Ischemic Stroke Pathophysiology and Cell Therapy

  • Changhong Ren
  • Rongrong Han
  • Jingfei Shi
  • Xunming JiEmail author


Current evidence shows great promise for stem cell transplantation as a new therapeutic strategy for stroke. However, stem cell transplantation for stroke is still in its infancy, with many issues that need to be addressed in order to achieve the full potential of stem cell therapy for stroke. Among the major hurdles for successful clinical translation is determining the therapeutic time window, stem cell type selection, delivery route, and underlying cellular and molecular mechanisms. In this chapter, we attempt to review the basic knowledge of pathophysiology and summarize the different stem cells for stroke treatment.


Stroke Ischemia Transplantation 


  1. 1.
    Abe K, Yamashita T, Takizawa S, Kuroda S, Kinouchi H, Kawahara N. Stem cell therapy for cerebral ischemia: from basic science to clinical applications. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab. 2012;32(7):1317–31. doi: 10.1038/jcbfm.2011.187.CrossRefGoogle Scholar
  2. 2.
    Abramova N, Charniga C, Goderie SK, Temple S. Stage-specific changes in gene expression in acutely isolated mouse CNS progenitor cells. Dev Biol. 2005;283(2):269–81.PubMedCrossRefGoogle Scholar
  3. 3.
    Alenzi F, Bahkali A. Stem cells: biology and clinical potential. Afr J Biotechnol. 2011;10(86):19929–40.Google Scholar
  4. 4.
    Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P, et al. Mechanism of activation of protein kinase B by insulin and IGF-1. Embo J. 1996;15(23):6541–51.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Alvarez-Buylla A, Garcia-Verdugo JM. Neurogenesis in adult subventricular zone. J Neurosci. 2002;22(3):629–34.PubMedGoogle Scholar
  6. 6.
    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(9):963–70.PubMedCrossRefGoogle Scholar
  7. 7.
    Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science (New York, NY). 1997;275(5302):964–7.CrossRefGoogle Scholar
  8. 8.
    Bain G, Kitchens D, Yao M, Huettner JE, Gottlieb DI. Embryonic stem cells express neuronal properties in vitro. Dev Biol. 1995;168(2):342–57. doi: 10.1006/dbio.1995.1085. S0012-1606(85)71085-8 [pii].PubMedCrossRefGoogle Scholar
  9. 9.
    Bang OY, Lee JS, Lee PH, Lee G. Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol. 2005;57(6):874–82. doi: 10.1002/ana.20501.PubMedCrossRefGoogle Scholar
  10. 10.
    Bernardi P, Petronilli V, Di Lisa F, Forte M. A mitochondrial perspective on cell death. Trends Biochem Sci. 2001;26(2):112–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Bjorklund A, Lindvall O. Cell replacement therapies for central nervous system disorders. Nat Neurosci. 2000;3(6):537–44.PubMedCrossRefGoogle Scholar
  12. 12.
    Borlongan CV, Tajima Y, Trojanowski JQ, Lee VM, Sanberg PR. Cerebral ischemia and CNS transplantation: differential effects of grafted fetal rat striatal cells and human neurons derived from a clonal cell line. Neuroreport. 1998;9(16):3703–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Borlongan CV, Tajima Y, Trojanowski JQ, Lee VM, Sanberg PR. Transplantation of cryopreserved human embryonal carcinoma-derived neurons (NT2N cells) promotes functional recovery in ischemic rats. Exp Neurol. 1998;149(2):310–21.PubMedCrossRefGoogle Scholar
  14. 14.
    Brederlau A, Correia AS, Anisimov SV, Elmi M, Paul G, Roybon L, et al. Transplantation of human embryonic stem cell-derived cells to a rat model of Parkinson’s disease: effect of in vitro differentiation on graft survival and teratoma formation. Stem Cells. 2006;24(6):1433–40. doi: 10.1634/stemcells.2005-0393. 2005-0393 [pii].PubMedCrossRefGoogle Scholar
  15. 15.
    Bruce AJ, Boling W, Kindy MS, Peschon J, Kraemer PJ, Carpenter MK, et al. Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors. Nat Med. 1996;2(7):788–94.PubMedCrossRefGoogle Scholar
  16. 16.
    Buhnemann C, Scholz A, Bernreuther C, Malik CY, Braun H, Schachner M, et al. Neuronal differentiation of transplanted embryonic stem cell-derived precursors in stroke lesions of adult rats. Brain. 2006;129(Pt 12):3238–48.PubMedCrossRefGoogle Scholar
  17. 17.
    Cai J, Yang M, Poremsky E, Kidd S, Schneider JS, Iacovitti L. Dopaminergic neurons derived from human induced pluripotent stem cells survive and integrate into 6-OHDA-lesioned rats. Stem Cells Dev. 2010;19(7):1017–23. doi: 10.1089/scd.2009.0319.PubMedCrossRefGoogle Scholar
  18. 18.
    Calegari F, Haubensak W, Haffner C, Huttner WB. Selective lengthening of the cell cycle in the neurogenic subpopulation of neural progenitor cells during mouse brain development. J Neurosci. 2005;25(28):6533–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Calzolari F, Michel J, Baumgart EV, Theis F, Gotz M, Ninkovic J. Fast clonal expansion and limited neural stem cell self-renewal in the adult subependymal zone. Nat Neurosci. 2015;18(4):490–2. doi: 10.1038/nn.3963. nn.3963 [pii].PubMedCrossRefGoogle Scholar
  20. 20.
    Camussi G, Deregibus MC, Cantaluppi V. Role of stem-cell-derived microvesicles in the paracrine action of stem cells. Biochem Soc Trans. 2013;41(1):283–7. doi: 10.1042/BST20120192. BST20120192 [pii].PubMedCrossRefGoogle Scholar
  21. 21.
    Chau MJ, Deveau TC, Song M, Gu X, Chen D, Wei L. iPSC transplantation increases regeneration and functional recovery after ischemic stroke in neonatal rats. Stem Cells (Dayton, Ohio). 2014;32(12):3075–87. doi: 10.1002/stem.1802.CrossRefGoogle Scholar
  22. 22.
    Chen J, Chopp M. Neurorestorative treatment of stroke: cell and pharmacological approaches. NeuroRx. 2006;3(4):466–73. doi: 10.1016/j.nurx.2006.07.007. S1545-5343(06)00129-5 [pii].PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Chen J, Li Y, Katakowski M, Chen X, Wang L, Lu D, et al. Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat. J Neurosci Res. 2003;73(6):778–86. doi: 10.1002/jnr.10691.PubMedCrossRefGoogle Scholar
  24. 24.
    Chen J, Li Y, Wang L, Lu M, Chopp M. Caspase inhibition by Z-VAD increases the survival of grafted bone marrow cells and improves functional outcome after MCAo in rats. J Neurol Sci. 2002;199(1–2):17–24. doi:S0022510X02000758 [pii].PubMedCrossRefGoogle Scholar
  25. 25.
    Chen J, Li Y, Wang L, Zhang Z, Lu D, Lu M, et al. Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke. 2001;32(4):1005–11.PubMedCrossRefGoogle Scholar
  26. 26.
    Chen J, Shehadah A, Pal A, Zacharek A, Cui X, Cui Y, et al. Neuroprotective effect of human placenta-derived cell treatment of stroke in rats. Cell Transplant. 2013;22(5):871–9. doi: 10.3727/096368911X637380. ct0613chen [pii].PubMedCrossRefGoogle Scholar
  27. 27.
    Chen J, Zhang C, Jiang H, Li Y, Zhang L, Robin A, et al. Atorvastatin induction of VEGF and BDNF promotes brain plasticity after stroke in mice. J Cereb Blood Flow Metab. 2005;25(2):281–90.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Chen J, Zhang ZG, Li Y, Wang Y, Wang L, Jiang H, et al. Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke. Ann Neurol. 2003;53(6):743–51.PubMedCrossRefGoogle Scholar
  29. 29.
    Chen JZ, Zhang FR, Tao QM, Wang XX, Zhu JH, Zhu JH. Number and activity of endothelial progenitor cells from peripheral blood in patients with hypercholesterolaemia. Clin Sci (London, England: 1979). 2004;107(3):273–80. doi: 10.1042/cs20030389.CrossRefGoogle Scholar
  30. 30.
    Chen SJ, Chang CM, Tsai SK, Chang YL, Chou SJ, Huang SS, et al. Functional improvement of focal cerebral ischemia injury by subdural transplantation of induced pluripotent stem cells with fibrin glue. Stem Cells Dev. 2010;19(11):1757–67. doi: 10.1089/scd.2009.0452.PubMedCrossRefGoogle Scholar
  31. 31.
    Chen TS, Lim SK. Measurement of precursor miRNA in exosomes from human ESC-derived mesenchymal stem cells. Methods Mol Biol. 2013;1024:69–86. doi: 10.1007/978-1-62703-453-1_6.PubMedCrossRefGoogle Scholar
  32. 32.
    Clarke DL, Johansson CB, Wilbertz J, Veress B, Nilsson E, Karlstrom H, et al. Generalized potential of adult neural stem cells. Science. 2000;288(5471):1660–3.PubMedCrossRefGoogle Scholar
  33. 33.
    Collino F, Deregibus MC, Bruno S, Sterpone L, Aghemo G, Viltono L, et al. Microvesicles derived from adult human bone marrow and tissue specific mesenchymal stem cells shuttle selected pattern of miRNAs. PLoS ONE. 2010;5(7), e11803. doi: 10.1371/journal.pone.0011803.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Curtis MA, Kam M, Nannmark U, Anderson MF, Axell MZ, Wikkelso C, et al. Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension. Science. 2007;315(5816):1243–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Czepiel M, Balasubramaniyan V, Schaafsma W, Stancic M, Mikkers H, Huisman C, et al. Differentiation of induced pluripotent stem cells into functional oligodendrocytes. Glia. 2011;59(6):882–92. doi: 10.1002/glia.21159.PubMedCrossRefGoogle Scholar
  36. 36.
