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Astrocytes as a Target for Ischemic Stroke

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Non-Neuronal Mechanisms of Brain Damage and Repair After Stroke

Part of the book series: Springer Series in Translational Stroke Research ((SSTSR))

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Abstract

Astrocytes are the most diverse and numerous glial cell types in the central nervous system (CNS). They provide structural, nutritional, and metabolic support to neurons and regulate synaptic activity. They are electrically non-excitable but their excitability is manifested by Ca2+ signaling. Astrocytes are also critically involved in many CNS disorders including focal ischemic stroke (FIS), the leading cause of brain injury and human disability. They undergo many changes at different stages after FIS. These changes will affect acute neuronal death and brain damage as well as brain recovery in the chronic phase after ischemic stroke. This chapter provides an overview of recent advances in astrocytic Ca2+ signaling, spatial and temporal dynamics of the morphology and proliferation of reactive astrocytes as well as signaling pathways involved in the reactive astrogliosis after ischemic stroke. This chapter also discusses stem cell properties of reactive astrocytes after FIS and their potential to differentiate into neurons under permissive conditions. The data are all from experimental studies performed in different animal models of ischemic stroke. As astrocytes exhibit high plasticity after FIS, we suggest that targeting local astrocytes is a promising strategy for cell-based stroke therapy.

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References

  1. Kimelberg HK. Functions of mature mammalian astrocytes: a current view. Neuroscientist. 2010;16:79–106.

    Article  CAS  PubMed  Google Scholar 

  2. Kimelberg H, Nedergaard M. Functions of astrocytes and their potential as therapeutic targets. Neurotherapeutics. 2010;7:338–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Zhang Y, Barres BA. Astrocyte heterogeneity: an underappreciated topic in neurobiology. Curr Opin Neurobiol. 2010;20:588–94.

    Article  CAS  PubMed  Google Scholar 

  4. Matyash V, Kettenmann H. Heterogeneity in astrocyte morphology and physiology. Brain Res Rev. 2010;63:2–10.

    Article  CAS  PubMed  Google Scholar 

  5. Wilhelmsson U, Bushong EA, Price DL, Smarr BL, Phung V, Terada M, et al. Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury. Proc Natl Acad Sci U S A. 2006;103:17513–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bushong EA, Martone ME, Jones YZ, Ellisman MH. Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. J Neurosci. 2002;22:183–92.

    CAS  PubMed  Google Scholar 

  7. Ding S. In vivo astrocytic Ca2+ signaling in health and brain disorders. Future Neurol. 2013;8:529–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Cahoy JD, Emery B, Kaushal A, Foo LC, Zamanian JL, Christopherson KS, et al. A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci. 2008;28:264–78.

    Article  CAS  PubMed  Google Scholar 

  9. Zhou M, Kimelberg HK. Freshly isolated astrocytes from rat hippocampus show two distinct current patterns and different [K+]o uptake capabilities. J Neurophysiol. 2000;84:2746–57.

    CAS  PubMed  Google Scholar 

  10. Takata N, Hirase H. Cortical layer 1 and layer 2/3 astrocytes exhibit distinct calcium dynamics in vivo. PLoS One. 2008;3:e2525.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Ding S, Fellin T, Zhu Y, Lee SY, Auberson YP, Meaney DF, et al. Enhanced astrocytic Ca2+ signals contribute to neuronal excitotoxicity after status epilepticus. J Neurosci. 2007;27:10674–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Fellin T, Pascual O, Gobbo S, Pozzan T, Haydon PG, Carmignoto G. Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron. 2004;43:729–43.

    Article  CAS  PubMed  Google Scholar 

  13. Sun W, McConnell E, Pare JF, Xu Q, Chen M, Peng W, et al. Glutamate-dependent neuroglial calcium signaling differs between young and adult brain. Science. 2013;339:197–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ding S, Wang T, Cui W, Haydon PG. Photothrombosis ischemia stimulates a sustained astrocytic Ca2+ signaling in vivo. Glia. 2009;57:767–76.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Thrane AS, Rangroo Thrane V, Zeppenfeld D, Lou N, Xu Q, Nagelhus EA, et al. General anesthesia selectively disrupts astrocyte calcium signaling in the awake mouse cortex. Proc Natl Acad Sci U S A. 2012;109:18974–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wang X, Lou N, Xu Q, Tian GF, Peng WG, Han X, et al. Astrocytic Ca2+ signaling evoked by sensory stimulation in vivo. Nat Neurosci. 2006;9:816–23.

    Article  CAS  PubMed  Google Scholar 

  17. Nizar K, Uhlirova H, Tian P, Saisan PA, Cheng Q, Reznichenko L, et al. In vivo stimulus-induced vasodilation occurs without IP3 receptor activation and may precede astrocytic calcium increase. J Neurosci. 2013;33:8411–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Meier SD, Kafitz KW, Rose CR, Meier SD, Kafitz KW, Rose CR. Developmental profile and mechanisms of GABA-induced calcium signaling in hippocampal astrocytes. Glia. 2008;56:1127–37.

