vallabhaneni KC, et al. Extracellular vesicles from bone marrow mesenchymal stem/stromal cells transport tumor regulatory microRNA, proteins, and metabolites. Oncotarget. 2015;6(7):4953-4967.
122. Zhang Y, Chopp M, Katakowski M, Liu X, Zhang Z. Exosomes derived from mesenchymal stromal cells promote axonal outgrowth. Stroke. 2015;46:A67.
123. Zhang ZG, Chopp M. Promoting brain remodeling to aid in stroke recovery. Trends Mol Med. 2015;21(9):543-548.
124. Jones EV, Bouvier DS. Astrocyte-secreted matricellular proteins in CNS remodelling during development and disease. Neural Plast. 2014;2014:321209.
125. Offner H, Vandenbark AA, Hurn PD. Effect of experimental stroke on peripheral immunity: CNS ischemia induces profound immunosuppression. Neuroscience. 2009;158(3):1098-1111.
126. Prass K, et al. Stroke-induced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by poststroke T helper cell type 1-like immunostimulation. J Exp Med. 2003;198(5):725-736.
127. Wong CH, Jenne CN, Lee WY, Leger C, Kubes P. Functional innervation of hepatic iNKT cells is immunosuppressive following stroke. Science. 2011;334(6052):101-105.
128. Mackie AR, et al. Sonic hedgehog-modified human CD34+ cells preserve cardiac function after acute myocardial infarction. Circ Res. 2012;111(3):312-321.
129. Ruiz i Altaba A, Sanchez P, Dahmane N. Gli and hedgehog in cancer: tumours, embryos and stem cells. Nat Rev Cancer. 2002;2(5):361-372.
130. Goetz JA, Suber LM, Zeng X, Robbins DJ. Sonic Hedgehog as a mediator of long-range signaling. Bioessays. 2002;24(2):157-165.
131. 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):3163-3174.
132. Androutsellis-Theotokis A, et al. Notch signalling regulates stem cell numbers in vitro and in vivo. Nature. 2006;442(7104):823-826.
133. Palma V, et al. Sonic hedgehog controls stem cell behavior in the postnatal and adult brain. Development. 2005;132(2):335-344.
134. Liu XS, et al. MicroRNA-17-92 cluster mediates the proliferation and survival of neural progenitor cells after stroke. J Biol Chem. 2013;288(18):12478-12488.
135. Wang L, et al. The Sonic hedgehog pathway mediates carbamylated erythropoietinenhanced proliferation and differentiation of adult neural progenitor cells. J Biol Chem. 2007;282(44):32462-32470.
136. Zhuang X, 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):1769-1779.
137. 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):341-345.
138. Liu Y, et al. Targeted exosome-mediated delivery of opioid receptor Mu siRNA for the treatment of morphine relapse. Sci Rep. 2015;5:17543.
139. Xin H, Li Y, Chopp M. Exosomes/miRNAs as mediating cell-based therapy of stroke. Front Cell Neurosci. 2014;8:377.
140. Liu XS, Chopp M, Zhang RL, Zhang ZG. MicroRNAs in cerebral ischemia-induced neurogenesis. J Neuropathol Exp Neurol. 2013;72(8):718-722.
141. Zhang R, Chopp M, Zhang ZG. Oligodendrogenesis after cerebral ischemia. Front Cell Neurosci. 2013;7:201.