    Daadi MM, Li Z, Arac A, Grueter BA, Sofilos M, Malenka RC, et al. Molecular and magnetic resonance imaging of human embryonic stem cell-derived neural stem cell grafts in ischemic rat brain. Mol Ther. 2009;17(7):1282–91.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Daadi MM, Maag AL, Steinberg GK. Adherent self-renewable human embryonic stem cell-derived neural stem cell line: functional engraftment in experimental stroke model. PLoS ONE. 2008;3(2), e1644.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Darsalia V, Kallur T, Kokaia Z. Survival, migration and neuronal differentiation of human fetal striatal and cortical neural stem cells grafted in stroke-damaged rat striatum. Eur J Neurosci. 2007;26(3):605–14.PubMedCrossRefGoogle Scholar
  39. 39.
    DeGraba TJ. The role of inflammation after acute stroke: utility of pursuing anti-adhesion molecule therapy. Neurology. 1998;51(3 Suppl 3):S62–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Del Zoppo GJ, Saver JL, Jauch EC, Adams Jr HP. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator: a science advisory from the American Heart Association/American Stroke Association. Stroke J Cereb Circ. 2009;40(8):2945–8. doi: 10.1161/strokeaha.109.192535.CrossRefGoogle Scholar
  41. 41.
    Ding DC, Shyu WC, Chiang MF, Lin SZ, Chang YC, Wang HJ, et al. Enhancement of neuroplasticity through upregulation of beta1-integrin in human umbilical cord-derived stromal cell implanted stroke model. Neurobiol Dis. 2007;27(3):339–53. doi: 10.1016/j.nbd.2007.06.010. S0969-9961(07)00114-3 [pii].PubMedCrossRefGoogle Scholar
  42. 42.
    Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 1999;22(9):391–7.PubMedCrossRefGoogle Scholar
  43. 43.
    Doetsch F, Garcia-Verdugo JM, Alvarez-Buylla A. Cellular composition and three-dimensional organization of the subventricular germinal zone in the adult mammalian brain. J Neurosci. 1997;17(13):5046–61.PubMedGoogle Scholar
  44. 44.
    Dome B, Timar J, Ladanyi A, Paku S, Renyi-Vamos F, Klepetko W, et al. Circulating endothelial cells, bone marrow-derived endothelial progenitor cells and proangiogenic hematopoietic cells in cancer: from biology to therapy. Crit Rev Oncol Hematol. 2009;69(2):108–24. doi: 10.1016/j.critrevonc.2008.06.009.PubMedCrossRefGoogle Scholar
  45. 45.
    Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–7. doi: 10.1080/14653240600855905. Q2183N8UT042W62H [pii].PubMedCrossRefGoogle Scholar
  46. 46.
    Doyle KP, Simon RP, Stenzel-Poore MP. Mechanisms of ischemic brain damage. Neuropharmacology. 2008;55(3):310–8. doi: 10.1016/j.neuropharm.2008.01.005.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Endres M, Wang ZQ, Namura S, Waeber C, Moskowitz MA. Ischemic brain injury is mediated by the activation of poly(ADP-ribose)polymerase. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab. 1997;17(11):1143–51. doi: 10.1097/00004647-199711000-00002.CrossRefGoogle Scholar
  48. 48.
    Erdo F, Buhrle C, Blunk J, Hoehn M, Xia Y, Fleischmann B, et al. Host-dependent tumorigenesis of embryonic stem cell transplantation in experimental stroke. J Cereb Blood Flow Metab. 2003;23(7):780–5. doi: 10.1097/01.WCB.0000071886.63724.FB.PubMedGoogle Scholar
  49. 49.
    Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981;292(5819):154–6.PubMedCrossRefGoogle Scholar
  50. 50.
    Fan Y, Shen F, Frenzel T, Zhu W, Ye J, Liu J, et al. Endothelial progenitor cell transplantation improves long-term stroke outcome in mice. Ann Neurol. 2010;67(4):488–97. doi: 10.1002/ana.21919.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Feigin VL, Lawes CM, Bennett DA, Barker-Collo SL, Parag V. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol. 2009;8(4):355–69. doi: 10.1016/s1474-4422(09)70025-0.PubMedCrossRefGoogle Scholar
  52. 52.
    Felderhoff-Mueser U, Taylor DL, Greenwood K, Kozma M, Stibenz D, Joashi UC, et al. Fas/CD95/APO-1 can function as a death receptor for neuronal cells in vitro and in vivo and is upregulated following cerebral hypoxic-ischemic injury to the developing rat brain. Brain Pathol (Zurich, Switzerland). 2000;10(1):17–29.CrossRefGoogle Scholar
  53. 53.
    Ferri KF, Jacotot E, Blanco J, Este JA, Zamzami N, Susin SA, et al. Apoptosis control in syncytia induced by the HIV type 1-envelope glycoprotein complex: role of mitochondria and caspases. J Exp Med. 2000;192(8):1081–92.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Fiskum G, Murphy AN, Beal MF. Mitochondria in neurodegeneration: acute ischemia and chronic neurodegenerative diseases. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab. 1999;19(4):351–69. doi: 10.1097/00004647-199904000-00001.CrossRefGoogle Scholar
  55. 55.
    Fong CY, Gauthaman K, Bongso A. Teratomas from pluripotent stem cells: a clinical hurdle. J Cell Biochem. 2010;111(4):769–81. doi: 10.1002/jcb.22775.PubMedCrossRefGoogle Scholar
  56. 56.
    Fournier BP, Larjava H, Hakkinen L. Gingiva as a source of stem cells with therapeutic potential. Stem Cells Dev. 2013;22(24):3157–77. doi: 10.1089/scd.2013.0015.PubMedCrossRefGoogle Scholar
  57. 57.
    Fox LE, Shen J, Ma K, Liu Q, Shi G, Pappas GD, et al. Membrane properties of neuron-like cells generated from adult human bone-marrow-derived mesenchymal stem cells. Stem Cells Dev. 2010;19(12):1831–41. doi: 10.1089/scd.2010.0089.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Friedenstein AJ, Piatetzky II S, Petrakova KV. Osteogenesis in transplants of bone marrow cells. J Embryol Exp Morphol. 1966;16(3):381–90.PubMedGoogle Scholar
  59. 59.
    Fujimoto M, Hayashi H, Takagi Y, Hayase M, Marumo T, Gomi M, et al. Transplantation of telencephalic neural progenitors induced from embryonic stem cells into subacute phase of focal cerebral ischemia. Lab Invest. 2012;92(4):522–31. doi: 10.1038/labinvest.2012.1. labinvest20121 [pii].PubMedCrossRefGoogle Scholar
  60. 60.
    Fujita Y, Yoshioka Y, Ito S, Araya J, Kuwano K, Ochiya T. Intercellular communication by extracellular vesicles and their microRNAs in asthma. Clin Ther. 2014;36(6):873–81. doi: 10.1016/j.clinthera.2014.05.006. S0149-2918(14)00263-X [pii].PubMedCrossRefGoogle Scholar
  61. 61.
    Fukuchi Y, Nakajima H, Sugiyama D, Hirose I, Kitamura T, Tsuji K. Human placenta-derived cells have mesenchymal stem/progenitor cell potential. Stem Cells. 2004;22(5):649–58. doi: 10.1634/stemcells.22-5-649. 22/5/649 [pii].PubMedCrossRefGoogle Scholar
  62. 62.
    Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med. 2008;359(9):938–49. doi: 10.1056/NEJMra0801082.PubMedCrossRefGoogle Scholar
  63. 63.
    Gimble JM, Bunnell BA, Guilak F. Human adipose-derived cells: an update on the transition to clinical translation. Regen Med. 2012;7(2):225–35. doi: 10.2217/rme.11.119.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Glover LE, Tajiri N, Weinbren NL, Ishikawa H, Shinozuka K, Kaneko Y, et al. A step-up approach for cell therapy in stroke: translational hurdles of bone marrow-derived stem cells. Transl Stroke Res. 2012;3(1):90–8. doi: 10.1007/s12975-011-0127-8. 127 [pii].PubMedCrossRefGoogle Scholar
  65. 65.
    Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, et al. Heart disease and stroke statistics – 2013 update: a report from the American Heart Association. Circulation. 2013;127(1):e6–245. doi: 10.1161/CIR.0b013e31828124ad.PubMedCrossRefGoogle Scholar
  66. 66.
    Graham SH, Chen J. Programmed cell death in cerebral ischemia. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab. 2001;21(2):99–109. doi: 10.1097/00004647-200102000-00001.CrossRefGoogle Scholar
  67. 67.
    Gribkoff VK, Starrett Jr JE, Dworetzky SI, Hewawasam P, Boissard CG, Cook DA, et al. Targeting acute ischemic stroke with a calcium-sensitive opener of maxi-K potassium channels. Nat Med. 2001;7(4):471–7. doi: 10.1038/86546.PubMedCrossRefGoogle Scholar
  68. 68.
    Gucciardo L, Lories R, Ochsenbein-Kolble N, Done E, Zwijsen A, Deprest J. Fetal mesenchymal stem cells: isolation, properties and potential use in perinatology and regenerative medicine. BJOG. 2009;116(2):166–72. doi: 10.1111/j.1471-0528.2008.02005.x. BJO2005 [pii].PubMedCrossRefGoogle Scholar
  69. 69.
    Gutierrez-Aranda I, Ramos-Mejia V, Bueno C, Munoz-Lopez M, Real PJ, Macia A, et al. Human induced pluripotent stem cells develop teratoma more efficiently and faster than human embryonic stem cells regardless the site of injection. Stem Cells (Dayton, Ohio). 2010;28(9):1568–70. doi: 10.1002/stem.471.CrossRefGoogle Scholar
  70. 70.
    Gutierrez-Fernandez M, Fuentes B, Rodriguez-Frutos B, Ramos-Cejudo J, Vallejo-Cremades MT, Diez-Tejedor E. Trophic factors and cell therapy to stimulate brain repair after ischaemic stroke. J Cell Mol Med. 2012;16(10):2280–90. doi: 10.1111/j.1582-4934.2012.01575.x.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Gutierrez-Fernandez M, Rodriguez-Frutos B, Otero-Ortega L, Ramos-Cejudo J, Fuentes B, Diez-Tejedor E. Adipose tissue-derived stem cells in stroke treatment: from bench to bedside. Discov Med. 2013;16(86):37–43.PubMedGoogle Scholar
  72. 72.