    Article  PubMed  Google Scholar 

  19. Bekar LK, He W, Nedergaard M. Locus coeruleus α-adrenergic-mediated activation of cortical astrocytes in vivo. Cereb Cortex. 2008;18:2789–95.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Haydon PG, Carmignoto G. Astrocyte control of synaptic transmission and neurovascular coupling. Physiol Rev. 2006;86:1009–31.

    Article  CAS  PubMed  Google Scholar 

  21. Ni Y, Malarkey EB, Parpura V, Ni Y, Malarkey EB, Parpura V. Vesicular release of glutamate mediates bidirectional signaling between astrocytes and neurons. [Review] [150 refs]. J Neurochem. 2007;103:1273–84.

    Article  CAS  PubMed  Google Scholar 

  22. Agulhon C, Petravicz J, McMullen AB, Sweger EJ, Minton SK, Taves SR, et al. What is the role of astrocyte calcium in neurophysiology? Neuron. 2008;59:932–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Haydon PG. GLIA: listening and talking to the synapse. Nat Rev Neurosci. 2001;2:185–93.

    Article  CAS  PubMed  Google Scholar 

  24. Petravicz J, Fiacco TA, McCarthy KD. Loss of IP3 receptor-dependent Ca2+ increases in hippocampal astrocytes does not affect baseline CA1 pyramidal neuron synaptic activity. J Neurosci. 2008;28:4967–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hertle DN, Yeckel MF, Hertle DN, Yeckel MF. Distribution of inositol-1,4,5-trisphosphate receptor isotypes and ryanodine receptor isotypes during maturation of the rat hippocampus. Neuroscience. 2007;150:625–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Holtzclaw LA, Pandhit S, Bare DJ, Mignery GA, Russell JT, Holtzclaw LA, et al. Astrocytes in adult rat brain express type 2 inositol 1,4,5-trisphosphate receptors. Glia. 2002;39:69–84.

    Article  PubMed  Google Scholar 

  27. Sharp AH, Nucifora Jr FC, Blondel O, Sheppard CA, Zhang C, Snyder SH, et al. Differential cellular expression of isoforms of inositol 1,4,5-triphosphate receptors in neurons and glia in brain. J Comp Neurol. 1999;406:207–20.

    Article  CAS  PubMed  Google Scholar 

  28. Petravicz J, Boyt KM, McCarthy KD. Astrocyte IP3R2-dependent Ca2+ signaling is not a major modulator of neuronal pathways governing behavior. Front Behav Neurosci. 2014;8:e384.

    Article  CAS  Google Scholar 

  29. Srinivasan R, Huang BS, Venugopal S, Johnston AD, Chai H, Zeng H, et al. Ca2+ signaling in astrocytes from Ip3r2-/- mice in brain slices and during startle responses in vivo. Nat Neurosci. 2015;18:708–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Rossi DJ, Brady JD, Mohr C. Astrocyte metabolism and signaling during brain ischemia. Nat Neurosci. 2007;10:1377–86.

    Article  CAS  PubMed  Google Scholar 

  31. Stapf C, Mohr JP. Ischemic stroke therapy. Annu Rev Med. 2002;53:453–75.

    Article  CAS  PubMed  Google Scholar 

  32. Huang Y, McNamara JO. Ischemic stroke: “acidotoxicity” is a perpetrator.[comment]. [Review] [7 refs]. Cell. 2004;118(6):665–6.

    Article  CAS  PubMed  Google Scholar 

  33. Nedergaard M, Dirnagl U. Role of glial cells in cerebral ischemia. Glia. 2005;50:281–6.

    Article  PubMed  Google Scholar 

  34. Barber PA, Demchuk AMH. Biochemistry ischemic stroke. Adv Neurol. 2003;92:151–64.

    PubMed  Google Scholar 

  35. Swanson RA, Ying W, Kauppinen TM. Astrocyte influences on ischemic neuronal death. Curr Mol Med. 2004;4:193–205.

    Article  CAS  PubMed  Google Scholar 

  36. Kimelberg HK. Astrocytic swelling in cerebral ischemia as a possible cause of injury and target for therapy. Glia. 2005;50:389–97.

    Article  PubMed  Google Scholar 

  37. Zheng W, Watts LT, Holstein DM, Prajapati SI, Keller C, Grass EH, et al. Purinergic receptor stimulation reduces cytotoxic edema and brain infarcts in mouse induced by photothrombosis by energizing glial mitochondria. PLoS One. 2010;5:e14401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Risher WC, Croom D, Kirov SA. Persistent astroglial swelling accompanies rapid reversible dendritic injury during stroke-induced spreading depolarizations. Glia. 2012;60:1709–20.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Lo EH, Dalkara T, Moskowitz MA. Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci. 2003;4:399–415.

