Getting Closer to an Effective Intervention of Ischemic Stroke: The Big Promise of Stem Cell

  • Deepaneeta Sarmah
  • Harpreet Kaur
  • Jackson Saraf
  • Kanta Pravalika
  • Avirag Goswami
  • Kiran Kalia
  • Anupom Borah
  • Xin Wang
  • Kunjan R. Dave
  • Dileep R. Yavagal
  • Pallab Bhattacharya
Review Article

Abstract

Stem cell therapy for ischemic stroke has widely been explored. Results from both preclinical and clinical studies have immensely supported the judicious use of stem cells as therapy. These provide an attractive means for preserving and replacing the damaged brain tissues following an ischemic attack. Since the past few years, researchers have used various types of stem cells to replenish insulted neuronal and glial cells in neurological disorders. In the present review, we discuss different types of stem cells employed for the treatment of ischemic stroke and mechanisms and challenges these cells face once introduced into the living system. Further, we also present different ways to maneuver and overcome challenges to translate the advances made at the preclinical level to clinics.

Keywords

Ischemic stroke Stem cells Neuroprotection Cell engineering Preclinical Clinical 

Notes

Acknowledgements

The authors acknowledge the Department of Science and Technology (DST), Govt. of India, for their financial support through grant (SB/YS/LS-196/2014), International Society for Neurochemistry (ISN) Return Home grant, Department of Pharmaceuticals, Ministry of Chemical and Fertilizers, Govt of India and National Institute of Pharmaceutical Education and Research (NIPER) Ahmedabad, Gandhinagar, India. The authors also want to express their thanks to Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA and the Director, NIPER Ahmedabad, for providing necessary support.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

The article does not contain any studies with animal or human subjects

References

  1. 1.
    Guzik A, Bushnell C. Stroke Epidemiology and Risk Factor Management. Continuum: Lifelong Learn Neurol. 2017;23(1, Cerebrovascular Disease):15–39.Google Scholar
  2. 2.
    Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Heart disease and stroke statistics—2016 update. Circulation. 2016;133(4):e38–e360.PubMedCrossRefGoogle Scholar
  3. 3.
    Seshadri S, Wolf PA. Lifetime risk of stroke and dementia: current concepts, and estimates from the Framingham Study. Lancet Neurol. 2007;6(12):1106–14.PubMedCrossRefGoogle Scholar
  4. 4.
    Reeves MJ, Bushnell CD, Howard G, Gargano JW, Duncan PW, Lynch G, et al. Sex differences in stroke: epidemiology, clinical presentation, medical care, and outcomes. Lancet Neurol. 2008;7(10):915–26.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Haas S, Weidner N, Winkler J. Adult stem cell therapy in stroke. Curr Opin Neurol. 2005;18(1):59–64.PubMedCrossRefGoogle Scholar
  6. 6.
    Hess DC, Borlongan CV. Cell-based therapy in ischemic stroke. Expert Rev Neurother. 2008;8(8):1193–201.PubMedCrossRefGoogle Scholar
  7. 7.
    Leader B, Baca QJ, Golan DE. Protein therapeutics: a summary and pharmacological classification. Nat Rev Drug Discov. 2008;7(1):21.PubMedCrossRefGoogle Scholar
  8. 8.
    Meurer WJ, Barth BE, Gaddis G, Vilke GM, Lam SH. Rapid systematic review: intra-arterial thrombectomy (“Clot Retrieval”) for selected patients with acute ischemic stroke. J Emerg Med. 2017;52(2):255–61.PubMedCrossRefGoogle Scholar
  9. 9.
    Nagpal A, Choy FC, Howell S, Hillier S, Chan F, Hamilton-Bruce MA, et al. Safety and effectiveness of stem cell therapies in early-phase clinical trials in stroke: a systematic review and meta-analysis. Stem Cell Res Ther. 2017;8(1):191.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Vahidy FS, Rahbar MH, Zhu H, Rowan PJ, Bambhroliya AB, Savitz SI. Systematic review and meta-analysis of bone marrow-derived mononuclear cells in animal models of ischemic stroke. Stroke. 2016;47(6):1632–9.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Banerjee S, Williamson D, Habib N, Gordon M, Chataway J. Human stem cell therapy in ischaemic stroke: a review. Age Ageing. 2010;40(1):7–13.PubMedCrossRefGoogle Scholar
  12. 12.