    Gutierrez-Fernandez M, Rodriguez-Frutos B, Ramos-Cejudo J, Teresa Vallejo-Cremades M, Fuentes B, Cerdan S, et al. Effects of intravenous administration of allogenic bone marrow- and adipose tissue-derived mesenchymal stem cells on functional recovery and brain repair markers in experimental ischemic stroke. Stem Cell Res Ther. 2013;4(1):11. doi: 10.1186/scrt159. scrt159 [pii].PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Hao L, Zou Z, Tian H, Zhang Y, Zhou H, Liu L. Stem cell-based therapies for ischemic stroke. Biomed Res Int. 2014;2014:468748. doi: 10.1155/2014/468748.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Harms KM, Li L, Cunningham LA. Murine neural stem/progenitor cells protect neurons against ischemia by HIF-1alpha-regulated VEGF signaling. PLoS ONE. 2010;5(3), e9767. doi: 10.1371/journal.pone.0009767.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Hayashi J, Takagi Y, Fukuda H, Imazato T, Nishimura M, Fujimoto M, et al. Primate embryonic stem cell-derived neuronal progenitors transplanted into ischemic brain. J Cereb Blood Flow Metab. 2006;26(7):906–14. doi: 10.1038/sj.jcbfm.9600247. 9600247 [pii].PubMedCrossRefGoogle Scholar
  76. 76.
    Hedlund M, Stenqvist AC, Nagaeva O, Kjellberg L, Wulff M, Baranov V, et al. Human placenta expresses and secretes NKG2D ligands via exosomes that down-modulate the cognate receptor expression: evidence for immunosuppressive function. J Immunol. 2009;183(1):340–51. doi: 10.4049/jimmunol.0803477. 183/1/340 [pii].PubMedCrossRefGoogle Scholar
  77. 77.
    Hicks AU, Lappalainen RS, Narkilahti S, Suuronen R, Corbett D, Sivenius J, et al. Transplantation of human embryonic stem cell-derived neural precursor cells and enriched environment after cortical stroke in rats: cell survival and functional recovery. Eur J Neurosci. 2009;29(3):562–74. doi: 10.1111/j.1460-9568.2008.06599.x. EJN6599 [pii].PubMedCrossRefGoogle Scholar
  78. 78.
    Hodges H, Sowinski P, Fleming P, Kershaw TR, Sinden JD, Meldrum BS, et al. Contrasting effects of fetal CA1 and CA3 hippocampal grafts on deficits in spatial learning and working memory induced by global cerebral ischaemia in rats. Neuroscience. 1996;72(4):959–88.PubMedCrossRefGoogle Scholar
  79. 79.
    Hoehn M, Kustermann E, Blunk J, Wiedermann D, Trapp T, Wecker S, et al. Monitoring of implanted stem cell migration in vivo: a highly resolved in vivo magnetic resonance imaging investigation of experimental stroke in rat. Proc Natl Acad Sci U S A. 2002;99(25):16267–72. doi: 10.1073/pnas.242435499. 242435499 [pii].PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Holvoet P, Collen D. Thrombosis and atherosclerosis. Curr Opin Lipidol. 1997;8(5):320–8.PubMedCrossRefGoogle Scholar
  81. 81.
    Honmou O, Onodera R, Sasaki M, Waxman SG, Kocsis JD. Mesenchymal stem cells: therapeutic outlook for stroke. Trends Mol Med. 2012;18(5):292–7. doi: 10.1016/j.molmed.2012.02.003. S1471-4914(12)00034-2 [pii].PubMedCrossRefGoogle Scholar
  82. 82.
    Hou SW, Wang YQ, Xu M, Shen DH, Wang JJ, Huang F, 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
  83. 83.
    Huang W, Mo X, Qin C, Zheng J, Liang Z, Zhang C. Transplantation of differentiated bone marrow stromal cells promotes motor functional recovery in rats with stroke. Neurol Res. 2013;35(3):320–8. doi: 10.1179/1743132812Y.0000000151.PubMedCrossRefGoogle Scholar
  84. 84.
    Huang Z, Huang PL, Panahian N, Dalkara T, Fishman MC, Moskowitz MA. Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science (New York, NY). 1994;265(5180):1883–5.CrossRefGoogle Scholar
  85. 85.
    Huttner WB, Kosodo Y. Symmetric versus asymmetric cell division during neurogenesis in the developing vertebrate central nervous system. Curr Opin Cell Biol. 2005;17(6):648–57.PubMedCrossRefGoogle Scholar
  86. 86.
    Iadecola C, Zhang F, Casey R, Nagayama M, Ross ME. Delayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene. J Neurosci Off J Soc Neurosci. 1997;17(23):9157–64.Google Scholar
  87. 87.
    Igura K, Zhang X, Takahashi K, Mitsuru A, Yamaguchi S, Takashi TA. Isolation and characterization of mesenchymal progenitor cells from chorionic villi of human placenta. Cytotherapy. 2004;6(6):543–53.PubMedCrossRefGoogle Scholar
  88. 88.
    Ikegame Y, Yamashita K, Hayashi S, Mizuno H, Tawada M, You F, et al. Comparison of mesenchymal stem cells from adipose tissue and bone marrow for ischemic stroke therapy. Cytotherapy. 2011;13(6):675–85. doi: 10.3109/14653249.2010.549122.PubMedCrossRefGoogle Scholar
  89. 89.
    Ikegame Y, Yamashita K, Nakashima S, Nomura Y, Yonezawa S, Asano Y, et al. Fate of graft cells: what should be clarified for development of mesenchymal stem cell therapy for ischemic stroke? Front Cell Neurosci. 2014;8:322. doi: 10.3389/fncel.2014.00322.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Isik S, Zaim M, Yildiz MT, Negis Y, Kunduraci T, Karakas N, et al. DNA topoisomerase IIbeta as a molecular switch in neural differentiation of mesenchymal stem cells. Ann Hematol. 2015;94(2):307–18. doi: 10.1007/s00277-014-2209-7.PubMedCrossRefGoogle Scholar
  91. 91.
    Janardhan V, Qureshi AI. Mechanisms of ischemic brain injury. Curr Cardiol Rep. 2004;6(2):117–23.PubMedCrossRefGoogle Scholar
  92. 92.
    Jensen MB, Yan H, Krishnaney-Davison R, Al Sawaf A, Zhang SC. Survival and differentiation of transplanted neural stem cells derived from human induced pluripotent stem cells in a rat stroke model. J Stroke Cerebrovasc Dis Off J Natl Stroke Assoc. 2013;22(4):304–8. doi: 10.1016/j.jstrokecerebrovasdis.2011.09.008.CrossRefGoogle Scholar
  93. 93.
    Jiang M, Lv L, Ji H, Yang X, Zhu W, Cai L, et al. Induction of pluripotent stem cells transplantation therapy for ischemic stroke. Mol Cell Biochem. 2011;354(1–2):67–75. doi: 10.1007/s11010-011-0806-5.PubMedCrossRefGoogle Scholar
  94. 94.
    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(8):4710–5.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Jin K, Wang X, Xie L, Mao XO, Zhu W, Wang Y, 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
  96. 96.
    Johnstone SA, Liley M, Dalby MJ, Barnett SC. Comparison of human olfactory and skeletal MSCs using osteogenic nanotopography to demonstrate bone-specific bioactivity of the surfaces. Acta Biomater. 2015;13:266–76. doi: 10.1016/j.actbio.2014.11.027. S1742-7061(14)00521-2 [pii].PubMedCrossRefGoogle Scholar
  97. 97.
    Jung KH, Chu K, Lee ST, Park HK, Kim DH, Kim JH, et al. Circulating endothelial progenitor cells as a pathogenetic marker of moyamoya disease. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab. 2008;28(11):1795–803. doi: 10.1038/jcbfm.2008.67.CrossRefGoogle Scholar
  98. 98.
    Jung KH, Roh JK. Circulating endothelial progenitor cells in cerebrovascular disease. J Clin Neurol (Seoul, Korea). 2008;4(4):139–47. doi: 10.3988/jcn.2008.4.4.139.CrossRefGoogle Scholar
  99. 99.
    Kageyama R, Ohtsuka T, Hatakeyama J, Ohsawa R. Roles of bHLH genes in neural stem cell differentiation. Exp Cell Res. 2005;306(2):343–8.PubMedCrossRefGoogle Scholar
  100. 100.
    Kallur T, Darsalia V, Lindvall O, Kokaia Z. Human fetal cortical and striatal neural stem cells generate region-specific neurons in vitro and differentiate extensively to neurons after intrastriatal transplantation in neonatal rats. J Neurosci Res. 2006;84(8):1630–44.PubMedCrossRefGoogle Scholar
  101. 101.
    Kaneko Y, Tajiri N, Shinozuka K, Glover LE, Weinbren NL, Cortes L, et al. Cell therapy for stroke: emphasis on optimizing safety and efficacy profile of endothelial progenitor cells. Curr Pharm Des. 2012;18(25):3731–4.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Katakowski M, Zhang ZG, Chen J, Zhang R, Wang Y, Jiang H, et al. Phosphoinositide 3-kinase promotes adult subventricular neuroblast migration after stroke. J Neurosci Res. 2003;74(4):494–501.PubMedCrossRefGoogle Scholar
  103. 103.
    Kawai H, Yamashita T, Ohta Y, Deguchi K, Nagotani S, Zhang X, et al. Tridermal tumorigenesis of induced pluripotent stem cells transplanted in ischemic brain. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab. 2010;30(8):1487–93. doi: 10.1038/jcbfm.2010.32.CrossRefGoogle Scholar
  104. 104.