    Article  CAS  PubMed  Google Scholar 

  40. Kasischke KA, Vishwasrao HD, Fisher PJ, Zipfel WR, Webb WW. Neural activity triggers neuronal oxidative metabolism followed by astrocytic glycolysis. Science. 2004;305:99–103.

    Article  CAS  PubMed  Google Scholar 

  41. Brown AM. Brain glycogen re-awakened. J Neurochem. 2004;89:537–52.

    Article  CAS  PubMed  Google Scholar 

  42. Gurer G, Gursoy-Ozdemir Y, Erdemli E, Can A, Dalkara T. Astrocytes are more resistant to focal cerebral ischemia than neurons and die by a delayed necrosis. Brain Pathol. 2009;19:630–41.

    Article  CAS  PubMed  Google Scholar 

  43. Brown AM, Ransom BR. Astrocyte glycogen and brain energy metabolism. Glia. 2007;55:1263–71.

    Article  PubMed  Google Scholar 

  44. Panickar KS, Norenberg MD. Astrocytes in cerebral ischemic injury: morphological and general considerations. Glia. 2005;50:287–98.

    Article  PubMed  Google Scholar 

  45. Li H, Zhang N, Sun G, Ding S. Inhibition of the group I mGluRs reduces acute brain damage and improves long-term histological outcomes after photothrombosis-induced ischaemia. ASN Neuro. 2013;5:e00117.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Barreto GE, Sun X, Xu L, Giffard RG. Astrocyte proliferation following stroke in the mouse depends on distance from the infarct. PLoS One. 2011;6:e27881.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Pekny M, Nilsson M. Astrocyte activation and reactive gliosis. Glia. 2005;50:427–34.

    Article  PubMed  Google Scholar 

  48. Zhao Y, Rempe D. Targeting astrocytes for stroke therapy. Neurotherapeutics. 2010;7:439–51.

    Article  CAS  PubMed  Google Scholar 

  49. Gleichman AJ, Carmichael ST. Astrocytic therapies for neuronal repair in stroke. Neurosci Lett. 2014;565:47–52.

    Article  CAS  PubMed  Google Scholar 

  50. Choudhury GR, Ding S. Reactive astrocytes and therapeutic potential in focal ischemic stroke. Neurobiol Dis. 2016;85:234–44.

    Article  PubMed  Google Scholar 

  51. Ding S. Ca2+ signaling in astrocytes and its role in ischemic stroke. In: Parpura V, Schousboe A, Verkhratsky A, editors. Glutamate and ATP at the interface of metabolism and signaling in the brain. 11th ed. Cham: Springer; 2014. p. 189–211.

    Google Scholar 

  52. Choi D. Glutamate neurotoxicity and diseases of the nervous system. Neuron. 1988;1:623–34.

    Article  CAS  PubMed  Google Scholar 

  53. Medvedeva YV, Lin B, Shuttleworth CW, Weiss JH. Intracellular Zn2+ accumulation contributes to synaptic failure, mitochondrial depolarization, and cell death in an acute slice oxygen-glucose deprivation model of ischemia. J Neurosci. 2009;29:1105–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Tanaka E, Yamamoto S, Kudo Y, Mihara S, Higashi H. Mechanisms underlying the rapid depolarization produced by deprivation of oxygen and glucose in rat hippocampal CA1 neurons in vitro. J Neurophysiol. 1997;78:891–902.

    CAS  PubMed  Google Scholar 

  55. Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 1999;22:391–7.

    Article  CAS  PubMed  Google Scholar 

  56. Rossi DJ, Oshima T, Attwell D. Glutamate release in severe brain ischaemia is mainly by reversed uptake. Nature. 2000;403:316–21.

    Article  CAS  PubMed  Google Scholar 

  57. Phillis JW, Ren J, ÖRegan MH. Transporter reversal as a mechanism of glutamate release from the ischemic rat cerebral cortex: studies with dl-threo-β-benzyloxyaspartate. Brain Res. 2000;868:105–12.

    Article  CAS  PubMed  Google Scholar 

  58. Mitani A, Tanaka K. Functional changes of glial glutamate transporter GLT-1 during ischemia: an in vivo study in the hippocampal CA1 of normal mice and mutant mice lacking GLT-1. J Neurosci. 2003;23:7176–82.

    CAS  PubMed  Google Scholar 

  59. Szydlowska K, Tymianski M. Calcium, ischemia and excitotoxicity. Cell Calcium. 2010;47:122–9.

    Article  CAS  PubMed  Google Scholar 

  60. Duffy S, MacVicar BA. In vitro ischemia promotes calcium influx and intracellular calcium release in hippocampal astrocytes. J Neurosci. 1996;16:71–81.