    Kalladka D, Muir KW. Brain repair: cell therapy in stroke. Stem Cells and Cloning: Adv Appl. 2014;7:31.Google Scholar
  13. 13.
    Hsuan YC, Lin CH, Chang CP, Lin MT. Mesenchymal stem cell-based treatments for stroke, neural trauma, and heat stroke. Brain Behav. 2016;6(10):e00526.Google Scholar
  14. 14.
    Tögel F, Weiss K, Yang Y, Hu Z, Zhang P, Westenfelder C. Vasculotropic, paracrine actions of infused mesenchymal stem cells are important to the recovery from acute kidney injury. Am J Physiol-Renal Physiol. 2007;292(5):F1626–F35.PubMedCrossRefGoogle Scholar
  15. 15.
    van Velthoven CT, Van De Looij Y, Kavelaars A, Zijlstra J, van Bel F, Huppi PS, et al. Mesenchymal stem cells restore cortical rewiring after neonatal ischemia in mice. Ann Neurol. 2012;71(6):785–96.PubMedCrossRefGoogle Scholar
  16. 16.
    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.PubMedCrossRefGoogle Scholar
  17. 17.
    Nomura T, Honmou O, Harada K, Houkin K, Hamada H, Kocsis JIV. infusion of brain-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat. Neuroscience. 2005;136(1):161–9.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Toyama K, Honmou O, Harada K, Suzuki J, Houkin K, Hamada H, et al. Therapeutic benefits of angiogenetic gene-modified human mesenchymal stem cells after cerebral ischemia. Exp Neurol. 2009;216(1):47–55.PubMedCrossRefGoogle Scholar
  19. 19.
    Yu X, Chen D, Zhang Y, Wu X, Huang Z, Zhou H, et al. Overexpression of CXCR4 in mesenchymal stem cells promotes migration, neuroprotection and angiogenesis in a rat model of stroke. J Neurol Sci. 2012;316(1):141–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Phinney DG, Pittenger MF. Concise review: MSC-derived exosomes for cell-free therapy. Stem Cells. 2017;35(4):851–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Zhao Y, Lai W, Xu Y, Li L, Chen Z, Wu W. Exogenous and endogenous therapeutic effects of combination sodium ferulate and bone marrow stromal cells (BMSCs) treatment enhance neurogenesis after rat focal cerebral ischemia. Metab Brain Dis. 2013;28(4):655–66.PubMedCrossRefGoogle Scholar
  22. 22.
    Tsai L-K, Wang Z, Munasinghe J, Leng Y, Leeds P, Chuang D-M. Mesenchymal stem cells primed with valproate and lithium robustly migrate to infarcted regions and facilitate recovery in a stroke model. Stroke. 2011;42(10):2932–9.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Hanabusa K, Nagaya N, Iwase T, Itoh T, Murakami S, Shimizu Y, et al. Adrenomedullin enhances therapeutic potency of mesenchymal stem cells after experimental stroke in rats. Stroke. 2005;36(4):853–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Neuhuber B, Himes BT, Shumsky JS, Gallo G, Fischer I. Axon growth and recovery of function supported by human bone marrow stromal cells in the injured spinal cord exhibit donor variations. Brain Res. 2005;1035(1):73–85.PubMedCrossRefGoogle Scholar
  25. 25.
    Tsai M-J, Tsai S-K, B-R H, Liou D-Y, Huang S-L, Huang M-C, et al. Recovery of neurological function of ischemic stroke by application of conditioned medium of bone marrow mesenchymal stem cells derived from normal and cerebral ischemia rats. J Biomed Sci. 2014;21(1):5.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Hokari M, Kuroda S, Shichinohe H, Yano S, Hida K, Iwasaki Y. Bone marrow stromal cells protect and repair damaged neurons through multiple mechanisms. J Neurosci Res. 2008;86(5):1024–35.PubMedCrossRefGoogle Scholar
  27. 27.