    Kelly S, Bliss TM, Shah AK, Sun GH, Ma M, Foo WC, et al. Transplanted human fetal neural stem cells survive, migrate, and differentiate in ischemic rat cerebral cortex. Proc Natl Acad Sci U S A. 2004;101(32):11839–44.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Kim DY, Park SH, Lee SU, Choi DH, Park HW, Paek SH, et al. Effect of human embryonic stem cell-derived neuronal precursor cell transplantation into the cerebral infarct model of rat with exercise. Neurosci Res. 2007;58(2):164–75. doi: 10.1016/j.neures.2007.02.016. S0168-0102(07)00087-9 [pii].PubMedCrossRefGoogle Scholar
  106. 106.
    Knoepfler PS. Deconstructing stem cell tumorigenicity: a roadmap to safe regenerative medicine. Stem Cells (Dayton, Ohio). 2009;27(5):1050–6. doi: 10.1002/stem.37.CrossRefGoogle Scholar
  107. 107.
    Kranz A, Wagner DC, Kamprad M, Scholz M, Schmidt UR, Nitzsche F, et al. Transplantation of placenta-derived mesenchymal stromal cells upon experimental stroke in rats. Brain Res. 2010;1315:128–36. doi: 10.1016/j.brainres.2009.12.001. S0006-8993(09)02602-X [pii].PubMedCrossRefGoogle Scholar
  108. 108.
    Kroemer G, Petit P, Zamzami N, Vayssiere JL, Mignotte B. The biochemistry of programmed cell death. FASEB J Off Publ Fed Am Soc Exp Biol. 1995;9(13):1277–87.Google Scholar
  109. 109.
    Kroemer G, Reed JC. Mitochondrial control of cell death. Nat Med. 2000;6(5):513–9. doi: 10.1038/74994.PubMedCrossRefGoogle Scholar
  110. 110.
    Kurozumi K, Nakamura K, Tamiya T, Kawano Y, Kobune M, Hirai S, et al. BDNF gene-modified mesenchymal stem cells promote functional recovery and reduce infarct size in the rat middle cerebral artery occlusion model. Mol Ther. 2004;9(2):189–97. doi: 10.1016/j.ymthe.2003.10.012. S152500160300354X [pii].PubMedCrossRefGoogle Scholar
  111. 111.
    Lai RC, Chen TS, Lim SK. Mesenchymal stem cell exosome: a novel stem cell-based therapy for cardiovascular disease. Regen Med. 2011;6(4):481–92. doi: 10.2217/rme.11.35.PubMedCrossRefGoogle Scholar
  112. 112.
    Lapergue B, Mohammad A, Shuaib A. Endothelial progenitor cells and cerebrovascular diseases. Prog Neurobiol. 2007;83(6):349–62. doi: 10.1016/j.pneurobio.2007.08.001.PubMedCrossRefGoogle Scholar
  113. 113.
    Lee JK, Park SR, Jung BK, Jeon YK, Lee YS, Kim MK, et al. Exosomes derived from mesenchymal stem cells suppress angiogenesis by down-regulating VEGF expression in breast cancer cells. PLoS ONE. 2013;8(12), e84256. doi: 10.1371/journal.pone.0084256. PONE-D-13-14677 [pii].PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Lee JS, Hong JM, Moon GJ, Lee PH, Ahn YH, Bang OY. A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells. 2010;28(6):1099–106. doi: 10.1002/stem.430.PubMedCrossRefGoogle Scholar
  115. 115.
    Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell. 1997;91(4):479–89.PubMedCrossRefGoogle Scholar
  116. 116.
    Li Y, Chen J, Chopp M. Adult bone marrow transplantation after stroke in adult rats. Cell Transplant. 2001;10(1):31–40.PubMedGoogle Scholar
  117. 117.
    Li Y, Chen J, Wang L, Lu M, Chopp M. Treatment of stroke in rat with intracarotid administration of marrow stromal cells. Neurology. 2001;56(12):1666–72.PubMedCrossRefGoogle Scholar
  118. 118.
    Li Y, Chopp M, Chen J, Wang L, Gautam SC, Xu YX, et al. Intrastriatal transplantation of bone marrow nonhematopoietic cells improves functional recovery after stroke in adult mice. J Cereb Blood Flow Metab. 2000;20(9):1311–9. doi: 10.1097/00004647-200009000-00006.PubMedCrossRefGoogle Scholar
  119. 119.
    Li YF, Ren LN, Guo G, Cannella LA, Chernaya V, Samuel S, et al. Endothelial progenitor cells in ischemic stroke: an exploration from hypothesis to therapy. J Hematol Oncol. 2015;8:33. doi: 10.1186/s13045-015-0130-8.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Liu J. Induced pluripotent stem cell-derived neural stem cells: new hope for stroke? Stem Cell Res Ther. 2013;4(5):115. doi: 10.1186/scrt326.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Liu N, Deguchi K, Yamashita T, Liu W, Ikeda Y, Abe K. Intracerebral transplantation of bone marrow stromal cells ameliorates tissue plasminogen activator-induced brain damage after cerebral ischemia in mice detected by in vivo and ex vivo optical imaging. J Neurosci Res. 2012;90(11):2086–93. doi: 10.1002/jnr.23104.PubMedCrossRefGoogle Scholar
  122. 122.
    Liu N, Zhang Y, Fan L, Yuan M, Du H, Cheng R, et al. Effects of transplantation with bone marrow-derived mesenchymal stem cells modified by survivin on experimental stroke in rats. J Transl Med. 2011;9:105. doi: 10.1186/1479-5876-9-105. 1479-5876-9-105 [pii].PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Liu X. Beyond the time window of intravenous thrombolysis: standing by or by stenting? Interv Neurol. 2012;1(1):3–15. doi: 10.1159/000338389.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Liu XS, Zhang ZG, Zhang RL, Gregg S, Morris DC, Wang Y, et al. Stroke induces gene profile changes associated with neurogenesis and angiogenesis in adult subventricular zone progenitor cells. J Cereb Blood Flow Metab. 2007;27(3):564–74.PubMedCrossRefGoogle Scholar
  125. 125.
    Liu YP, Seckin H, Izci Y, Du ZW, Yan YP, Baskaya MK. Neuroprotective effects of mesenchymal stem cells derived from human embryonic stem cells in transient focal cerebral ischemia in rats. J Cereb Blood Flow Metab. 2009;29(4):780–91. doi: 10.1038/jcbfm.2009.1. jcbfm20091 [pii].PubMedCrossRefGoogle Scholar
  126. 126.
    Lo EH, Dalkara T, Moskowitz MA. Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci. 2003;4(5):399–415. doi: 10.1038/nrn1106.PubMedCrossRefGoogle Scholar
  127. 127.
    Lorenzo HK, Susin SA, Penninger J, Kroemer G. Apoptosis inducing factor (AIF): a phylogenetically old, caspase-independent effector of cell death. Cell Death Differ. 1999;6(6):516–24. doi: 10.1038/sj.cdd.4400527.PubMedCrossRefGoogle Scholar
  128. 128.
    Love S. Apoptosis and brain ischaemia. Prog Neuro-Psychopharmacol Biol Psychiatry. 2003;27(2):267–82. doi: 10.1016/s0278-5846(03)00022-8.CrossRefGoogle Scholar
  129. 129.
    Luo Y, Cao G, Pei W, O’Horo C, Graham SH, Chen J. Induction of caspase-activated deoxyribonuclease activity after focal cerebral ischemia and reperfusion. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab. 2002;22(1):15–20. doi: 10.1097/00004647-200201000-00002.CrossRefGoogle Scholar
  130. 130.
    Luskin MB, Zigova T, Soteres BJ, Stewart RR. Neuronal progenitor cells derived from the anterior subventricular zone of the neonatal rat forebrain continue to proliferate in vitro and express a neuronal phenotype. Mol Cell Neurosci. 1997;8(5):351–66.PubMedCrossRefGoogle Scholar
  131. 131.
    Ma F, Morancho A, Montaner J, Rosell A. Endothelial progenitor cells and revascularization following stroke. Brain Res. 1623;2015:150–9. doi: 10.1016/j.brainres.2015.02.010.Google Scholar
  132. 132.
    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):13114–9.PubMedCrossRefGoogle Scholar
  133. 133.
    Maherali N, Sridharan R, Xie W, Utikal J, Eminli S, Arnold K, et al. Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell. 2007;1(1):55–70. doi: 10.1016/j.stem.2007.05.014.PubMedCrossRefGoogle Scholar
  134. 134.
    Marion RM, Strati K, Li H, Murga M, Blanco R, Ortega S, et al. A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature. 2009;460(7259):1149–53. doi: 10.1038/nature08287.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Martin GR. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci U S A. 1981;78(12):7634–8.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Matsuyama T, Hata R, Yamamoto Y, Tagaya M, Akita H, Uno H, et al. Localization of Fas antigen mRNA induced in postischemic murine forebrain by in situ hybridization. Brain Res Mol Brain Res. 1995;34(1):166–72.PubMedCrossRefGoogle Scholar
  137. 137.
    Mattsson B, Sorensen JC, Zimmer J, Johansson BB. Neural grafting to experimental neocortical infarcts improves behavioral outcome and reduces thalamic atrophy in rats housed in enriched but not in standard environments. Stroke. 1997;28(6):1225–31. discussion 31–2.PubMedCrossRefGoogle Scholar
  138. 138.
    Mayfield AE, Tilokee EL, Davis DR. Resident cardiac stem cells and their role in stem cell therapies for myocardial repair. Can J Cardiol. 2014;30(11):1288–98. doi: 10.1016/j.cjca.2014.03.018. S0828-282X(14)00164-0 [pii].PubMedCrossRefGoogle Scholar
  139. 139.
    Mehrabi M, Mansouri K, Hosseinkhani S, Yarani R, Yari K, Bakhtiari M, et al. Differentiation of human skin-derived precursor cells into functional islet-like insulin-producing cell clusters. In Vitro Cell Dev Biol Anim. 2015;51(6):595–603. doi: 10.1007/s11626-015-9866-2.PubMedCrossRefGoogle Scholar
  140. 140.