    CAS  PubMed  Google Scholar 

  61. Dong Q, He J, Chai Z. Astrocytic Ca2+ waves mediate activation of extrasynaptic NMDA receptors in hippocampal neurons to aggravate brain damage during ischemia. Neurobiol Dis. 2013;58:68–75.

    Article  CAS  PubMed  Google Scholar 

  62. Dunwiddie TV, Masino SA. The role and regulation of adenosine in the central nervous system. Annu Rev Neurosci. 2001;24:31–55.

    Article  CAS  PubMed  Google Scholar 

  63. Winship IR, Murphy TH. In vivo calcium imaging reveals functional rewiring of single somatosensory neurons after stroke. J Neurosci. 2008;28:6592–606.

    Article  CAS  PubMed  Google Scholar 

  64. Takatsuru Y, Eto K, Kaneko R, Masuda H, Shimokawa N, Koibuchi N, et al. Critical role of the astrocyte for functional remodeling in contralateral hemisphere of somatosensory cortex after stroke. J Neurosci. 2013;33:4683–92.

    Article  CAS  PubMed  Google Scholar 

  65. Li H, Xie Y, Zhang N, Yu Y, Zhang Q, Ding S. Disruption of IP3R2-mediated Ca2+ signaling pathway in astrocytes ameliorates neuronal death and brain damage while reducing behavioral deficits after focal ischemic stroke. Cell Calcium. 2015;58(6):565–76.

    Article  CAS  PubMed  Google Scholar 

  66. Zheng W, Talley Watts L, Holstein DM, Wewer J, Lechleiter JD. P2Y1R-initiated, IP3R-dependent stimulation of astrocyte mitochondrial metabolism reduces and partially reverses ischemic neuronal damage in mouse. J Cereb Blood Flow Metab. 2013;33:600–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kanemaru K, Kubota J, Sekiya H, Hirose K, Okubo Y, Iino M. Calcium-dependent N-cadherin up-regulation mediates reactive astrogliosis and neuroprotection after brain injury. Proc Natl Acad Sci U S A. 2013;110:11612–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Li H, Zhang N, Lin H, Yu Y, Cai QM, et al. Histological, cellular and behavioral assessments of stroke outcomes after photothrombosis-induced ischemia in adult mice. BMC Neurosci. 2014;15:58.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Ding S. Dynamic reactive astrocytes after focal ischemia. Neural Regen Res. 2014;9:2048–52.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Zhang W, Xie Y, Wang T, Bi J, Li H, Zhang LQ, et al. Neuronal protective role of PBEF in a mouse model of cerebral ischemia. J Cereb Blood Flow Metab. 2010;30:1962–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Mestriner RG, Saur L, Bagatini PB, Baptista PPA, Vaz SP, Ferreira K, et al. Astrocyte morphology after ischemic and hemorrhagic experimental stroke has no influence on the different recovery patterns. Behav Brain Res. 2015;278:257–61.

    Article  PubMed  Google Scholar 

  72. Wagner DC, Scheibe J, Glocke I, Weise G, Deten A, Boltze J, Kranz A. Object-based analysis of astroglial reaction and astrocyte subtype morphology after ischemic brain injury. Acta Neurobiol Exp (Wars). 2013;73:79–87.

    Google Scholar 

  73. Haupt C, Witte OW, Frahm C. Up-regulation of Connexin 43 in the glial scar following photothrombotic ischemic injury. Mol Cell Neurosci. 2007;35:89–99.

    Article  CAS  PubMed  Google Scholar 

  74. Oberheim NA, Tian GF, Han X, Peng W, Takano T, Ransom B, et al. Loss of astrocytic domain organization in the epileptic brain. J Neurosci. 2008;28:3264–76.

    Article  CAS  PubMed  Google Scholar 

  75. Nowicka D. Spatiotemporal dynamics of astroglial and microglial responses after photothrombotic stroke in the rat brain. Acta Neurobiol Exp. 2008;68(2):155–68.

    Google Scholar 

  76. Shen J, Ishii Y, Xu G, Dang TC, Hamashima T, Matsushima T, et al. PDGFR-[beta] as a positive regulator of tissue repair in a mouse model of focal cerebral ischemia. J Cereb Blood Flow Metab. 2012;32:353–67.

    Article  CAS  PubMed  Google Scholar 

  77. Stoll G, Jander S, Schroeter M. Inflammation and glial responses in ischemic brain lesions. Prog Neurobiol. 1998;56:149–71.

    Article  CAS  PubMed  Google Scholar 

  78. Schroeter M, Jander S, Stoll G. Non-invasive induction of focal cerebral ischemia in mice by photothrombosis of cortical microvessels: characterization of inflammatory responses. J Neurosci Methods. 2002;117:43–9.

