Modulating Endogenous Adult Neural Stem Cells to Improve Regeneration in Stroke Brain

  • Fucheng Luo
  • Yu LuoEmail author
Part of the Springer Series in Translational Stroke Research book series (SSTSR)


Stroke is a major cause of death and disability globally. Experimental and clinical stroke studies have demonstrated that endogenous brain repair processes could be activated in the brain following stroke. However, the spontaneous brain repair process is constrained with limited improvement of neurological outcome. Neurogenesis, oligodendrogenesis, angiogenesis, axonal outgrowth, and synaptogenesis are major brain repair processes during stroke recovery. In adult rodents and human, there are endogenous neural stem cells that generate new neurons, astrocyte, oligodendrocyte, and NG2-glia under physiological or pathological conditions. Much progress has been made in preclinical studies on the roles of endogenous neural stem cells in brain repair processes in response to stroke. In this review, we will summarize recent progress on the cellular and molecular mechanisms underlying how endogenous adult neural stem cells contribute to neurogenesis and oligodendrogenesis, and their modulatory effects on angiogenesis and inflammation, which may play critical roles in brain repair and leads to improvement of neurological function after stroke.


Stroke Neural stem cells Neurogenesis Oligodendrogenesis Brain repair 



Third ventricle




Brain-derived neurotrophic factor


Bone morphogenetic protein


Cannabinoid type-2 receptor


C-C chemokine receptor type 2


Choline acetyl-transferase


Central nervous system


Ciliary neurotrophic factor


Chondroitin sulfate proteoglycans


CX3C chemokine receptor 1


C-X-C motif chemokine 12


C-X-C chemokine receptor type 4


cAMP-regulated neuronal phosphoprotein




Dentate gyrus


Extracellular matrix


Epidermal growth factor


Epidermal growth factor receptor


Fibroblast growth factor 10


Fibroblast growth factor 2


Gamma aminobutyric acid


Glutamic acid decarboxylase


Growth Associated Protein 43


Glycogen synthase kinase-3β


Histone deacetylases


Insulin-like growth factor 1


Middle cerebral artery occlusion


Monocyte chemoattractant protein 1


Matrix metalloproteases


Mechanistic target of rapamycin complex 1


Neurofibromatosis type 1


Neural progenitor cells


Neural stem cells


Olfactory bulb


Cyclin-dependent kinase inhibitor 1C


Platelet-derived growth factor


Platelet-derived growth factor receptor α


Patched 1




Rostral migratory stream




Rho-associated kinase


Stromal cell-derived factor 1


Subgranular zone


Sonic hedgehog


Short interfering ribonucleic acid




Subventricular zone


Transforming growth factor-alpha


Transient ischemic attack


Regulatory T cells


Ubiquitin-specific peptidase 9, X-linked


Vascular endothelial growth factor


  1. 1.
    Feigin VL, Norrving B, Mensah GA. Global burden of stroke. Circ Res. 2017;120(3):439–48.PubMedCrossRefGoogle Scholar
  2. 2.
    Zhang R, Zhang Z, Chopp M. Function of neural stem cells in ischemic brain repair processes. J Cereb Blood Flow Metab. 2016;36(12):2034–43.PubMedCrossRefGoogle Scholar
  3. 3.
    Koh SH, Park HH. Neurogenesis in stroke recovery. Transl Stroke Res. 2017;8(1):3–13.PubMedCrossRefGoogle Scholar
  4. 4.
    Ahmad M, Graham SH. Inflammation after stroke: mechanisms and therapeutic approaches. Transl Stroke Res. 2010;1(2):74–84.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Tobin MK, et al. Neurogenesis and inflammation after ischemic stroke: what is known and where we go from here. J Cereb Blood Flow Metab. 2014;34(10):1573–84.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Lee DA, et al. Tanycytes of the hypothalamic median eminence form a diet-responsive neurogenic niche. Nat Neurosci. 2012;15(5):700–2.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Tonchev AB, et al. Enhanced proliferation of progenitor cells in the subventricular zone and limited neuronal production in the striatum and neocortex of adult macaque monkeys after global cerebral ischemia. J Neurosci Res. 2005;81(6):776–88.PubMedCrossRefGoogle Scholar
  8. 8.
    Jin K, et al. Evidence for stroke-induced neurogenesis in the human brain. Proc Natl Acad Sci U S A. 2006;103(35):13198–202.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Macas J, et al. Increased generation of neuronal progenitors after ischemic injury in the aged adult human forebrain. J Neurosci. 2006;26(50):13114–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Minger SL, et al. Endogenous neurogenesis in the human brain following cerebral infarction. Regen Med. 2007;2(1):69–74.PubMedCrossRefGoogle Scholar
  11. 11.
    Arvidsson A, et al. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med. 2002;8(9):963–70.PubMedCrossRefGoogle Scholar
  12. 12.
    Jin K, et al. Directed migration of neuronal precursors into the ischemic cerebral cortex and striatum. Mol Cell Neurosci. 2003;24(1):171–89.PubMedCrossRefGoogle Scholar
  13. 13.
    Zhang RL, et al. Ascl1 lineage cells contribute to ischemia-induced neurogenesis and oligodendrogenesis. J Cereb Blood Flow Metab. 2011;31(2):614–25.PubMedCrossRefGoogle Scholar
  14. 14.