    Mendez-Ferrer S, Michurina TV, Ferraro F, Mazloom AR, Macarthur BD, Lira SA, et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature. 2010;466(7308):829–34. doi: 10.1038/nature09262. nature09262 [pii].PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    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.PubMedCrossRefGoogle Scholar
  142. 142.
    Miura K, Okada Y, Aoi T, Okada A, Takahashi K, Okita K, et al. Variation in the safety of induced pluripotent stem cell lines. Nat Biotechnol. 2009;27(8):743–5. doi: 10.1038/nbt.1554.PubMedCrossRefGoogle Scholar
  143. 143.
    Moniche F, Gonzalez A, Gonzalez-Marcos JR, Carmona M, Pinero P, Espigado I, et al. Intra-arterial bone marrow mononuclear cells in ischemic stroke: a pilot clinical trial. Stroke. 2012;43(8):2242–4. doi: 10.1161/STROKEAHA.112.659409. STROKEAHA.112.659409 [pii].PubMedCrossRefGoogle Scholar
  144. 144.
    Moubarik C, Guillet B, Youssef B, Codaccioni JL, Piercecchi MD, Sabatier F, et al. Transplanted late outgrowth endothelial progenitor cells as cell therapy product for stroke. Stem Cell Rev. 2011;7(1):208–20. doi: 10.1007/s12015-010-9157-y.PubMedCrossRefGoogle Scholar
  145. 145.
    Nagai N, Kawao N, Okada K, Okumoto K, Teramura T, Ueshima S, et al. Systemic transplantation of embryonic stem cells accelerates brain lesion decrease and angiogenesis. Neuroreport. 2010;21(8):575–9. doi: 10.1097/WNR.0b013e32833a7d2c.PubMedCrossRefGoogle Scholar
  146. 146.
    Nakagawa M, Koyanagi M, Tanabe K, Takahashi K, Ichisaka T, Aoi T, et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol. 2008;26(1):101–6. doi: 10.1038/nbt1374.PubMedCrossRefGoogle Scholar
  147. 147.
    Nakagawa M, Taniguchi Y, Senda S, Takizawa N, Ichisaka T, Asano K, et al. A novel efficient feeder-free culture system for the derivation of human induced pluripotent stem cells. Sci Rep. 2014;4:3594. doi: 10.1038/srep03594.PubMedPubMedCentralGoogle Scholar
  148. 148.
    Nawashiro H, Martin D, Hallenbeck JM. Neuroprotective effects of TNF binding protein in focal cerebral ischemia. Brain Res. 1997;778(2):265–71.PubMedCrossRefGoogle Scholar
  149. 149.
    Nishishita T, Ouchi K, Zhang X, Inoue M, Inazawa T, Yoshiura K, et al. A potential pro-angiogenic cell therapy with human placenta-derived mesenchymal cells. Biochem Biophys Res Commun. 2004;325(1):24–31. doi: 10.1016/j.bbrc.2004.10.003. S0006-291X(04)02289-2 [pii].PubMedCrossRefGoogle Scholar
  150. 150.
    Nolan DJ, Ciarrocchi A, Mellick AS, Jaggi JS, Bambino K, Gupta S, et al. Bone marrow-derived endothelial progenitor cells are a major determinant of nascent tumor neovascularization. Genes Dev. 2007;21(12):1546–58. doi: 10.1101/gad.436307.PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Nowakowski RS, Lewin SB, Miller MW. Bromodeoxyuridine immunohistochemical determination of the lengths of the cell cycle and the DNA-synthetic phase for an anatomically defined population. J Neurocytol. 1989;18(3):311–8.PubMedCrossRefGoogle Scholar
  152. 152.
    Ohta T, Kikuta K, Imamura H, Takagi Y, Nishimura M, Arakawa Y, et al. Administration of ex vivo-expanded bone marrow-derived endothelial progenitor cells attenuates focal cerebral ischemia-reperfusion injury in rats. Neurosurgery. 2006;59(3):679–86. doi: 10.1227/01.neu.0000229058.08706.88. discussion -86.PubMedCrossRefGoogle Scholar
  153. 153.
    Okabe S, Forsberg-Nilsson K, Spiro AC, Segal M, McKay RD. Development of neuronal precursor cells and functional postmitotic neurons from embryonic stem cells in vitro. Mech Dev. 1996;59(1):89–102. doi:0925477396005722 [pii].PubMedCrossRefGoogle Scholar
  154. 154.
    Okazaki T, Magaki T, Takeda M, Kajiwara Y, Hanaya R, Sugiyama K, et al. Intravenous administration of bone marrow stromal cells increases survivin and Bcl-2 protein expression and improves sensorimotor function following ischemia in rats. Neurosci Lett. 2008;430(2):109–14. doi: 10.1016/j.neulet.2007.10.046. S0304-3940(07)01140-8 [pii].PubMedCrossRefGoogle Scholar
  155. 155.
    Oki K, Tatarishvili J, Wood J, Koch P, Wattananit S, Mine Y, et al. Human-induced pluripotent stem cells form functional neurons and improve recovery after grafting in stroke-damaged brain. Stem Cells (Dayton, Ohio). 2012;30(6):1120–33. doi: 10.1002/stem.1104.CrossRefGoogle Scholar
  156. 156.
    Okita K, Ichisaka T, Yamanaka S. Generation of germline-competent induced pluripotent stem cells. Nature. 2007;448(7151):313–7. doi: 10.1038/nature05934.PubMedCrossRefGoogle Scholar
  157. 157.
    Okita K, Matsumura Y, Sato Y, Okada A, Morizane A, Okamoto S, et al. A more efficient method to generate integration-free human iPS cells. Nat Methods. 2011;8(5):409–12. doi: 10.1038/nmeth.1591.PubMedCrossRefGoogle Scholar
  158. 158.
    Okita K, Nakagawa M, Hyenjong H, Ichisaka T, Yamanaka S. Generation of mouse induced pluripotent stem cells without viral vectors. Science (New York, NY). 2008;322(5903):949–53. doi: 10.1126/science.1164270.CrossRefGoogle Scholar
  159. 159.
    Onda T, Honmou O, Harada K, Houkin K, Hamada H, Kocsis JD. Therapeutic benefits by human mesenchymal stem cells (hMSCs) and Ang-1 gene-modified hMSCs after cerebral ischemia. J Cereb Blood Flow Metab. 2008;28(2):329–40. doi: 10.1038/sj.jcbfm.9600527. 9600527 [pii].PubMedCrossRefGoogle Scholar
  160. 160.
    Oyamada N, Itoh H, Sone M, Yamahara K, Miyashita K, Park K, et al. Transplantation of vascular cells derived from human embryonic stem cells contributes to vascular regeneration after stroke in mice. J Transl Med. 2008;6:54. doi: 10.1186/1479-5876-6-54. 1479-5876-6-54 [pii].PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Parent JM, Vexler ZS, Gong C, Derugin N, Ferriero DM. Rat forebrain neurogenesis and striatal neuron replacement after focal stroke. Ann Neurol. 2002;52(6):802–13.PubMedCrossRefGoogle Scholar
  162. 162.
    Park S, Koh SE, Maeng S, Lee WD, Lim J, Lee YJ. Neural progenitors generated from the mesenchymal stem cells of first-trimester human placenta matured in the hypoxic-ischemic rat brain and mediated restoration of locomotor activity. Placenta. 2011;32(3):269–76. doi: 10.1016/j.placenta.2010.12.027. S0143-4004(11)00011-7 [pii].PubMedCrossRefGoogle Scholar
  163. 163.
    Parras CM, Galli R, Britz O, Soares S, Galichet C, Battiste J, et al. Mash1 specifies neurons and oligodendrocytes in the postnatal brain. Embo J. 2004;23(22):4495–505.PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Paspala SA, Murthy TV, Mahaboob VS, Habeeb MA. Pluripotent stem cells – a review of the current status in neural regeneration. Neurol India. 2011;59(4):558–65.PubMedCrossRefGoogle Scholar
  165. 165.
    Paul G, Ozen I, Christophersen NS, Reinbothe T, Bengzon J, Visse E, et al. The adult human brain harbors multipotent perivascular mesenchymal stem cells. PLoS ONE. 2012;7(4), e35577. doi: 10.1371/journal.pone.0035577. PONE-D-11-11140 [pii].PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Polentes J, Jendelova P, Cailleret M, Braun H, Romanyuk N, Tropel P, et al. Human induced pluripotent stem cells improve stroke outcome and reduce secondary degeneration in the recipient brain. Cell Transplant. 2012;21(12):2587–602. doi: 10.3727/096368912x653228.PubMedCrossRefGoogle Scholar
  167. 167.
    Portmann-Lanz CB, Schoeberlein A, Huber A, Sager R, Malek A, Holzgreve W, et al. Placental mesenchymal stem cells as potential autologous graft for pre- and perinatal neuroregeneration. Am J Obstet Gynecol. 2006;194(3):664–73. doi: 10.1016/j.ajog.2006.01.101. S0002-9378(06)00175-X [pii].PubMedCrossRefGoogle Scholar
  168. 168.
    Prather WR, Toren A, Meiron M, Ofir R, Tschope C, Horwitz EM. The role of placental-derived adherent stromal cell (PLX-PAD) in the treatment of critical limb ischemia. Cytotherapy. 2009;11(4):427–34. doi: 10.1080/14653240902849762. 912390024 [pii].PubMedCrossRefGoogle Scholar
  169. 169.
    Quinones-Hinojosa A, Sanai N, Soriano-Navarro M, Gonzalez-Perez O, Mirzadeh Z, Gil-Perotin S, et al. Cellular composition and cytoarchitecture of the adult human subventricular zone: a niche of neural stem cells. J Comp Neurol. 2006;494(3):415–34.PubMedCrossRefGoogle Scholar
  170. 170.
    Record M, Carayon K, Poirot M, Silvente-Poirot S. Exosomes as new vesicular lipid transporters involved in cell-cell communication and various pathophysiologies. Biochim Biophys Acta. 2014;1841(1):108–20. doi: 10.1016/j.bbalip.2013.10.004. S1388-1981(13)00219-9 [pii].PubMedCrossRefGoogle Scholar
  171. 171.