    Article  PubMed  Google Scholar 

  79. Cramer SC. Repairing the human brain after stroke: I. Mechanisms of spontaneous recovery. Ann Neurol. 2008;63:272–87.

    Article  PubMed  Google Scholar 

  80. Zamanian JL, Xu L, Foo LC, Nouri N, Zhou L, Giffard RG, et al. Genomic analysis of reactive astrogliosis. J Neurosci. 2012;32:6391–410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Wanner IB, Anderson MA, Song B, Levine J, Fernandez A, Gray-Thompson Z, et al. Glial scar borders are formed by newly proliferated, elongated astrocytes that interact to corral inflammatory and fibrotic cells via STAT3-dependent mechanisms after spinal cord injury. J Neurosci. 2013;33:12870–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Ridet JL, Privat A, Malhotra SK, Gage FH. Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci. 1997;20:570–7.

    Article  CAS  PubMed  Google Scholar 

  83. Colangelo AM, Alberghina L, Papa M. Astrogliosis as a therapeutic target for neurodegenerative diseases. Neurosci Lett. 2014;565:59–64.

    Article  CAS  PubMed  Google Scholar 

  84. Sofroniew M, Vinters H. Astrocytes: biology and pathology. Acta Neuropathol. 2010;119:7–35.

    Article  PubMed  Google Scholar 

  85. Kang W, Hebert J. Signaling pathways in reactive astrocytes, a genetic perspective. Mol Neurobiol. 2011;43(3):147–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Hanbury R, Ling ZD, Wuu J, Kordower JH. GFAP knockout mice have increased levels of GDNF that protect striatal neurons from metabolic and excitotoxic insults. J Comp Neurol. 2003;461:307–16.

    Article  CAS  PubMed  Google Scholar 

  87. Nawashiro H, Brenner M, Fukui S, Shima K, Hallenbeck JM. High susceptibility to cerebral ischemia in GFAP-null mice. J Cereb Blood Flow Metab. 2000;20:1040–4.

    Article  CAS  PubMed  Google Scholar 

  88. Li L, Lundkvist A, Andersson D, Wilhelmsson U, Nagai N, Pardo AC, et al. Protective role of reactive astrocytes in brain ischemia. J Cereb Blood Flow Metab. 2007;28:468–81.

    Article  CAS  PubMed  Google Scholar 

  89. Liu Z, Li Y, Cui Y, Roberts C, Lu M, Wilhelmsson U, et al. Beneficial effects of gfap/vimentin reactive astrocytes for axonal remodeling and motor behavioral recovery in mice after stroke. Glia. 2014;62:2022–33.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Kaminska B. MAPK signalling pathways as molecular targets for anti-inflammatory therapy-from molecular mechanisms to therapeutic benefits. Biochim Biophys Acta. 2005;1754:253–62.

    Article  CAS  PubMed  Google Scholar 

  91. Cuadrado A, Nebreda AR. Mechanisms and functions of p38 MAPK signalling. Biochem J. 2010;429:403–17.

    Article  CAS  PubMed  Google Scholar 

  92. Nozaki K, Nishimura M, Hashimoto N. Mitogen-activated protein kinases and cerebral ischemia. Mol Neurobiol. 2001;23:1–19.

    Article  CAS  PubMed  Google Scholar 

  93. Ferrer I, Friguls B, Dalfo E, Planas AM. Early modifications in the expression of mitogen-activated protein kinase (MAPK/ERK), stress-activated kinases SAPK/JNK and p38, and their phosphorylated substrates following focal cerebral ischemia. Acta Neuropathol. 2003;105:425–37.

    CAS  PubMed  Google Scholar 

  94. Krupinski J, Slevin M, Marti E, Catena E, Rubio F, Gaffney J. Time-course phosphorylation of the mitogen activated protein (MAP) kinase group of signalling proteins and related molecules following middle cerebral artery occlusion (MCAO) in rats. Neuropathol Appl Neurobiol. 2003;29:144–58.

    Article  CAS  PubMed  Google Scholar 

  95. Roy Choudhury G, Ryou MG, Poteet E, Wen Y, He R, Sun F, et al. Involvement of p38 MAPK in reactive astrogliosis induced by ischemic stroke. Brain Res. 2014;1551:45–58.

    Article  CAS  PubMed  Google Scholar 

  96. Yoon K, Gaiano N. Notch signaling in the mammalian central nervous system: insights from mouse mutants. Nat Neurosci. 2005;8:709–15.

    Article  CAS  PubMed  Google Scholar 

  97. Marumo T, Takagi Y, Muraki K, Hashimoto N, Miyamoto S, Tanigaki K. Notch signaling regulates nucleocytoplasmic Olig2 translocation in reactive astrocytes differentiation after ischemic stroke. Neurosci Res. 2013;75:204–9.