    Tang G, Liu Y, Zhang Z, Lu Y, Wang Y, Huang J, et al. Mesenchymal stem cells maintain blood-brain barrier integrity by inhibiting aquaporin-4 upregulation after cerebral ischemia. Stem Cells. 2014;32(12):3150–62.PubMedCrossRefGoogle Scholar
  28. 28.
    Choi YK, Urnukhsaikhan E, Yoon HH, Seo YK, Park JK. Human mesenchymal stem cell transplantation promote neural differentiation and behavioral performance in the photothrombotic mouse model. Biotechnol J. 2016;11(11):1397–404.Google Scholar
  29. 29.
    Kurozumi KNK, Tamiya T, Kawano Y, Ishii K, Kobune M, Hirai S, et al. Mesenchymal stem cells that produce neurotrophic factors reduce ischemic damage in the rat middle cerebral artery occlusion model. Mol Ther. 2005;11(1):96–104.PubMedCrossRefGoogle Scholar
  30. 30.
    Moisan A, Favre I, Rome C, De Fraipont F, Grillon E, Coquery N, et al. Intravenous injection of clinical grade human MSCs after experimental stroke: functional benefit and microvascular effect. Cell Transplant. 2016;25(12):2157–71.PubMedCrossRefGoogle Scholar
  31. 31.
    Lee N, Jo K, Kim K, Yang J, Chang J, Na D. Intra-arterial delivery of human mesenchymal stem cells into the brains of New Zealand white rabbits. Cytotherapy. 2017;19(5):S201.CrossRefGoogle Scholar
  32. 32.
    Fukuda Y, Horie N, Satoh K, Yamaguchi S, Morofuji Y, Hiu T, et al. Intra-arterial transplantation of low-dose stem cells provides functional recovery without adverse effects after stroke. Cell Mol Neurobiol. 2015;35(3):399–406.PubMedCrossRefGoogle Scholar
  33. 33.
    Park HW, Kim Y, Chang JW, Yang YS, Oh W, Lee JM, et al. Effect of single and double administration of human umbilical cord blood-derived mesenchymal stem cells following focal cerebral ischemia in rats. Experimental Neurobiol. 2017;26(1):55–65.CrossRefGoogle Scholar
  34. 34.
    Nakazaki M, Sasaki M, Kataoka-Sasaki Y, Oka S, Namioka T, Namioka A et al. Intravenous infusion of mesenchymal stem cells inhibits intracranial hemorrhage after recombinant tissue plasminogen activator therapy for transient middle cerebral artery occlusion in rats. J Neurosurg 2017:1-10.Google Scholar
  35. 35.
    Chen J, Zhang ZG, Li Y, Wang L, YX X, Gautam SC, et al. Intravenous administration of human bone marrow stromal cells induces angiogenesis in the ischemic boundary zone after stroke in rats. Circ Res. 2003;92(6):692–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Yavagal DR, Lin B, Raval AP, Garza PS, Dong C, Zhao W, et al. Efficacy and dose-dependent safety of intra-arterial delivery of mesenchymal stem cells in a rodent stroke model. PLoS One. 2014;9(5):e93735.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Toyoshima A, Yasuhara T, Kameda M, Morimoto J, Takeuchi H, Wang F, et al. Intra-arterial transplantation of allogeneic mesenchymal stem cells mounts neuroprotective effects in a transient ischemic stroke model in rats: analyses of therapeutic time window and its mechanisms. PLoS One. 2015;10(6):e0127302.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Feng N, Hao G, Yang F, Qu F, Zheng H, Liang S, et al. Transplantation of mesenchymal stem cells promotes the functional recovery of the central nervous system following cerebral ischemia by inhibiting myelin-associated inhibitor expression and neural apoptosis. Experimental Ther Med. 2016;11(5):1595–600.CrossRefGoogle Scholar
  39. 39.
    Nakajima M, Nito C, Sowa K, Suda S, Nishiyama Y, Nakamura-Takahashi A, et al. Mesenchymal stem cells overexpressing interleukin-10 promote neuroprotection in experimental acute ischemic stroke. Mol Therapy-Methods Clin. 2017;6:102–11.CrossRefGoogle Scholar
  40. 40.