    Record M, Subra C, Silvente-Poirot S, Poirot M. Exosomes as intercellular signalosomes and pharmacological effectors. Biochem Pharmacol. 2011;81(10):1171–82. doi: 10.1016/j.bcp.2011.02.011. S0006-2952(11)00115-8 [pii].PubMedCrossRefGoogle Scholar
  172. 172.
    Reubinoff BE, Itsykson P, Turetsky T, Pera MF, Reinhartz E, Itzik A, et al. Neural progenitors from human embryonic stem cells. Nat Biotechnol. 2001;19(12):1134–40. doi: 10.1038/nbt1201-1134. nbt1201-1134 [pii].PubMedCrossRefGoogle Scholar
  173. 173.
    Reubinoff BE, Pera MF, Fong CY, Trounson A, Bongso A. Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro. Nat Biotechnol. 2000;18(4):399–404. doi: 10.1038/74447.PubMedCrossRefGoogle Scholar
  174. 174.
    Rosell A, Morancho A, Navarro-Sobrino M, Martinez-Saez E, Hernandez-Guillamon M, Lope-Piedrafita S, et al. Factors secreted by endothelial progenitor cells enhance neurorepair responses after cerebral ischemia in mice. PLoS ONE. 2013;8(9), e73244. doi: 10.1371/journal.pone.0073244.PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Rothman SM, Olney JW. Excitotoxicity and the NMDA receptor – still lethal after eight years. Trends Neurosci. 1995;18(2):57–8.PubMedGoogle Scholar
  176. 176.
    Rouhl RP, van Oostenbrugge RJ, Damoiseaux J, Tervaert JW, Lodder J. Endothelial progenitor cell research in stroke: a potential shift in pathophysiological and therapeutical concepts. Stroke J Cereb Circ. 2008;39(7):2158–65. doi: 10.1161/strokeaha.107.507251.CrossRefGoogle Scholar
  177. 177.
    Sakaguchi M, Okano H. Neural stem cells, adult neurogenesis, and galectin-1: from bench to bedside. Dev Neurobiol. 2012;72(7):1059–67.PubMedCrossRefGoogle Scholar
  178. 178.
    Sanai N, Tramontin AD, Quinones-Hinojosa A, Barbaro NM, Gupta N, Kunwar S, et al. Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature. 2004;427(6976):740–4.PubMedCrossRefGoogle Scholar
  179. 179.
    Sanberg PR, Eve DJ, Metcalf C, Borlongan CV. Advantages and challenges of alternative sources of adult-derived stem cells for brain repair in stroke. Prog Brain Res. 2012;201:99–117. doi: 10.1016/B978-0-444-59544-7.00006-8. B978-0-444-59544-7.00006-8 [pii].PubMedCrossRefGoogle Scholar
  180. 180.
    Schoeberlein A, Mueller M, Reinhart U, Sager R, Messerli M, Surbek DV. Homing of placenta-derived mesenchymal stem cells after perinatal intracerebral transplantation in a rat model. Am J Obstet Gynecol. 2011;205(3):277 e1–6. doi: 10.1016/j.ajog.2011.06.044. S0002-9378(11)00772-1 [pii].CrossRefGoogle Scholar
  181. 181.
    Seminatore C, Polentes J, Ellman D, Kozubenko N, Itier V, Tine S, et al. The postischemic environment differentially impacts teratoma or tumor formation after transplantation of human embryonic stem cell-derived neural progenitors. Stroke. 2010;41(1):153–9. doi: 10.1161/STROKEAHA.109.563015. STROKEAHA.109.563015 [pii].PubMedCrossRefGoogle Scholar
  182. 182.
    Shah S, Stroke Pathophysiology. Foundation for education and research in neurological emergencies. www.uicedu/com/ferne/pdf/pathophys0501pdf,2000. 2000.
  183. 183.
    Shen LH, Xin H, Li Y, Zhang RL, Cui Y, Zhang L, et al. Endogenous tissue plasminogen activator mediates bone marrow stromal cell-induced neurite remodeling after stroke in mice. Stroke. 2011;42(2):459–64. doi: 10.1161/STROKEAHA.110.593863. STROKEAHA.110.593863 [pii].PubMedPubMedCentralCrossRefGoogle Scholar
  184. 184.
    Shiraishi K, Sharp FR, Simon RP. Sequential metabolic changes in rat brain following middle cerebral artery occlusion: a 2-deoxyglucose study. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab. 1989;9(6):765–73. doi: 10.1038/jcbfm.1989.110.CrossRefGoogle Scholar
  185. 185.
    Shiratsuki S, Terai S, Murata Y, Takami T, Yamamoto N, Fujisawa K, et al. Enhanced survival of mice infused with bone marrow-derived as compared with adipose-derived mesenchymal stem cells. Hepatol Res. 2015;45(13):1353–9. doi: 10.1111/hepr.12507.PubMedCrossRefGoogle Scholar
  186. 186.
    Siesjo BK. Cell damage in the brain: a speculative synthesis. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab. 1981;1(2):155–85. doi: 10.1038/jcbfm.1981.18.CrossRefGoogle Scholar
  187. 187.
    Sinden JD, Rashid-Doubell F, Kershaw TR, Nelson A, Chadwick A, Jat PS, et al. Recovery of spatial learning by grafts of a conditionally immortalized hippocampal neuroepithelial cell line into the ischaemia-lesioned hippocampus. Neuroscience. 1997;81(3):599–608.PubMedCrossRefGoogle Scholar
  188. 188.
    Singh VK, Kalsan M, Kumar N, Saini A, Chandra R. Induced pluripotent stem cells: applications in regenerative medicine, disease modeling, and drug discovery. Front Cell Dev Biol. 2015;3:2. doi: 10.3389/fcell.2015.00002.PubMedPubMedCentralCrossRefGoogle Scholar
  189. 189.
    Sinor AD, Lillien L. Akt-1 expression level regulates CNS precursors. J Neurosci. 2004;24(39):8531–41.PubMedCrossRefGoogle Scholar
  190. 190.
    Snyder EY, Deitcher DL, Walsh C, Arnold-Aldea S, Hartwieg EA, Cepko CL. Multipotent neural cell lines can engraft and participate in development of mouse cerebellum. Cell. 1992;68(1):33–51.PubMedCrossRefGoogle Scholar
  191. 191.
    Sobrino T, Hurtado O, Moro MA, Rodriguez-Yanez M, Castellanos M, Brea D, et al. The increase of circulating endothelial progenitor cells after acute ischemic stroke is associated with good outcome. Stroke J Cereb Circ. 2007;38(10):2759–64. doi: 10.1161/strokeaha.107.484386.CrossRefGoogle Scholar
  192. 192.
    Sonntag KC, Pruszak J, Yoshizaki T, van Arensbergen J, Sanchez-Pernaute R, Isacson O. Enhanced yield of neuroepithelial precursors and midbrain-like dopaminergic neurons from human embryonic stem cells using the bone morphogenic protein antagonist noggin. Stem Cells. 2007;25(2):411–8. doi: 10.1634/stemcells.2006-0380. 2006-0380 [pii].PubMedCrossRefGoogle Scholar
  193. 193.
    Sorensen JC, Grabowski M, Zimmer J, Johansson BB. Fetal neocortical tissue blocks implanted in brain infarcts of adult rats interconnect with the host brain. Exp Neurol. 1996;138(2):227–35.PubMedCrossRefGoogle Scholar
  194. 194.
    Sorensen JC, Mattsson B, Andreasen A, Johansson BB. Rapid disappearance of zinc positive terminals in focal brain ischemia. Brain Res. 1998;812(1–2):265–9.PubMedCrossRefGoogle Scholar
  195. 195.
    Stenderup K, Justesen J, Clausen C, Kassem M. Aging is associated with decreased maximal life span and accelerated senescence of bone marrow stromal cells. Bone. 2003;33(6):919–26. doi:S8756328203002679 [pii].PubMedCrossRefGoogle Scholar
  196. 196.
    Stephan RP, Reilly CR, Witte PL. Impaired ability of bone marrow stromal cells to support B-lymphopoiesis with age. Blood. 1998;91(1):75–88.PubMedGoogle Scholar
  197. 197.
    Stock P, Bruckner S, Winkler S, Dollinger MM, Christ B. Human bone marrow mesenchymal stem cell-derived hepatocytes improve the mouse liver after acute acetaminophen intoxication by preventing progress of injury. Int J Mol Sci. 2014;15(4):7004–28. doi: 10.3390/ijms15047004. ijms15047004 [pii].PubMedPubMedCentralCrossRefGoogle Scholar
  198. 198.
    Suarez-Monteagudo C, Hernandez-Ramirez P, Alvarez-Gonzalez L, Garcia-Maeso I, de la Cuetara-Bernal K, Castillo-Diaz L, et al. Autologous bone marrow stem cell neurotransplantation in stroke patients. An open study. Restor Neurol Neurosci. 2009;27(3):151–61. doi: 10.3233/RNN-2009-0483. 085W5360088471V2 [pii].PubMedGoogle Scholar
  199. 199.
    Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, et al. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature. 1999;397(6718):441–6. doi: 10.1038/17135.PubMedCrossRefGoogle Scholar
  200. 200.
    Tae-Hoon L, Yoon-Seok L. Transplantation of mouse embryonic stem cell after middle cerebral artery occlusion. Acta Cir Bras. 2012;27(4):333–9. doi:S0102-86502012000400009 [pii].PubMedCrossRefGoogle Scholar
  201. 201.
    Taguchi A, Matsuyama T, Moriwaki H, Hayashi T, Hayashida K, Nagatsuka K, et al. Circulating CD34-positive cells provide an index of cerebrovascular function. Circulation. 2004;109(24):2972–5. doi: 10.1161/ Scholar
  202. 202.
    Takagi Y, Nishimura M, Morizane A, Takahashi J, Nozaki K, Hayashi J, et al. Survival and differentiation of neural progenitor cells derived from embryonic stem cells and transplanted into ischemic brain. J Neurosurg. 2005;103(2):304–10. doi: 10.3171/jns.2005.103.2.0304.PubMedCrossRefGoogle Scholar
  203. 203.
    Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72. doi: 10.1016/j.cell.2007.11.019.PubMedCrossRefGoogle Scholar
  204. 204.
    Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76. doi: 10.1016/j.cell.2006.07.024.PubMedCrossRefGoogle Scholar
  205. 205.
    Takahashi T, Kalka C, Masuda H, Chen D, Silver M, Kearney M, et al. Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med. 1999;5(4):434–8. doi: 10.1038/7434.PubMedCrossRefGoogle Scholar
  206. 206.
    Tang YH, Ma YY, Zhang ZJ, Wang YT, Yang GY. Opportunities and challenges: stem cell-based therapy for the treatment of ischemic stroke. CNS Neurosci Ther. 2015;21(4):337–47. doi: 10.1111/cns.12386.PubMedCrossRefGoogle Scholar
  207. 207.
    Taupin P, Gage FH. Adult neurogenesis and neural stem cells of the central nervous system in mammals. J Neurosci Res. 2002;69(6):745–9.PubMedCrossRefGoogle Scholar
  208. 208.
    Temple S. Division and differentiation of isolated CNS blast cells in microculture. Nature. 1989;340(6233):471–3.PubMedCrossRefGoogle Scholar
  209. 209.
    Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, et al. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282(5391):1145–7.PubMedCrossRefGoogle Scholar
  210. 210.
    Thored P, Arvidsson A, Cacci E, Ahlenius H, Kallur T, Darsalia V, et al. Persistent production of neurons from adult brain stem cells during recovery after stroke. Stem Cells. 2006;24(3):739–47.PubMedCrossRefGoogle Scholar
  211. 211.
    Tobita M, Orbay H, Mizuno H. Adipose-derived stem cells: current findings and future perspectives. Discov Med. 2011;11(57):160–70.PubMedGoogle Scholar
  212. 212.
    Tohill M, Mantovani C, Wiberg M, Terenghi G. Rat bone marrow mesenchymal stem cells express glial markers and stimulate nerve regeneration. Neurosci Lett. 2004;362(3):200–3. doi: 10.1016/j.neulet.2004.03.077. S0304394004002861 [pii].PubMedCrossRefGoogle Scholar
  213. 213.
    Tomasoni S, Longaretti L, Rota C, Morigi M, Conti S, Gotti E, et al. Transfer of growth factor receptor mRNA via exosomes unravels the regenerative effect of mesenchymal stem cells. Stem Cells Dev. 2013;22(5):772–80. doi: 10.1089/scd.2012.0266.PubMedCrossRefGoogle Scholar
  214. 214.
    Tornero D, Wattananit S, Gronning Madsen M, Koch P, Wood J, Tatarishvili J, et al. Human induced pluripotent stem cell-derived cortical neurons integrate in stroke-injured cortex and improve functional recovery. Brain J Neurol. 2013;136(Pt 12):3561–77. doi: 10.1093/brain/awt278.CrossRefGoogle Scholar
  215. 215.
    Turturici G, Tinnirello R, Sconzo G, Geraci F. Extracellular membrane vesicles as a mechanism of cell-to-cell communication: advantages and disadvantages. Am J Physiol Cell Physiol. 2014;306(7):C621–33. doi: 10.1152/ajpcell.00228.2013. ajpcell.00228.2013 [pii].PubMedCrossRefGoogle Scholar
  216. 216.
    Uccelli A, Laroni A, Freedman MS. Mesenchymal stem cells for the treatment of multiple sclerosis and other neurological diseases. Lancet Neurol. 2011;10(7):649–56. doi: 10.1016/S1474-4422(11)70121-1. S1474-4422(11)70121-1 [pii].PubMedCrossRefGoogle Scholar
  217. 217.
    Umemura T, Soga J, Hidaka T, Takemoto H, Nakamura S, Jitsuiki D, et al. Aging and hypertension are independent risk factors for reduced number of circulating endothelial progenitor cells. Am J Hypertens. 2008;21(11):1203–9. doi: 10.1038/ajh.2008.278.PubMedCrossRefGoogle Scholar
  218. 218.
    van der Strate BW, Popa ER, Schipper M, Brouwer LA, Hendriks M, Harmsen MC, et al. Circulating human CD34+ progenitor cells modulate neovascularization and inflammation in a nude mouse model. J Mol Cell Cardiol. 2007;42(6):1086–97. doi: 10.1016/j.yjmcc.2007.03.907.PubMedCrossRefGoogle Scholar
  219. 219.
    Varga G, Gerber G. Mesenchymal stem cells of dental origin as promising tools for neuroregeneration. Stem Cell Res Ther. 2014;5(2):61. doi: 10.1186/scrt450. scrt450 [pii].PubMedPubMedCentralCrossRefGoogle Scholar
  220. 220.
    Vojtek AB, Taylor J, DeRuiter SL, Yu JY, Figueroa C, Kwok RP, et al. Akt regulates basic helix-loop-helix transcription factor-coactivator complex formation and activity during neuronal differentiation. Mol Cell Biol. 2003;23(13):4417–27.PubMedPubMedCentralCrossRefGoogle Scholar
  221. 221.
    Wakabayashi K, Nagai A, Sheikh AM, Shiota Y, Narantuya D, Watanabe T, et al. Transplantation of human mesenchymal stem cells promotes functional improvement and increased expression of neurotrophic factors in a rat focal cerebral ischemia model. J Neurosci Res. 2010;88(5):1017–25. doi: 10.1002/jnr.22279.PubMedGoogle Scholar
  222. 222.
    Wang J, Chao F, Han F, Zhang G, Xi Q, Li J, et al. PET demonstrates functional recovery after transplantation of induced pluripotent stem cells in a rat model of cerebral ischemic injury. J Nucl Med Off Publ Soc Nucl Med. 2013;54(5):785–92. doi: 10.2967/jnumed.112.111112.Google Scholar
  223. 223.
    Wang J, Hendrix A, Hernot S, Lemaire M, De Bruyne E, Van Valckenborgh E, et al. Bone marrow stromal cell-derived exosomes as communicators in drug resistance in multiple myeloma cells. Blood. 2014;124(4):555–66. doi: 10.1182/blood-2014-03-562439. blood-2014-03-562439 [pii].PubMedCrossRefGoogle Scholar
  224. 224.
    Wang L, Gang Zhang Z, Lan Zhang R, Chopp M. Activation of the PI3-K/Akt pathway mediates cGMP enhanced-neurogenesis in the adult progenitor cells derived from the subventricular zone. J Cereb Blood Flow Metab. 2005;25(9):1150–8.PubMedCrossRefGoogle Scholar
  225. 225.
    Wang L, Zhang Z, Wang Y, Zhang R, Chopp M. Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke. 2004;35(7):1732–7.PubMedCrossRefGoogle Scholar
  226. 226.
    Wang L, Zhang ZG, Gregg SR, Zhang RL, Jiao Z, LeTourneau Y, et al. The sonic hedgehog pathway mediates carbamylated erythropoietin-enhanced proliferation and differentiation of adult neural progenitor cells. J Biol Chem. 2007;282(44):32462–70.PubMedCrossRefGoogle Scholar
  227. 227.
    Wang L, Zhang ZG, Zhang RL, Jiao ZX, Wang Y, Pourabdollah-Nejad DS, et al. Neurogenin 1 mediates erythropoietin enhanced differentiation of adult neural progenitor cells. J Cereb Blood Flow Metab. 2006;26(4):556–64.PubMedCrossRefGoogle Scholar
  228. 228.
    Wang X, Yue TL, Barone FC, White RF, Gagnon RC, Feuerstein GZ. Concomitant cortical expression of TNF-alpha and IL-1 beta mRNAs follows early response gene expression in transient focal ischemia. Mol Chem Neuropathol Sponsored Int Soc Neurochem World Fed Neurol Res Group Neurochem Cerebrospinal Fluid. 1994;23(2–3):103–14.Google Scholar
  229. 229.
    Warrier S, Haridas N, Bhonde R. Inherent propensity of amnion-derived mesenchymal stem cells towards endothelial lineage: vascularization from an avascular tissue. Placenta. 2012;33(10):850–8. doi: 10.1016/j.placenta.2012.07.001. S0143-4004(12)00260-3 [pii].PubMedCrossRefGoogle Scholar
  230. 230.
    Wei L, Cui L, Snider BJ, Rivkin M, Yu SS, Lee CS, et al. Transplantation of embryonic stem cells overexpressing Bcl-2 promotes functional recovery after transient cerebral ischemia. Neurobiol Dis. 2005;19(1–2):183–93. doi: 10.1016/j.nbd.2004.12.016. S0969-9961(04)00319-5 [pii].PubMedCrossRefGoogle Scholar
  231. 231.
    Wernig M, Meissner A, Foreman R, Brambrink T, Ku M, Hochedlinger K, et al. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature. 2007;448(7151):318–24. doi: 10.1038/nature05944.PubMedCrossRefGoogle Scholar
  232. 232.
    Wislet-Gendebien S, Hans G, Leprince P, Rigo JM, Moonen G, Rogister B. Plasticity of cultured mesenchymal stem cells: switch from nestin-positive to excitable neuron-like phenotype. Stem Cells. 2005;23(3):392–402. doi: 10.1634/stemcells.2004-0149. doi:23/3/392 [pii].PubMedCrossRefGoogle Scholar
  233. 233.
    Xie N, Tang B. The application of human iPSCs in neurological diseases: from bench to bedside. Stem Cells Int. 2016;2016:6484713. doi: 10.1155/2016/6484713.PubMedPubMedCentralGoogle Scholar
  234. 234.
    Xin H, Li Y, Buller B, Katakowski M, Zhang Y, Wang X, et al. Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells. 2012;30(7):1556–64. doi: 10.1002/stem.1129.PubMedPubMedCentralCrossRefGoogle Scholar
  235. 235.
    Xin H, Li Y, Chopp M. Exosomes/miRNAs as mediating cell-based therapy of stroke. Front Cell Neurosci. 2014;8:377. doi: 10.3389/fncel.2014.00377.PubMedPubMedCentralCrossRefGoogle Scholar
  236. 236.