    Article  CAS  PubMed  Google Scholar 

  98. Shimada IS, Borders A, Aronshtam A, Spees JL. Proliferating reactive astrocytes are regulated by Notch-1 in the peri-infarct area after stroke. Stroke. 2011;42:3231–7.

    Article  PubMed  PubMed Central  Google Scholar 

  99. LeComte MD, Shimada IS, Sherwin C, Spees JL. Notch1-STAT3-ETBR signaling axis controls reactive astrocyte proliferation after brain injury. Proc Natl Acad Sci U S A. 2015;112:8726–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Komitova M, Serwanski DR, Lu QR, Nishiyama A. NG2 cells are not a major source of reactive astrocytes after neocortical stab wound injury. Glia. 2011;59:800–9.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Magnusson JP, Goritz C, Tatarishvili J, Dias DO, Smith EMK, Lindvall O, et al. A latent neurogenic program in astrocytes regulated by Notch signaling in the mouse. Science. 2014;346:237–41.

    Article  CAS  PubMed  Google Scholar 

  102. Nicolas CS, Amici M, Bortolotto ZA, Doherty A, Csaba Z, Fafouri A, et al. The role of JAK-STAT signaling within the CNS. JAKSTAT. 2013;2:e22925.

    PubMed  PubMed Central  Google Scholar 

  103. Herrmann JE, Imura T, Song B, Qi J, Ao Y, Nguyen TK, et al. STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. J Neurosci. 2008;28:7231–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Sofroniew MV. Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci. 2009;32:638–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Karimi-Abdolrezaee S, Billakanti R. Reactive astrogliosis after spinal cord injury-beneficial and detrimental effects. Mol Neurobiol. 2012;46:251–64.

    Article  CAS  PubMed  Google Scholar 

  106. Lei C, Deng J, Wang B, Cheng D, Yang Q, Dong H, et al. Reactive oxygen species scavenger inhibits STAT3 activation after transient focal cerebral ischemia-reperfusion injury in rats. Anesth Analg. 2011;113:153–9.

    Article  CAS  PubMed  Google Scholar 

  107. Zhu H, Zou L, Tian J, Du G, Gao Y. SMND-309, a novel derivative of salvianolic acid B, protects rat brains ischemia and reperfusion injury by targeting the JAK2/STAT3 pathway. Eur J Pharmacol. 2013;714:23–31.

    Article  CAS  PubMed  Google Scholar 

  108. Suzuki S, Tanaka K, Nogawa S, Dembo T, Kosakai A, Fukuuchi Y. Phosphorylation of signal transducer and activator of transcription-3 (Stat3) after focal cerebral ischemia in rats. Exp Neurol. 2001;170:63–71.

    Article  CAS  PubMed  Google Scholar 

  109. Wen TC, Peng H, Hata R, Desaki J, Sakanaka M. Induction of phosphorylated-Stat3 following focal cerebral ischemia in mice. Neurosci Lett. 2001;303:153–6.

    Article  CAS  PubMed  Google Scholar 

  110. Justicia C, Gabriel C, Planas AM. Activation of the JAK/STAT pathway following transient focal cerebral ischemia: signaling through Jak1 and Stat3 in astrocytes. Glia. 2000;30:253–70.

    Article  CAS  PubMed  Google Scholar 

  111. Choi JS, Kim SY, Cha JH, Choi YS, Sung KW, Oh ST, et al. Upregulation of gp130 and STAT3 activation in the rat hippocampus following transient forebrain ischemia. Glia. 2003;41:237–46.

    Article  PubMed  Google Scholar 

  112. Sriram K, Benkovic SA, Hebert MA, Miller DB, O’Callaghan JP. Induction of gp130-related cytokines and activation of JAK2/STAT3 pathway in astrocytes precedes up-regulation of glial fibrillary acidic protein in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of neurodegeneration: key signaling pathway for astrogliosis in vivo? J Biol Chem. 2004;279:19936–47.

    Article  CAS  PubMed  Google Scholar 

  113. O’Callaghan JP, Kelly KA, VanGilder RL, Sofroniew MV, Miller DB. Early activation of STAT3 regulates reactive astrogliosis induced by diverse forms of neurotoxicity. PLos One. 2014;9:e102003.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Krupinski J, Kumar P, Kumar S, Kaluza J. Increased expression of TGF-beta 1 in brain tissue after ischemic stroke in humans. Stroke. 1996;27:852–7.

    Article  CAS  PubMed  Google Scholar 

  115. Wang X, Yue TL, White RF, Barone FC, Feuerstein GZ. Transforming growth factor-beta 1 exhibits delayed gene expression following focal cerebral ischemia. Brain Res Bull. 1995;36:607–9.