    Wei ZZ, Gu X, Ferdinand A, Lee JH, Ji X, Ji XM, et al. Intranasal delivery of bone marrow mesenchymal stem cells improved neurovascular regeneration and rescued neuropsychiatric deficits after neonatal stroke in rats. Cell Transplant. 2015;24(3):391–402.PubMedCrossRefGoogle Scholar
  41. 41.
    Gutiérrez-Fernández M, Rodríguez-Frutos B, Ramos-Cejudo J, Otero-Ortega L, Fuentes B, Vallejo-Cremades MT, et al. Comparison between xenogeneic and allogeneic adipose mesenchymal stem cells in the treatment of acute cerebral infarct: proof of concept in rats. J Transl Med. 2015;13(1):46.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    He X, Jiang L, Dan Q-Q, Lv Q, Hu Y, Liu J, et al. Bone marrow stromal cells promote neuroplasticity of cerebral ischemic rats via a phosphorylated CRMP2-mediated mechanism. Behav Brain Res. 2017;320:494–503.PubMedCrossRefGoogle Scholar
  43. 43.
    Chen K-H, Chen C-H, Wallace CG, Yuen C-M, Kao G-S, Chen Y-L, et al. Intravenous administration of xenogenic adipose-derived mesenchymal stem cells (ADMSC) and ADMSC-derived exosomes markedly reduced brain infarct volume and preserved neurological function in rat after acute ischemic stroke. Oncotarget. 2016;7(46):74537.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Kasahara Y, Yamahara K, Soma T, Stern DM, Nakagomi T, Matsuyama T, et al. Transplantation of hematopoietic stem cells: intra-arterial versus intravenous administration impacts stroke outcomes in a murine model. Transl Res. 2016;176:69–80.PubMedCrossRefGoogle Scholar
  45. 45.
    Drury-Stewart D, Song M, Mohamad O, Guo Y, Gu X, Chen D, et al. Highly efficient differentiation of neural precursors from human embryonic stem cells and benefits of transplantation after ischemic stroke in mice. Stem Cell Res Ther. 2013;4(4):93.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Bühnemann CSA, Bernreuther C, Malik CY, Braun H, Schachner M, Reymann KG, et al. Neuronal differentiation of transplanted embryonic stem cell-derived precursors in stroke lesions of adult rats. Brain. 2006;129(12):3238–48.PubMedCrossRefGoogle Scholar
  47. 47.
    Chu KPK, Lee ST, Jung KH, Ko SY, Kang L, Sinn DI, et al. Combined treatment of vascular endothelial growth factor and human neural stem cells in experimental focal cerebral ischemia. Neurosci Res. 2005;53:384–90.PubMedCrossRefGoogle Scholar
  48. 48.
    Abeysinghe HC, Bokhari L, Quigley A, Choolani M, Chan J, Dusting GJ, et al. Pre-differentiation of human neural stem cells into GABAergic neurons prior to transplant results in greater repopulation of the damaged brain and accelerates functional recovery after transient ischemic stroke. Stem Cell Res Ther. 2015;6(1):186.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    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. 2014;32(12):3075–87.PubMedCrossRefGoogle Scholar
  50. 50.
    Chen JSP, Li Y, Wang L, Lu M, Willing AE, Sanchez-Ramos J, et al. Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats. Stroke. 2001;32(11):2682–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Napoli E, Borlongan CV. Recent advances in stem cell-based therapeutics for stroke. Springer; 2016.Google Scholar
  52. 52.
    Katakowski M, Chen J, Zhang ZG, Santra M, Wang Y, Chopp M. Stroke-induced subventricular zone proliferation is promoted by tumor necrosis factor-α-converting enzyme protease activity. J Cereb Blood Flow Metab. 2007;27(4):669–78.PubMedCrossRefGoogle Scholar
  53. 53.
    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.PubMedCrossRefGoogle Scholar
  54. 54.
    Mahabadi VP, Movahedin M, Semnanian S, Mirnajafi-zadeh J, Faizi M. vitro differentiation of neural stem cells into noradrenergic-like cells. International Journal of molecular and cellular medicine. 2015;4(1):22.Google Scholar
  55. 55.