    Li L, et al. Focal cerebral ischemia induces a multilineage cytogenic response from adult subventricular zone that is predominantly gliogenic. Glia. 2010;58(13):1610–9.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Faiz M, et al. Adult neural stem cells from the subventricular zone give rise to reactive astrocytes in the cortex after stroke. Cell Stem Cell. 2015;17(5):624–34.PubMedCrossRefGoogle Scholar
  16. 16.
    Suh H, et al. In vivo fate analysis reveals the multipotent and self-renewal capacities of Sox2+ neural stem cells in the adult hippocampus. Cell Stem Cell. 2007;1(5):515–28.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Braun SM, et al. Programming hippocampal neural stem/progenitor cells into oligodendrocytes enhances remyelination in the adult brain after injury. Cell Rep. 2015;11(11):1679–85.PubMedCrossRefGoogle Scholar
  18. 18.
    Jadasz JJ, et al. p57kip2 regulates glial fate decision in adult neural stem cells. Development. 2012;139(18):3306–15.PubMedCrossRefGoogle Scholar
  19. 19.
    Oishi S, et al. USP9X deletion elevates the density of oligodendrocytes within the postnatal dentate gyrus. Neurogenesis (Austin). 2016;3(1):e1235524.CrossRefGoogle Scholar
  20. 20.
    Rolando C, et al. Multipotency of adult hippocampal nscs in vivo is restricted by drosha/NFIB. Cell Stem Cell. 2016;19(5):653–62.PubMedCrossRefGoogle Scholar
  21. 21.
    Sun GJ, et al. Latent tri-lineage potential of adult hippocampal neural stem cells revealed by Nf1 inactivation. Nat Neurosci. 2015;18(12):1722–4.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Marlier Q, et al. Mechanisms and functional significance of stroke-induced neurogenesis. Front Neurosci. 2015;9:458.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Ratan RR. Beyond neuroprotection to brain repair: exploring the next frontier in clinical neuroscience to expand the therapeutic window for stroke. Transl Stroke Res. 2010;1(2):71–3.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Gouaze A, et al. Cerebral cell renewal in adult mice controls the onset of obesity. PLoS One. 2013;8(8):e72029.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Lee DA, Blackshaw S. Functional implications of hypothalamic neurogenesis in the adult mammalian brain. Int J Dev Neurosci. 2012;30(8):615–21.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Kokoeva MV, Yin H, Flier JS. Neurogenesis in the hypothalamus of adult mice: potential role in energy balance. Science. 2005;310(5748):679–83.PubMedCrossRefGoogle Scholar
  27. 27.
    Recabal A, Caprile T, Garcia-Robles MLA. Hypothalamic neurogenesis as an adaptive metabolic mechanism. Front Neurosci. 2017;11:190.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Lin R, et al. Neurogenesis is enhanced by stroke in multiple new stem cell niches along the ventricular system at sites of high BBB permeability. Neurobiol Dis. 2015;74:229–39.PubMedCrossRefGoogle Scholar
  29. 29.
    Zhang R, et al. Stroke transiently increases subventricular zone cell division from asymmetric to symmetric and increases neuronal differentiation in the adult rat. J Neurosci. 2004;24(25):5810–5.PubMedCrossRefGoogle Scholar
  30. 30.
    Zhang RL, et al. Reduction of the cell cycle length by decreasing G1 phase and cell cycle reentry expand neuronal progenitor cells in the subventricular zone of adult rat after stroke. J Cereb Blood Flow Metab. 2006;26(6):857–63.PubMedCrossRefGoogle Scholar
  31. 31.
    Zhang RL, et al. Lengthening the G(1) phase of neural progenitor cells is concurrent with an increase of symmetric neuron generating division after stroke. J Cereb Blood Flow Metab. 2008;28(3):602–11.PubMedCrossRefGoogle Scholar
  32. 32.
    Balordi F, Fishell G. Mosaic removal of hedgehog signaling in the adult SVZ reveals that the residual wild-type stem cells have a limited capacity for self-renewal. J Neurosci. 2007;27(52):14248–59.PubMedCrossRefGoogle Scholar
  33. 33.
    Jin Y, et al. The shh signaling pathway is upregulated in multiple cell types in cortical ischemia and influences the outcome of stroke in an animal model. PLoS One. 2015;10(4):e0124657.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Sims JR, et al. Sonic hedgehog regulates ischemia/hypoxia-induced neural progenitor proliferation. Stroke. 2009;40(11):3618–26.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Wang L, et al. The Sonic hedgehog pathway mediates carbamylated erythropoietin-enhanced proliferation and differentiation of adult neural progenitor cells. J Biol Chem. 2007;282(44):32462–70.PubMedCrossRefGoogle Scholar
  36. 36.
    Jin Y, et al. Poststroke sonic hedgehog agonist treatment improves functional recovery by enhancing neurogenesis and angiogenesis. Stroke. 2017;48(6):1636–45.PubMedCrossRefGoogle Scholar
  37. 37.
    Tanaka R, et al. Neurogenesis after transient global ischemia in the adult hippocampus visualized by improved retroviral vector. Stroke. 2004;35(6):1454–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Naylor M, et al. Preconditioning-induced ischemic tolerance stimulates growth factor expression and neurogenesis in adult rat hippocampus. Neurochem Int. 2005;47(8):565–72.PubMedCrossRefGoogle Scholar
  39. 39.