    Article  CAS  PubMed  Google Scholar 

  116. Ruocco A, Nicole O, Docagne F, Ali C, Chazalviel L, Komesli S, et al. A transforming growth factor-beta antagonist unmasks the neuroprotective role of this endogenous cytokine in excitotoxic and ischemic brain injury. J Cereb Blood Flow Metab. 1999;19:1345–53.

    Article  CAS  PubMed  Google Scholar 

  117. Ali C, Docagne F, Nicole O, Lesne S, Toutain J, Young A, et al. Increased expression of transforming growth factor-beta after cerebral ischemia in the baboon: an endogenous marker of neuronal stress? J Cereb Blood Flow Metab. 2001;21:820–7.

    Article  CAS  PubMed  Google Scholar 

  118. Prehn JH, Backhauss C, Krieglstein J. Transforming growth factor-beta 1 prevents glutamate neurotoxicity in rat neocortical cultures and protects mouse neocortex from ischemic injury in vivo. J Cereb Blood Flow Metab. 1993;13:521–5.

    Article  CAS  PubMed  Google Scholar 

  119. Buisson A, Nicole O, Docagne F, Sartelet H, MacKenzie ET, Vivien D. Up-regulation of a serine protease inhibitor in astrocytes mediates the neuroprotective activity of transforming growth factor beta1. FASEB J. 1998;12:1683–91.

    CAS  PubMed  Google Scholar 

  120. Docagne F, Nicole O, Marti HH, MacKenzie ET, Buisson A, Vivien D. Transforming growth factor-beta1 as a regulator of the serpins/t-PA axis in cerebral ischemia. FASEB J. 1999;13:1315–24.

    CAS  PubMed  Google Scholar 

  121. Kang W, Balordi F, Su N, Chen L, Fishell G, Hebert JM. Astrocyte activation is suppressed in both normal and injured brain by FGF signaling. Proc Natl Acad Sci U S A. 2014;111:E2987–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Cekanaviciute E, Fathali N, Doyle KP, Williams AM, Han J, Buckwalter MS. Astrocytic transforming growth factor-beta signaling reduces subacute neuroinflammation after stroke in mice. Glia. 2014;62:1227–40.

    Article  PubMed  PubMed Central  Google Scholar 

  123. Anderson MA, Ao Y, Sofroniew MV. Heterogeneity of reactive astrocytes. Neurosci Lett. 2014;565:23–9.

    Article  CAS  PubMed  Google Scholar 

  124. Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O’Keeffe S, et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci. 2014;34:11929–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Doyle JP, Dougherty JD, Heiman M, Schmidt EF, Stevens TR, Ma G, et al. Application of a translational profiling approach for the comparative analysis of CNS cell types. Cell. 2008;135:749–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Tobin MK, Bonds JA, Minshall RD, Pelligrino DA, Testai FD, Lazarov O. Neurogenesis and inflammation after ischemic stroke: what is known and where we go from here. J Cereb Blood Flow Metab. 2014;34:1573–84.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Nakatomi H, Kuriu T, Okabe S, Yamamoto S, Hatano O, Kawahara N, et al. Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell. 2002;110:429–41.

    Article  CAS  PubMed  Google Scholar 

  128. Jin K, Minami M, Lan JQ, Mao XO, Batteur S, Simon RP, et al. Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat. Proc Natl Acad Sci U S A. 2001;98:4710–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med. 2002;8:963–70.

    Article  CAS  PubMed  Google Scholar 

  130. Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell. 1999;97:703–16.

    Article  CAS  PubMed  Google Scholar 

  131. Seri B, Garcia-Verdugo JM, McEwen BS, Alvarez-Buylla A. Astrocytes give rise to new neurons in the adult mammalian hippocampus. J Neurosci. 2001;21:7153–60.

    CAS  PubMed  Google Scholar 

  132. Buffo A, Rite I, Tripathi P, Lepier A, Colak D, Horn AP, et al. Origin and progeny of reactive gliosis: a source of multipotent cells in the injured brain. Proc Natl Acad Sci U S A. 2008;105:3581–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Sirko S, Behrendt G, Johansson P, Tripathi P, Costa MR, Bek S, et al. Reactive glia in the injured brain acquire stem cell properties in response to sonic hedgehog. Cell Stem Cell. 2013;12:426–39.

    Article  CAS  PubMed  Google Scholar 

  134. Robel S, Berninger B, Gotz M. The stem cell potential of glia: lessons from reactive gliosis. Nat Rev Neurosci. 2011;12:88–104.

    Article  CAS  PubMed  Google Scholar 

  135. Dimou LG, Götz M. Glial cells as progenitors and stem cells: new roles in the healthy and diseased brain. Physiol Rev. 2014;94:709–37.

    Article  CAS  PubMed  Google Scholar 

  136. Shimada IS, LeComte MD, Granger JC, Quinlan NJ, Spees JL. Self-renewal and differentiation of reactive astrocyte-derived neural stem/progenitor cells isolated from the cortical peri-infarct area after stroke. J Neurosci. 2012;32:7926–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Ohab JJ, Fleming S, Blesch A, Carmichael ST. A neurovascular niche for neurogenesis after stroke. J Neurosci. 2006;26:13007–16.