    Goh ELK, Ma D, Ming G-L, Song H. Adult neural stem cells and repair of the adult central nervous system. J Hematother Stem Cell Res. 2003;12(6):671–9.PubMedCrossRefGoogle Scholar
  56. 56.
    Andres RH, Horie N, Slikker W, Keren-Gill H, Zhan K, Sun G, et al. Human neural stem cells enhance structural plasticity and axonal transport in the ischaemic brain. Brain. 2011;134(6):1777–89.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Takahashi K, Yasuhara T, Shingo T, Muraoka K, Kameda M, Takeuchi A, et al. Embryonic neural stem cells transplanted in middle cerebral artery occlusion model of rats demonstrated potent therapeutic effects, compared to adult neural stem cells. Brain Res. 2008;1234:172–82.PubMedCrossRefGoogle Scholar
  58. 58.
    Kelly S, Bliss T, Shah A, Sun G, Ma M, Foo W, 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
  59. 59.
    Jin K, Sun Y, Xie L, Mao XO, Childs J, Peel A, et al. Comparison of ischemia-directed migration of neural precursor cells after intrastriatal, intraventricular, or intravenous transplantation in the rat. Neurobiol Dis. 2005;18(2):366–74.PubMedCrossRefGoogle Scholar
  60. 60.
    Jakel RJ, Schneider BL, Svendsen CN. Using human neural stem cells to model neurological disease. Nat Rev Genet. 2004;5(2):136.PubMedCrossRefGoogle Scholar
  61. 61.
    Vroemen M, Aigner L, Winkler J, Weidner N. Adult neural progenitor cell grafts survive after acute spinal cord injury and integrate along axonal pathways. Eur J Neurosci. 2003;18(4):743–51.PubMedCrossRefGoogle Scholar
  62. 62.
    Modo M, Mellodew K, Cash D, Fraser SE, Meade TJ, Price J, et al. Mapping transplanted stem cell migration after a stroke: a serial, in vivo magnetic resonance imaging study. NeuroImage. 2004;21(1):311–7.PubMedCrossRefGoogle Scholar
  63. 63.
    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
  64. 64.
    Hao L, Zou Z, Tian H, Zhang Y, Zhou H, Liu L. Stem cell-based therapies for ischemic stroke. Biomed Res Int. 2014;2014Google Scholar
  65. 65.
    Yanagisawa D, Qi M, Kim D-h, 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.PubMedCrossRefGoogle Scholar
  66. 66.
    Allegrucci C, Y-Z W, Thurston A, Denning CN, Priddle H, Mummery CL, et al. Restriction landmark genome scanning identifies culture-induced DNA methylation instability in the human embryonic stem cell epigenome. Hum Mol Genet. 2007;16(10):1253–68.PubMedCrossRefGoogle Scholar
  67. 67.
    Wei L, Cui L, Snider BJ, Rivkin M, Steven SY, Lee C-S, et al. Transplantation of embryonic stem cells overexpressing Bcl-2 promotes functional recovery after transient cerebral ischemia. Neurobiol Dis. 2005;19(1):183–93.PubMedCrossRefGoogle Scholar
  68. 68.
    Daadi MM, Maag A-L, 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
  69. 69.
    Li Z, McKercher SR, Cui J, Nie Z, Soussou W, Roberts AJ, et al. Myocyte enhancer factor 2C as a neurogenic and antiapoptotic transcription factor in murine embryonic stem cells. J Neurosci. 2008;28(26):6557–68.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Theus MH, Wei L, Cui L, Francis K, Hu X, Keogh C, et al. In vitro hypoxic preconditioning of embryonic stem cells as a strategy of promoting cell survival and functional benefits after transplantation into the ischemic rat brain. Exp Neurol. 2008;210(2):656–70.PubMedCrossRefGoogle Scholar
  71. 71.
    Chen S-J, Chang C-M, Tsai S-K, Chang Y-L, Chou S-J, Huang S-S, 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.PubMedCrossRefGoogle Scholar
  72. 72.