    Ninomiya M, et al. Enhanced neurogenesis in the ischemic striatum following EGF-induced expansion of transit-amplifying cells in the subventricular zone. Neurosci Lett. 2006;403(1-2):63–7.PubMedCrossRefGoogle Scholar
  40. 40.
    Yoshimura S, et al. FGF-2 regulation of neurogenesis in adult hippocampus after brain injury. Proc Natl Acad Sci U S A. 2001;98(10):5874–9.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Craig CG, et al. In vivo growth factor expansion of endogenous subependymal neural precursor cell populations in the adult mouse brain. J Neurosci. 1996;16(8):2649–58.PubMedGoogle Scholar
  42. 42.
    Tureyen K, et al. EGF and FGF-2 infusion increases post-ischemic neural progenitor cell proliferation in the adult rat brain. Neurosurgery. 2005;57(6):1254–63. discussion 1254-63PubMedCrossRefGoogle Scholar
  43. 43.
    Nakatomi H, et al. Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell. 2002;110(4):429–41.PubMedCrossRefGoogle Scholar
  44. 44.
    Yan YP, et al. Insulin-like growth factor-1 is an endogenous mediator of focal ischemia-induced neural progenitor proliferation. Eur J Neurosci. 2006;24(1):45–54.PubMedCrossRefGoogle Scholar
  45. 45.
    Kalluri HS, Vemuganti R, Dempsey RJ. Mechanism of insulin-like growth factor I-mediated proliferation of adult neural progenitor cells: role of Akt. Eur J Neurosci. 2007;25(4):1041–8.PubMedCrossRefGoogle Scholar
  46. 46.
    Dempsey RJ, et al. Stroke-induced progenitor cell proliferation in adult spontaneously hypertensive rat brain: effect of exogenous IGF-1 and GDNF. J Neurochem. 2003;87(3):586–97.PubMedCrossRefGoogle Scholar
  47. 47.
    Zhu W, et al. Postischemic IGF-1 gene transfer promotes neurovascular regeneration after experimental stroke. J Cereb Blood Flow Metab. 2009;29(9):1528–37.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Wang X, et al. Involvement of Notch1 signaling in neurogenesis in the subventricular zone of normal and ischemic rat brain in vivo. J Cereb Blood Flow Metab. 2009;29(10):1644–54.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Androutsellis-Theotokis A, et al. Notch signalling regulates stem cell numbers in vitro and in vivo. Nature. 2006;442(7104):823–6.PubMedCrossRefGoogle Scholar
  50. 50.
    Wang L, et al. The Notch pathway mediates expansion of a progenitor pool and neuronal differentiation in adult neural progenitor cells after stroke. Neuroscience. 2009;158(4):1356–63.PubMedCrossRefGoogle Scholar
  51. 51.
    Magnusson JP, et al. A latent neurogenic program in astrocytes regulated by Notch signaling in the mouse. Science. 2014;346(6206):237–41.PubMedCrossRefGoogle Scholar
  52. 52.
    Wang Y, et al. VEGF-overexpressing transgenic mice show enhanced post-ischemic neurogenesis and neuromigration. J Neurosci Res. 2007;85(4):740–7.PubMedCrossRefGoogle Scholar
  53. 53.
    Kobayashi T, et al. Intracerebral infusion of glial cell line-derived neurotrophic factor promotes striatal neurogenesis after stroke in adult rats. Stroke. 2006;37(9):2361–7.PubMedCrossRefGoogle Scholar
  54. 54.
    Schabitz WR, et al. Intravenous brain-derived neurotrophic factor enhances poststroke sensorimotor recovery and stimulates neurogenesis. Stroke. 2007;38(7):2165–72.PubMedCrossRefGoogle Scholar
  55. 55.
    Plane JM, et al. Retinoic acid and environmental enrichment alter subventricular zone and striatal neurogenesis after stroke. Exp Neurol. 2008;214(1):125–34.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Chou J, et al. Neuroregenerative effects of BMP7 after stroke in rats. J Neurol Sci. 2006;240(1-2):21–9.PubMedCrossRefGoogle Scholar
  57. 57.
    Liu XS, et al. MicroRNAs in cerebral ischemia-induced neurogenesis. J Neuropathol Exp Neurol. 2013;72(8):718–22.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Volvert ML, et al. MicroRNAs tune cerebral cortical neurogenesis. Cell Death Differ. 2012;19(10):1573–81.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Choi JY, et al. M2 phenotype microglia-derived cytokine stimulates proliferation and neuronal differentiation of endogenous stem cells in ischemic brain. Exp Neurobiol. 2017;26(1):33–41.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Wang J, et al. Activated regulatory T cell regulates neural stem cell proliferation in the subventricular zone of normal and ischemic mouse brain through interleukin 10. Front Cell Neurosci. 2015;9:361.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Kraft A, et al. Astrocytic calcium waves signal brain injury to neural stem and progenitor cells. Stem Cell Rep. 2017;8(3):701–14.CrossRefGoogle Scholar
  62. 62.
    Matthys P, et al. AMD3100, a potent and specific antagonist of the stromal cell-derived factor-1 chemokine receptor CXCR4, inhibits autoimmune joint inflammation in IFN-gamma receptor-deficient mice. J Immunol. 2001;167(8):4686–92.PubMedCrossRefGoogle Scholar
  63. 63.
    Hattori K, Heissig B, Rafii S. The regulation of hematopoietic stem cell and progenitor mobilization by chemokine SDF-1. Leuk Lymphoma. 2003;44(4):575–82.PubMedCrossRefGoogle Scholar
  64. 64.
    Petit I, et al. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat Immunol. 2002;3(7):687–94.PubMedCrossRefGoogle Scholar
  65. 65.