    Article  CAS  PubMed  Google Scholar 

  138. Buffo A, Vosko MR, Ertork D, Hamann GF, Jucker M, Rowitch D, et al. Expression pattern of the transcription factor Olig2 in response to brain injuries: implications for neuronal repair. Proc Natl Acad Sci U S A. 2005;102:18183–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Duan CL, Liu CW, Shen SW, Yu Z, Mo JL, Chen XH, et al. Striatal astrocytes transdifferentiate into functional mature neurons following ischemic brain injury. Glia. 2015;63:1660–70.

    Article  PubMed  Google Scholar 

  140. Young CC, van der Harg JM, Lewis NJ, Brooks KJ, Buchan AM, Szele FG. Ependymal ciliary dysfunction and reactive astrocytosis in a reorganized subventricular zone after stroke. Cereb Cortex. 2013;23:647–59.

    Article  PubMed  Google Scholar 

  141. Su Z, Niu W, Liu ML, Zou Y, Zhang CL. In vivo conversion of astrocytes to neurons in the injured adult spinal cord. Nat Commun. 2014;5:e3338.

    Google Scholar 

  142. Niu W, Zang T, Zou Y, Fang S, Smith DK, Bachoo R, et al. In vivo reprogramming of astrocytes to neuroblasts in the adult brain. Nat Cell Biol. 2013;15:1164–75.

    Article  CAS  PubMed  Google Scholar 

  143. Berninger B, Costa MR, Koch U, Schroeder T, Sutor B, Grothe B, et al. Functional properties of neurons derived from in vitro reprogrammed postnatal astroglia. J Neurosci. 2007;27:8654–64.

    Article  CAS  PubMed  Google Scholar 

  144. Heinrich C, Blum R, Gascón S, Masserdotti G, Tripathi P, Sánchez R, et al. Directing astroglia from the cerebral cortex into subtype specific functional neurons. PLoS Biol. 2010;8:e1000373.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Masserdotti G, Gillotin S, Sutor B, Drechsel D, Irmler M, Jorgensen H, et al. Transcriptional mechanisms of proneural factors and REST in regulating neuronal reprogramming of astrocytes. Cell Stem Cell. 2015;17:74–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Guo Z, Zhang L, Wu Z, Chen Y, Wang F, Chen G. In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer’s disease model. Cell Stem Cell. 2013;14:188–202.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Heinrich C, Gascon S, Masserdotti G, Lepier A, Sanchez R, Simon-Ebert T, et al. Generation of subtype-specific neurons from postnatal astroglia of the mouse cerebral cortex. Nat Protoc. 2011;6:214–28.

    Article  CAS  PubMed  Google Scholar 

  148. Addis RC, Hsu FC, Wright RL, Dichter MA, Coulter DA, Gearhart JD. Efficient conversion of astrocytes to functional midbrain dopaminergic neurons using a single polycistronic vector. PLoS One. 2011;6:e28719.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Corti S, Nizzardo M, Simone C, Falcone M, Donadoni C, Salani S, et al. Direct reprogramming of human astrocytes into neural stem cells and neurons. Exp Cell Res. 2012;318:1528–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Li X, Zuo X, Jing J, Ma Y, Wang J, Liu D, et al. Small-molecule-driven direct reprogramming of mouse fibroblasts into functional neurons. Cell Stem Cell. 2015;17:195–203.

    Article  CAS  PubMed  Google Scholar 

  151. Hu W, Qiu B, Guan W, Wang Q, Wang M, Li W, et al. Direct conversion of normal and alzheimer’s disease human fibroblasts into neuronal cells by small molecules. Cell Stem Cell. 2015;17:204–12.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the National Institutes of Health [R01NS069726, R01NS094539] and the American Heart Association [13GRNT17020004] to S.D.

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  1. Department of Bioengineering, Dalton Cardiovascular Research Center, University of Missouri, 134 Research Park Drive, Columbia, MO, 65211, USA

    Shinghua Ding Ph.D.

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  1. Shinghua Ding Ph.D.
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Correspondence to Shinghua Ding Ph.D. .

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  1. Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Jun Chen

  2. Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    John H. Zhang

  3. Department of Anesthesiology, Loma Linda University School of Medicine, Loma Linda, California, USA

    Xiaoming Hu

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Ding, S. (2016). Astrocytes as a Target for Ischemic Stroke. In: Chen, J., Zhang, J., Hu, X. (eds) Non-Neuronal Mechanisms of Brain Damage and Repair After Stroke. Springer Series in Translational Stroke Research. Springer, Cham. https://doi.org/10.1007/978-3-319-32337-4_6

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