    Xin H, Li Y, Shen LH, Liu X, Wang X, Zhang J, et al. Increasing tPA activity in astrocytes induced by multipotent mesenchymal stromal cells facilitate neurite outgrowth after stroke in the mouse. PLoS ONE. 2010;5(2), e9027. doi: 10.1371/journal.pone.0009027.PubMedPubMedCentralCrossRefGoogle Scholar
  237. 237.
    Xu C, Inokuma MS, Denham J, Golds K, Kundu P, Gold JD, et al. Feeder-free growth of undifferentiated human embryonic stem cells. Nat Biotechnol. 2001;19(10):971–4. doi: 10.1038/nbt1001-971. nbt1001-971 [pii].PubMedCrossRefGoogle Scholar
  238. 238.
    Yamashita T, Abe K. Mechanisms of endogenous endothelial repair in stroke. Curr Pharm Des. 2012;18(25):3649–52.PubMedCrossRefGoogle Scholar
  239. 239.
    Yamashita T, Kawai H, Tian F, Ohta Y, Abe K. Tumorigenic development of induced pluripotent stem cells in ischemic mouse brain. Cell Transplant. 2011;20(6):883–91. doi: 10.3727/096368910x539092.PubMedCrossRefGoogle Scholar
  240. 240.
    Yanagisawa D, Qi M, Kim DH, Kitamura Y, Inden M, Tsuchiya D, et al. Improvement of focal ischemia-induced rat dopaminergic dysfunction by striatal transplantation of mouse embryonic stem cells. Neurosci Lett. 2006;407(1):74–9. doi: 10.1016/j.neulet.2006.08.007. S0304-3940(06)00799-3 [pii].PubMedCrossRefGoogle Scholar
  241. 241.
    Yang JM, Gould SJ. The cis-acting signals that target proteins to exosomes and microvesicles. Biochem Soc Trans. 2013;41(1):277–82. doi: 10.1042/BST20120275. BST20120275 [pii].PubMedCrossRefGoogle Scholar
  242. 242.
    Yarygin KN, Kholodenko IV, Konieva AA, Burunova VV, Tairova RT, Gubsky LV, et al. Mechanisms of positive effects of transplantation of human placental mesenchymal stem cells on recovery of rats after experimental ischemic stroke. Bull Exp Biol Med. 2009;148(6):862–8.PubMedCrossRefGoogle Scholar
  243. 243.
    Ying QL, Stavridis M, Griffiths D, Li M, Smith A. Conversion of embryonic stem cells into neuroectodermal precursors in adherent monoculture. Nat Biotechnol. 2003;21(2):183–6. doi: 10.1038/nbt780. nbt780 [pii].PubMedCrossRefGoogle Scholar
  244. 244.
    Yip HK, Chang LT, Chang WN, Lu CH, Liou CW, Lan MY, et al. Level and value of circulating endothelial progenitor cells in patients after acute ischemic stroke. Stroke J Cereb Circ. 2008;39(1):69–74. doi: 10.1161/strokeaha.107.489401.CrossRefGoogle Scholar
  245. 245.
    Yoo KH, Jang IK, Lee MW, Kim HE, Yang MS, Eom Y, et al. Comparison of immunomodulatory properties of mesenchymal stem cells derived from adult human tissues. Cell Immunol. 2009;259(2):150–6. doi: 10.1016/j.cellimm.2009.06.010. S0008-8749(09)00115-4 [pii].PubMedCrossRefGoogle Scholar
  246. 246.
    Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science (New York, NY). 2007;318(5858):1917–20. doi: 10.1126/science.1151526.CrossRefGoogle Scholar
  247. 247.
    Yu JX, Huang XF, Lv WM, Ye CS, Peng XZ, Zhang H, et al. Combination of stromal-derived factor-1alpha and vascular endothelial growth factor gene-modified endothelial progenitor cells is more effective for ischemic neovascularization. J Vasc Surg. 2009;50(3):608–16. doi: 10.1016/j.jvs.2009.05.049.PubMedCrossRefGoogle Scholar
  248. 248.
    Yuan T, Liao W, Feng NH, Lou YL, Niu X, Zhang AJ, et al. Human induced pluripotent stem cell-derived neural stem cells survive, migrate, differentiate, and improve neurologic function in a rat model of middle cerebral artery occlusion. Stem Cell Res Ther. 2013;4(3):73. doi: 10.1186/scrt224.PubMedPubMedCentralCrossRefGoogle Scholar
  249. 249.
    Zhang H, Song F, Xu C, Liu H, Wang Z, Li J, et al. Spatiotemporal PET imaging of dynamic metabolic changes after therapeutic approaches of induced pluripotent stem cells, neuronal stem cells, and a Chinese patent medicine in stroke. J Nucl Med Off Publ Soc Nucl Med. 2015;56(11):1774–9. doi: 10.2967/jnumed.115.163170.Google Scholar
  250. 250.
    Zhang HG, Grizzle WE. Exosomes: a novel pathway of local and distant intercellular communication that facilitates the growth and metastasis of neoplastic lesions. Am J Pathol. 2014;184(1):28–41. doi: 10.1016/j.ajpath.2013.09.027. S0002-9440(13)00738-4 [pii].PubMedPubMedCentralCrossRefGoogle Scholar
  251. 251.
    Zhang HT, Liu ZL, Yao XQ, Yang ZJ, Xu RX. Neural differentiation ability of mesenchymal stromal cells from bone marrow and adipose tissue: a comparative study. Cytotherapy. 2012;14(10):1203–14. doi: 10.3109/14653249.2012.711470.PubMedCrossRefGoogle Scholar
  252. 252.
    Zhang J, Li Y, Chen J, Yang M, Katakowski M, Lu M, et al. Expression of insulin-like growth factor 1 and receptor in ischemic rats treated with human marrow stromal cells. Brain Res. 2004;1030(1):19–27. doi: 10.1016/j.brainres.2004.09.061. S0006-8993(04)01571-9 [pii].PubMedCrossRefGoogle Scholar
  253. 253.
    Zhang R, Zhang Z, Tsang W, Wang L, Chopp M. Down-regulation of p27kip1 increases proliferation of progenitor cells in adult rats. Neuroreport. 2004;15(11):1797–800.PubMedCrossRefGoogle Scholar
  254. 254.
    Zhang R, Zhang Z, Wang L, Wang Y, Gousev A, Zhang L, et al. Activated neural stem cells contribute to stroke-induced neurogenesis and neuroblast migration toward the infarct boundary in adult rats. J Cereb Blood Flow Metab. 2004;24(4):441–8.PubMedCrossRefGoogle Scholar
  255. 255.
    Zhang RL, Zhang ZG, Chopp M. Ischemic stroke and neurogenesis in the subventricular zone. Neuropharmacology. 2008;55(3):345–52.PubMedPubMedCentralCrossRefGoogle Scholar
  256. 256.
    Zhang RL, Zhang ZG, Roberts C, LeTourneau Y, Lu M, Zhang L, 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
  257. 257.
    Zhang RL, Zhang ZG, Zhang L, Chopp M. Proliferation and differentiation of progenitor cells in the cortex and the subventricular zone in the adult rat after focal cerebral ischemia. Neuroscience. 2001;105(1):33–41.PubMedCrossRefGoogle Scholar
  258. 258.
    Zhang SC, Wernig M, Duncan ID, Brustle O, Thomson JA. In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nat Biotechnol. 2001;19(12):1129–33. doi: 10.1038/nbt1201-1129. nbt1201-1129 [pii].PubMedCrossRefGoogle Scholar
  259. 259.
    Zhang ZG, Zhang L, Jiang Q, Chopp M. Bone marrow-derived endothelial progenitor cells participate in cerebral neovascularization after focal cerebral ischemia in the adult mouse. Circ Res. 2002;90(3):284–8.PubMedCrossRefGoogle Scholar
  260. 260.
    Zhao LR, Duan WM, Reyes M, Keene CD, Verfaillie CM, Low WC. Human bone marrow stem cells exhibit neural phenotypes and ameliorate neurological deficits after grafting into the ischemic brain of rats. Exp Neurol. 2002;174(1):11–20. doi: 10.1006/exnr.2001.7853. S0014488601978537 [pii].PubMedCrossRefGoogle Scholar
  261. 261.
    Zhao YH, Yuan B, Chen J, Feng DH, Zhao B, Qin C, et al. Endothelial progenitor cells: therapeutic perspective for ischemic stroke. CNS Neurosci Ther. 2013;19(2):67–75. doi: 10.1111/cns.12040.PubMedCrossRefGoogle Scholar
  262. 262.
    Zhou T, Benda C, Dunzinger S, Huang Y, Ho JC, Yang J, et al. Generation of human induced pluripotent stem cells from urine samples. Nat Protoc. 2012;7(12):2080–9. doi: 10.1038/nprot.2012.115.PubMedCrossRefGoogle Scholar
  263. 263.
    Zhu Y, Wan S, Zhan RY. Inducible pluripotent stem cells for the treatment of ischemic stroke: current status and problems. Rev Neurosci. 2012;23(4):393–402. doi: 10.1515/revneuro-2012-0042.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2017

Authors and Affiliations

  • Changhong Ren
    • 1
  • Rongrong Han
    • 1
  • Jingfei Shi
    • 2
  • Xunming Ji
    • 3
    • 4
    • 5
    Email author
  1. 1.Institute of Hypoxia Medicine, Xuanwu HospitalCapital Medical UniversityBeijingChina
  2. 2.China-America Joint Institute for Neuroscience, Xuanwu HospitalCapital medical UniversityBeijingChina
  3. 3.Department of Neurosurgery, Xuanwu HospitalCapital Medical UniversityBeijingChina
  4. 4.Institute of Hypoxia Medicine, Xuanwu HospitalCapital Medical UniversityBeijingChina
  5. 5.China-America Joint Institute for Neuroscience, Xuanwu HospitalCapital Medical UniversityBeijingChina

Personalised recommendations