    Kokovay E, et al. Adult SVZ lineage cells home to and leave the vascular niche via differential responses to SDF1/CXCR4 signaling. Cell Stem Cell. 2010;7(2):163–73.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Ohab JJ, et al. A neurovascular niche for neurogenesis after stroke. J Neurosci. 2006;26(50):13007–16.PubMedCrossRefGoogle Scholar
  67. 67.
    Robin AM, et al. Stromal cell-derived factor 1alpha mediates neural progenitor cell motility after focal cerebral ischemia. J Cereb Blood Flow Metab. 2006;26(1):125–34.PubMedCrossRefGoogle Scholar
  68. 68.
    Thored P, et al. Persistent production of neurons from adult brain stem cells during recovery after stroke. Stem Cells. 2006;24(3):739–47.PubMedCrossRefGoogle Scholar
  69. 69.
    Imitola J, et al. Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1alpha/CXC chemokine receptor 4 pathway. Proc Natl Acad Sci U S A. 2004;101(52):18117–22.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Deshmane SL, et al. Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interferon Cytokine Res. 2009;29(6):313–26.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Deng YY, et al. Monocyte chemoattractant protein-1 (MCP-1) produced via NF-kappaB signaling pathway mediates migration of amoeboid microglia in the periventricular white matter in hypoxic neonatal rats. Glia. 2009;57(6):604–21.PubMedCrossRefGoogle Scholar
  72. 72.
    Che X, et al. Monocyte chemoattractant protein-1 expressed in neurons and astrocytes during focal ischemia in mice. Brain Res. 2001;902(2):171–7.PubMedCrossRefGoogle Scholar
  73. 73.
    Yan YP, et al. Monocyte chemoattractant protein-1 plays a critical role in neuroblast migration after focal cerebral ischemia. J Cereb Blood Flow Metab. 2007;27(6):1213–24.PubMedCrossRefGoogle Scholar
  74. 74.
    Loffek S, Schilling O, Franzke CW. Series “matrix metalloproteinases in lung health and disease”: biological role of matrix metalloproteinases: a critical balance. Eur Respir J. 2011;38(1):191–208.PubMedCrossRefGoogle Scholar
  75. 75.
    Grade S, et al. Brain-derived neurotrophic factor promotes vasculature-associated migration of neuronal precursors toward the ischemic striatum. PLoS One. 2013;8(1):e55039.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Barkho BZ, et al. Endogenous matrix metalloproteinase (MMP)-3 and MMP-9 promote the differentiation and migration of adult neural progenitor cells in response to chemokines. Stem Cells. 2008;26(12):3139–49.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Lee SR, et al. Involvement of matrix metalloproteinase in neuroblast cell migration from the subventricular zone after stroke. J Neurosci. 2006;26(13):3491–5.PubMedCrossRefGoogle Scholar
  78. 78.
    Wang L, et al. Matrix metalloproteinase 2 (MMP2) and MMP9 secreted by erythropoietin-activated endothelial cells promote neural progenitor cell migration. J Neurosci. 2006;26(22):5996–6003.PubMedCrossRefGoogle Scholar
  79. 79.
    Katona I, Freund TF. Endocannabinoid signaling as a synaptic circuit breaker in neurological disease. Nat Med. 2008;14(9):923–30.PubMedCrossRefGoogle Scholar
  80. 80.
    Hosoya T, et al. In vivo TSPO and cannabinoid receptor type 2 availability early in post-stroke neuroinflammation in rats: a positron emission tomography study. J Neuroinflammation. 2017;14(1):69.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Palazuelos J, et al. CB2 cannabinoid receptors promote neural progenitor cell proliferation via mTORC1 signaling. J Biol Chem. 2012;287(2):1198–209.PubMedCrossRefGoogle Scholar
  82. 82.
    Bravo-Ferrer I, et al. Cannabinoid type-2 receptor drives neurogenesis and improves functional outcome after stroke. Stroke. 2017;48(1):204–12.PubMedCrossRefGoogle Scholar
  83. 83.
    Hallmann R, et al. Expression and function of laminins in the embryonic and mature vasculature. Physiol Rev. 2005;85(3):979–1000.PubMedCrossRefGoogle Scholar
  84. 84.
    Belvindrah R, et al. Beta1 integrins control the formation of cell chains in the adult rostral migratory stream. J Neurosci. 2007;27(10):2704–17.PubMedCrossRefGoogle Scholar
  85. 85.
    Emsley JG, Hagg T. alpha6beta1 integrin directs migration of neuronal precursors in adult mouse forebrain. Exp Neurol. 2003;183(2):273–85.PubMedCrossRefGoogle Scholar
  86. 86.
    Fujioka T, et al. beta1 integrin signaling promotes neuronal migration along vascular scaffolds in the post-stroke brain. EBioMedicine. 2017;16:195–203.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    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):6627–36.PubMedCrossRefGoogle Scholar
  88. 88.
    Le Magueresse C, et al. Subventricular zone-derived neuroblasts use vasculature as a scaffold to migrate radially to the cortex in neonatal mice. Cereb Cortex. 2012;22(10):2285–96.PubMedCrossRefGoogle Scholar
  89. 89.
    Kojima T, et al. Subventricular zone-derived neural progenitor cells migrate along a blood vessel scaffold toward the post-stroke striatum. Stem Cells. 2010;28(3):545–54.PubMedGoogle Scholar
  90. 90.
    Young CC, et al. Cellular and molecular determinants of stroke-induced changes in subventricular zone cell migration. Antioxid Redox Signal. 2011;14(10):1877–88.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Wei ZZ, et al. Neuroprotective and regenerative roles of intranasal Wnt-3a Administration after focal ischemic stroke in mice. J Cereb Blood Flow Metab. 2017: 271678X17702669.Google Scholar