    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.PubMedCrossRefGoogle Scholar
  73. 73.
    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):73–82.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Ziai WC. Hematology and inflammatory signaling of intracerebral hemorrhage. Stroke. 2013;44(6 suppl 1):S74–S8.PubMedCrossRefGoogle Scholar
  75. 75.
    Qin J, Ma X, Qi H, Song B, Wang Y, Wen X, et al. Transplantation of induced pluripotent stem cells alleviates cerebral inflammation and neural damage in hemorrhagic stroke. PLoS One. 2015;10(6):e0129881.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Carmichael ST. Gene expression changes after focal stroke, traumatic brain and spinal cord injuries. Curr Opin Neurol. 2003;16(6):699–704.PubMedCrossRefGoogle Scholar
  77. 77.
    Eckert A, Huang L, Gonzalez R, Kim H-S, Hamblin MH, Lee J-P. Bystander effect fuels human induced pluripotent stem cell-derived neural stem cells to quickly attenuate early stage neurological deficits after stroke. Stem Cells Transl Med. 2015;4(7):841–51.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Guha P, Morgan JW, Mostoslavsky G, Rodrigues NP, Boyd AS. Lack of immune response to differentiated cells derived from syngeneic induced pluripotent stem cells. Cell Stem Cell. 2013;12(4):407–12.PubMedCrossRefGoogle Scholar
  79. 79.
    Sundberg M, Andersson P-H, Åkesson E, Odeberg J, Holmberg L, Inzunza J, et al. Markers of pluripotency and differentiation in human neural precursor cells derived from embryonic stem cells and CNS tissue. Cell Transplant. 2011;20(2):177–91.PubMedCrossRefGoogle Scholar
  80. 80.
    Lees JS, Sena ES, Egan KJ, Antonic A, Koblar SA, Howells DW, et al. Stem cell-based therapy for experimental stroke: a systematic review and meta-analysis. Int J Stroke. 2012;7(7):582–8.PubMedCrossRefGoogle Scholar
  81. 81.
    Bang OY, Kim EH, Cha JM, Moon GJ. Adult stem cell therapy for stroke: challenges and progress. Journal of Stroke. 2016;18(3):256.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Prass K, Meisel C, Höflich C, Braun J, Halle E, Wolf T, et al. Stroke-induced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by poststroke T helper cell type 1–like immunostimulation. J Exp Med. 2003;198(5):725–36.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Courties G, Herisson F, Sager HB, Heidt T, Ye Y, Wei Y, et al. Ischemic stroke activates hematopoietic bone marrow stem cellsnovelty and significance. Circ Res. 2015;116(3):407–17.PubMedCrossRefGoogle Scholar
  84. 84.
    Dunac A, Frelin C, Popolo-Blondeau M, Chatel M, Mahagne MH, Philip PJ-M. Neurological and functional recovery in human stroke are associated with peripheral blood CD34+ cell mobilization. J Neurol. 2007;254(3):327–32.PubMedCrossRefGoogle Scholar
  85. 85.
    Felfly H, Muotri A, Yao H, Haddad GG. Hematopoietic stem cell transplantation protects mice from lethal stroke. Exp Neurol. 2010;225(2):284–93.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Doycheva D, Shih G, Chen H, Applegate R, Zhang JH, Tang J. Granulocyte-colony stimulating factor in combination with stem cell factor confers greater neuroprotection after hypoxic–ischemic brain damage in the neonatal rats than a solitary treatment. Transl Stroke Res. 2013;4(2):171–8.PubMedCrossRefGoogle Scholar
  87. 87.
    Terada N, Hamazaki T, Oka M, Hoki M, Mastalerz DM, Nakano Y, et al. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature. 2002;416(6880):542–5.PubMedCrossRefGoogle Scholar
  88. 88.
    Taguchi A, Nakagomi N, Matsuyama T, Kikuchi-Taura A, Yoshikawa H, Kasahara Y, et al. Circulating CD34-positive cells have prognostic value for neurologic function in patients with past cerebral infarction. J Cereb Blood Flow Metab. 2009;29(1):34–8.PubMedCrossRefGoogle Scholar
  89. 89.