  92. 92.
    Zhao Y, et al. GSK-3beta inhibition induced neuroprotection, regeneration, and functional recovery after intracerebral hemorrhagic stroke. Cell Transplant. 2017;26(3):395–407.PubMedCrossRefGoogle Scholar
  93. 93.
    Xu W, et al. Chloride co-transporter NKCC1 inhibitor bumetanide enhances neurogenesis and behavioral recovery in rats after experimental stroke. Mol Neurobiol. 2017;54(4):2406–14.PubMedCrossRefGoogle Scholar
  94. 94.
    Carmichael ST. Rodent models of focal stroke: size, mechanism, and purpose. NeuroRx. 2005;2(3):396–409.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Galindo LT, et al. Chondroitin sulfate impairs neural stem cell migration through ROCK activation. Mol Neurobiol. 2017;Google Scholar
  96. 96.
    Thored P, et al. Long-term neuroblast migration along blood vessels in an area with transient angiogenesis and increased vascularization after stroke. Stroke. 2007;38(11):3032–9.PubMedCrossRefGoogle Scholar
  97. 97.
    Hou SW, et al. Functional integration of newly generated neurons into striatum after cerebral ischemia in the adult rat brain. Stroke. 2008;39(10):2837–44.PubMedCrossRefGoogle Scholar
  98. 98.
    Parent JM, et al. Rat forebrain neurogenesis and striatal neuron replacement after focal stroke. Ann Neurol. 2002;52(6):802–13.PubMedCrossRefGoogle Scholar
  99. 99.
    Teramoto T, et al. EGF amplifies the replacement of parvalbumin-expressing striatal interneurons after ischemia. J Clin Invest. 2003;111(8):1125–32.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Stokowska A, et al. Complement peptide C3a stimulates neural plasticity after experimental brain ischaemia. Brain. 2017;140(Pt 2):353–69.PubMedCrossRefGoogle Scholar
  101. 101.
    Luo Y, et al. Delayed treatment with a p53 inhibitor enhances recovery in stroke brain. Ann Neurol. 2009;65(5):520–30.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Turnley AM, Basrai HS, Christie KJ. Is integration and survival of newborn neurons the bottleneck for effective neural repair by endogenous neural precursor cells? Front Neurosci. 2014;8:29.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Gu W, Brannstrom T, Wester P. Cortical neurogenesis in adult rats after reversible photothrombotic stroke. J Cereb Blood Flow Metab. 2000;20(8):1166–73.PubMedCrossRefGoogle Scholar
  104. 104.
    Jiang L, et al. Oligogenesis and oligodendrocyte progenitor maturation vary in different brain regions and partially correlate with local angiogenesis after ischemic stroke. Transl Stroke Res. 2011;2(3):366–75.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Eda H, et al. Ischemic damage and subsequent proliferation of oligodendrocytes in hippocampal CA1 region following repeated brief cerebral ischemia. Pathobiology. 2009;76(4):204–11.PubMedCrossRefGoogle Scholar
  106. 106.
    Mandai K, et al. Ischemic damage and subsequent proliferation of oligodendrocytes in focal cerebral ischemia. Neuroscience. 1997;77(3):849–61.PubMedCrossRefGoogle Scholar
  107. 107.
    Tanaka K, et al. Activation of NG2-positive oligodendrocyte progenitor cells during post-ischemic reperfusion in the rat brain. Neuroreport. 2001;12(10):2169–74.PubMedCrossRefGoogle Scholar
  108. 108.
    Bain JM, et al. Vascular endothelial growth factors A and C are induced in the SVZ following neonatal hypoxia-ischemia and exert different effects on neonatal glial progenitors. Transl Stroke Res. 2013;4(2):158–70.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Kim HJ, Chuang DM. HDAC inhibitors mitigate ischemia-induced oligodendrocyte damage: potential roles of oligodendrogenesis, VEGF, and anti-inflammation. Am J Transl Res. 2014;6(3):206–23.PubMedPubMedCentralGoogle Scholar
  110. 110.
    Zhang L, et al. Erythropoietin amplifies stroke-induced oligodendrogenesis in the rat. PLoS One. 2010;5(6):e11016.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Zhang RL, et al. Sildenafil enhances neurogenesis and oligodendrogenesis in ischemic brain of middle-aged mouse. PLoS One. 2012;7(10):e48141.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Ferent J, et al. Sonic Hedgehog signaling is a positive oligodendrocyte regulator during demyelination. J Neurosci. 2013;33(5):1759–72.PubMedCrossRefGoogle Scholar
  113. 113.
    Tong CK, et al. A dorsal SHH-dependent domain in the V-SVZ produces large numbers of oligodendroglial lineage cells in the postnatal brain. Stem Cell Rep. 2015;5(4):461–70.CrossRefGoogle Scholar
  114. 114.
    Zhang L, et al. Sonic hedgehog signaling pathway mediates cerebrolysin-improved neurological function after stroke. Stroke. 2013;44(7):1965–72.PubMedCrossRefGoogle Scholar
  115. 115.
    Ding X, et al. The sonic hedgehog pathway mediates brain plasticity and subsequent functional recovery after bone marrow stromal cell treatment of stroke in mice. J Cereb Blood Flow Metab. 2013;33(7):1015–24.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Li M, et al. Chemokine CXCL12 in neurodegenerative diseases: an SOS signal for stem cell-based repair. Trends Neurosci. 2012;35(10):619–28.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Li Y, et al. Postacute stromal cell-derived factor-1alpha expression promotes neurovascular recovery in ischemic mice. Stroke. 2014;45(6):1822–9.PubMedCrossRefGoogle Scholar
  118. 118.
    Dziembowska M, et al. A role for CXCR4 signaling in survival and migration of neural and oligodendrocyte precursors. Glia. 2005;50(3):258–69.PubMedCrossRefGoogle Scholar
  119. 119.
    Kadi L, et al. Differential effects of chemokines on oligodendrocyte precursor proliferation and myelin formation in vitro. J Neuroimmunol. 2006;174(1-2):133–46.PubMedCrossRefGoogle Scholar
  120. 120.
    Maysami S, et al. Modulation of rat oligodendrocyte precursor cells by the chemokine CXCL12. Neuroreport. 2006;17(11):1187–90.PubMedCrossRefGoogle Scholar
  121. 121.
    Li Y, et al. CXCL12 gene therapy ameliorates ischemia-induced white matter injury in mouse brain. Stem Cells Transl Med. 2015;4(10):1122–30.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Sun Y, et al. VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J Clin Invest. 2003;111(12):1843–51.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Le Bras B, et al. VEGF-C is a trophic factor for neural progenitors in the vertebrate embryonic brain. Nat Neurosci. 2006;9(3):340–8.PubMedCrossRefGoogle Scholar
  124. 124.
    Hayakawa K, et al. Vascular endothelial growth factor regulates the migration of oligodendrocyte precursor cells. J Neurosci. 2011;31(29):10666–70.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Cellerino A, et al. Reduced size of retinal ganglion cell axons and hypomyelination in mice lacking brain-derived neurotrophic factor. Mol Cell Neurosci. 1997;9(5-6):397–408.PubMedCrossRefGoogle Scholar
  126. 126.
    Xiao J, et al. Brain-derived neurotrophic factor promotes central nervous system myelination via a direct effect upon oligodendrocytes. Neurosignals. 2010;18(3):186–202.PubMedCrossRefGoogle Scholar
  127. 127.
    Tsiperson V, et al. Brain-derived neurotrophic factor deficiency restricts proliferation of oligodendrocyte progenitors following cuprizone-induced demyelination. ASN Neuro. 2015;7(1):1759091414566878.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Miyamoto N, et al. Astrocytes promote oligodendrogenesis after white matter damage via brain-derived neurotrophic factor. J Neurosci. 2015;35(41):14002–8.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Fulmer CG, et al. Astrocyte-derived BDNF supports myelin protein synthesis after cuprizone-induced demyelination. J Neurosci. 2014;34(24):8186–96.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Ramos-Cejudo J, et al. Brain-derived neurotrophic factor administration mediated oligodendrocyte differentiation and myelin formation in subcortical ischemic stroke. Stroke. 2015;46(1):221–8.PubMedCrossRefGoogle Scholar
  131. 131.
    Itoh K, et al. Mechanisms of cell-cell interaction in oligodendrogenesis and remyelination after stroke. Brain Res. 2015;1623:135–49.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Canoll PD, et al. GGF/neuregulin is a neuronal signal that promotes the proliferation and survival and inhibits the differentiation of oligodendrocyte progenitors. Neuron. 1996;17(2):229–43.PubMedCrossRefGoogle Scholar
  133. 133.
    Deierborg T, et al. Brain injury activates microglia that induce neural stem cell proliferation ex vivo and promote differentiation of neurosphere-derived cells into neurons and oligodendrocytes. Neuroscience. 2010;171(4):1386–96.PubMedCrossRefGoogle Scholar
  134. 134.
    Woodruff RH, et al. Platelet-derived growth factor regulates oligodendrocyte progenitor numbers in adult CNS and their response following CNS demyelination. Mol Cell Neurosci. 2004;25(2):252–62.PubMedCrossRefGoogle Scholar
  135. 135.
    Hsieh J, et al. IGF-I instructs multipotent adult neural progenitor cells to become oligodendrocytes. J Cell Biol. 2004;164(1):111–22.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Gonzalez-Perez O, et al. Epidermal growth factor induces the progeny of subventricular zone type B cells to migrate and differentiate into oligodendrocytes. Stem Cells. 2009;27(8):2032–43.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Chan SJ, et al. Endogenous regeneration: engineering growth factors for stroke. Neurochem Int. 2017;107:57.PubMedCrossRefGoogle Scholar
  138. 138.
    Chuang JC, Jones PA. Epigenetics and microRNAs. Pediatr Res. 2007;61(5 Pt 2):24R–9R.PubMedCrossRefGoogle Scholar
  139. 139.
    Liu J, et al. Epigenetic control of oligodendrocyte development: adding new players to old keepers. Curr Opin Neurobiol. 2016;39:133–8.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Purger D, Gibson EM, Monje M. Myelin plasticity in the central nervous system. Neuropharmacology. 2016;110(Pt B):563–73.PubMedCrossRefGoogle Scholar
  141. 141.
    Yu Y, et al. Olig2 targets chromatin remodelers to enhancers to initiate oligodendrocyte differentiation. Cell. 2013;152(1-2):248–61.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Liu J, Casaccia P. Epigenetic regulation of oligodendrocyte identity. Trends Neurosci. 2010;33(4):193–201.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Barca-Mayo O, Lu QR. Fine-tuning oligodendrocyte development by microRNAs. Front Neurosci. 2012;6:13.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Maki T, et al. Mechanisms of oligodendrocyte regeneration from ventricular-subventricular zone-derived progenitor cells in white matter diseases. Front Cell Neurosci. 2013;7:275.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Dugas JC, et al. Dicer1 and miR-219 are required for normal oligodendrocyte differentiation and myelination. Neuron. 2010;65(5):597–611.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Liu XS, et al. MicroRNA-146a promotes oligodendrogenesis in stroke. Mol Neurobiol. 2017;54(1):227–37.PubMedCrossRefGoogle Scholar
  147. 147.
    Liu XS, et al. MicroRNAs in cerebral ischemia-induced neurogenesis. J Neuropathol Exp Neurol. 2013;72(8):717–21.CrossRefGoogle Scholar
  148. 148.
    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):12478–88.PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Xin H, et al. MicroRNA cluster miR-17-92 cluster in exosomes enhance neuroplasticity and functional recovery after stroke in rats. Stroke. 2017;48(3):747–53.PubMedCrossRefGoogle Scholar
  150. 150.
    Buller B, et al. Regulation of serum response factor by miRNA-200 and miRNA-9 modulates oligodendrocyte progenitor cell differentiation. Glia. 2012;60(12):1906–14.PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Siegel C, et al. miR-23a regulation of X-linked inhibitor of apoptosis (XIAP) contributes to sex differences in the response to cerebral ischemia. Proc Natl Acad Sci U S A. 2011;108(28):11662–7.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Baltan S, et al. Histone deacetylase inhibitors preserve white matter structure and function during ischemia by conserving ATP and reducing excitotoxicity. J Neurosci. 2011;31(11):3990–9.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Faraco G, et al. Pharmacological inhibition of histone deacetylases by suberoylanilide hydroxamic acid specifically alters gene expression and reduces ischemic injury in the mouse brain. Mol Pharmacol. 2006;70(6):1876–84.PubMedCrossRefGoogle Scholar
  154. 154.
    Shen S, Casaccia-Bonnefil P. Post-translational modifications of nucleosomal histones in oligodendrocyte lineage cells in development and disease. J Mol Neurosci. 2008;35(1):13–22.PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Shen S, et al. Epigenetic memory loss in aging oligodendrocytes in the corpus callosum. Neurobiol Aging. 2008;29(3):452–63.PubMedCrossRefGoogle Scholar
  156. 156.
    Shen S, et al. Age-dependent epigenetic control of differentiation inhibitors is critical for remyelination efficiency. Nat Neurosci. 2008;11(9):1024–34.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Ye F, et al. HDAC1 and HDAC2 regulate oligodendrocyte differentiation by disrupting the beta-catenin-TCF interaction. Nat Neurosci. 2009;12(7):829–38.PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Kassis H, et al. Histone deacetylase expression in white matter oligodendrocytes after stroke. Neurochem Int. 2014;77:17–23.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Liu XS, et al. Valproic acid increases white matter repair and neurogenesis after stroke. Neuroscience. 2012;220:313–21.PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Kazanis I, et al. The late response of rat subependymal zone stem and progenitor cells to stroke is restricted to directly affected areas of their niche. Exp Neurol. 2013;248:387–97.PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Sun F, et al. Ablation of neurogenesis attenuates recovery of motor function after focal cerebral ischemia in middle-aged mice. PLoS One. 2012;7(10):e46326.PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Bonfanti L. Adult neurogenesis 50 years later: limits and opportunities in mammals. Front Neurosci. 2016;10:44.PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Liu F, et al. Brain injury does not alter the intrinsic differentiation potential of adult neuroblasts. J Neurosci. 2009;29(16):5075–87.PubMedCrossRefGoogle Scholar
  164. 164.
    Obernier K, Tong CK, Alvarez-Buylla A. Restricted nature of adult neural stem cells: re-evaluation of their potential for brain repair. Front Neurosci. 2014;8:162.PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Gregersen R, et al. Focal cerebral ischemia induces increased myelin basic protein and growth-associated protein-43 gene transcription in peri-infarct areas in the rat brain. Exp Brain Res. 2001;138(3):384–92.PubMedCrossRefGoogle Scholar
  166. 166.
    Ueno Y, et al. Axonal outgrowth and dendritic plasticity in the cortical peri-infarct area after experimental stroke. Stroke. 2012;43(8):2221–8.PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Zhang R, Chopp M, Zhang ZG. Oligodendrogenesis after cerebral ischemia. Front Cell Neurosci. 2013;7:201.PubMedPubMedCentralGoogle Scholar
  168. 168.
    Mirzadeh Z, et al. Neural stem cells confer unique pinwheel architecture to the ventricular surface in neurogenic regions of the adult brain. Cell Stem Cell. 2008;3(3):265–78.PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Hayashi T, et al. Temporal profile of angiogenesis and expression of related genes in the brain after ischemia. J Cereb Blood Flow Metab. 2003;23(2):166–80.PubMedCrossRefGoogle Scholar
  170. 170.
    Arenillas JF, et al. The role of angiogenesis in damage and recovery from ischemic stroke. Curr Treat Options Cardiovasc Med. 2007;9(3):205–12.PubMedCrossRefGoogle Scholar
  171. 171.
    Zhang Z, Chopp M. Neural stem cells and ischemic brain. J Stroke. 2016;18(3):267–72.PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    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):764–71.PubMedCrossRefGoogle Scholar
  173. 173.
    Maki T, et al. Potential interactions between pericytes and oligodendrocyte precursor cells in perivascular regions of cerebral white matter. Neurosci Lett. 2015;597:164–9.PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Shindo A, et al. Subcortical ischemic vascular disease: roles of oligodendrocyte function in experimental models of subcortical white-matter injury. J Cereb Blood Flow Metab. 2016;36(1):187–98.PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Sakry D, et al. Oligodendrocyte precursor cells synthesize neuromodulatory factors. PLoS One. 2015;10(5):e0127222.PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Wilkins A, et al. Oligodendrocytes promote neuronal survival and axonal length by distinct intracellular mechanisms: a novel role for oligodendrocyte-derived glial cell line-derived neurotrophic factor. J Neurosci. 2003;23(12):4967–74.PubMedGoogle Scholar
  177. 177.
    Seo JH, et al. Oligodendrocyte precursor cells support blood-brain barrier integrity via TGF-beta signaling. PLoS One. 2014;9(7):e103174.PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Yuen TJ, et al. Oligodendrocyte-encoded HIF function couples postnatal myelination and white matter angiogenesis. Cell. 2014;158(2):383–96.PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Butovsky O, et al. Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol Cell Neurosci. 2006;31(1):149–60.PubMedCrossRefGoogle Scholar
  180. 180.
    Liu Q, et al. Neural stem cells sustain natural killer cells that dictate recovery from brain inflammation. Nat Neurosci. 2016;19(2):243–52.PubMedPubMedCentralCrossRefGoogle Scholar
  181. 181.
    Ribeiro Xavier AL, et al. A distinct population of microglia supports adult neurogenesis in the subventricular zone. J Neurosci. 2015;35(34):11848–61.PubMedPubMedCentralCrossRefGoogle Scholar
  182. 182.
    Drago D, et al. Metabolic determinants of the immune modulatory function of neural stem cells. J Neuroinflammation. 2016;13(1):232.PubMedPubMedCentralCrossRefGoogle Scholar
  183. 183.
    Ben-Hur T. Immunomodulation by neural stem cells. J Neurol Sci. 2008;265(1-2):102–4.PubMedCrossRefGoogle Scholar
  184. 184.
    Pluchino S, et al. Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism. Nature. 2005;436(7048):266–71.PubMedCrossRefGoogle Scholar
  185. 185.
    Kokaia Z, et al. Cross-talk between neural stem cells and immune cells: the key to better brain repair? Nat Neurosci. 2012;15(8):1078–87.PubMedCrossRefGoogle Scholar
  186. 186.
    Cabral GA, Ferreira GA, Jamerson MJ. Endocannabinoids and the immune system in health and disease. Handb Exp Pharmacol. 2015;231:185–211.PubMedCrossRefGoogle Scholar
  187. 187.
    Acharya N, et al. Endocannabinoid system acts as a regulator of immune homeostasis in the gut. Proc Natl Acad Sci U S A. 2017;114(19):5005–10.PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Butti E, et al. Subventricular zone neural progenitors protect striatal neurons from glutamatergic excitotoxicity. Brain. 2012;135(Pt 11):3320–35.PubMedCrossRefGoogle Scholar
  189. 189.
    Gan Y, et al. Ischemic neurons recruit natural killer cells that accelerate brain infarction. Proc Natl Acad Sci U S A. 2014;111(7):2704–9.PubMedPubMedCentralCrossRefGoogle Scholar
  190. 190.
    Liu Q, et al. Brain ischemia suppresses immunity in the periphery and brain via different neurogenic innervations. Immunity. 2017;46(3):474–87.PubMedCrossRefGoogle Scholar
  191. 191.
    Zhang Y, et al. Accumulation of natural killer cells in ischemic brain tissues and the chemotactic effect of IP-10. J Neuroinflammation. 2014;11:79.PubMedPubMedCentralCrossRefGoogle Scholar
  192. 192.
    Zeis T, Enz L, Schaeren-Wiemers N. The immunomodulatory oligodendrocyte. Brain Res. 2016;1641(Pt A):139–48.PubMedCrossRefGoogle Scholar
  193. 193.
    Fitzner D, et al. Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis. J Cell Sci. 2011;124(Pt 3):447–58.PubMedCrossRefGoogle Scholar
  194. 194.
    Shin J, et al. Single-cell RNA-seq with waterfall reveals molecular cascades underlying adult neurogenesis. Cell Stem Cell. 2015;17(3):360–72.PubMedCrossRefGoogle Scholar
  195. 195.
    Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science. 1992;255(5052):1707–10.PubMedCrossRefGoogle Scholar
  196. 196.
    Anderson MA, et al. Astrocyte scar formation aids central nervous system axon regeneration. Nature. 2016;532(7598):195–200.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Neurological SurgeryCase Western Reserve UniversityClevelandUSA
  2. 2.Department of NeurosciencesCase Western Reserve UniversityClevelandUSA

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