    Garzón-Muvdi T, Quiñones-Hinojosa A. Neural stem cell niches and homing: recruitment and integration into functional tissues. ILAR J. 2010;51(1):3–23.CrossRefGoogle Scholar
  90. 90.
    Yang C, Zhang ZH, Li ZJ, Yang RC, Qian GQ, Han ZC. Enhancement of neovascularization with cord blood CD133^+ cell-derived endothelial progenitor cell transplantation. Thromb Haemostasis-Stuttgart. 2004;91:1202–12.Google Scholar
  91. 91.
    Cho S-W, Moon S-H, Lee S-H, Kang S-W, Kim J, Lim JM, et al. Improvement of postnatal neovascularization by human embryonic stem cell–derived endothelial-like cell transplantation in a mouse model of hindlimb ischemia. Circulation. 2007;116(21):2409–19.PubMedCrossRefGoogle Scholar
  92. 92.
    Li J, Tang Y, Wang Y, Tang R, Jiang W, Yang G-Y, et al. Neurovascular recovery via cotransplanted neural and vascular progenitors leads to improved functional restoration after ischemic stroke in rats. Stem Cell Rep. 2014;3(1):101–14.CrossRefGoogle Scholar
  93. 93.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Tilling L, Chowienczyk P, Clapp B. Progenitors in motion: mechanisms of mobilization of endothelial progenitor cells. Br J Clin Pharmacol. 2009;68(4):484–92.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Ohki Y, Heissig B, Sato Y, Akiyama H, Zhu Z, Hicklin DJ et al. Granulocyte colony-stimulating factor promotes neovascularization by releasing vascular endothelial growth factor from neutrophils. FASEB J 2005;19(14).Google Scholar
  96. 96.
    Taguchi A, Soma T, Tanaka H, Kanda T, Nishimura H, Yoshikawa H, et al. Administration of CD34+ cells after stroke enhances neurogenesis via angiogenesisin a mouse model. J Clin Investig. 2004;114(3):330.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Chen C, Lin X, Wang J, Tang G, Mu Z, Chen X, et al. Effect of HMGB1 on the paracrine action of EPC promotes post-ischemic neovascularization in mice. Stem Cells. 2014;32(10):2679–89.PubMedCrossRefGoogle Scholar
  98. 98.
    Mead B, Logan A, Berry M, Leadbeater W, Scheven BA. Concise review: dental pulp stem cells: a novel cell therapy for retinal and central nervous system repair. Stem Cells. 2017;35(1):61–7.PubMedCrossRefGoogle Scholar
  99. 99.
    Leong WK, Henshall TL, Arthur A, Kremer KL, Lewis MD, Helps SC, et al. Human adult dental pulp stem cells enhance poststroke functional recovery through non-neural replacement mechanisms. Stem Cells Transl Med. 2012;1(3):177–87.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Fang C-z, Yang Y-J, Wang Q-H, Yao Y, Zhang X-Y, He X-H. Intraventricular injection of human dental pulp stem cells improves hypoxic-ischemic brain damage in neonatal rats. PLoS One. 2013;8(6):e66748.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Pimentel-Coelho PM, Mendez-Otero R. Cell therapy for neonatal hypoxic–ischemic encephalopathy. Stem Cells Dev. 2010;19(3):299–310.PubMedCrossRefGoogle Scholar
  102. 102.
    Park KI, Lachyankar M, Nissim S, Snyder EY. Neural stem cells for CNS repair: state of the art and future directions. Lacrimal Gland Tear Film and Dry Eye Syndromes 3. Springer; 2002. p. 1291-6.Google Scholar
  103. 103.
    Englund U, Björklund A, Wictorin K, Lindvall O, Kokaia M. Grafted neural stem cells develop into functional pyramidal neurons and integrate into host cortical circuitry. Proc Natl Acad Sci. 2002;99(26):17089–94.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Titomanlio L, Kavelaars A, Dalous J, Mani S, El Ghouzzi V, Heijnen C, et al. Stem cell therapy for neonatal brain injury: perspectives and challenges. Ann Neurol. 2011;70(5):698–712.PubMedCrossRefGoogle Scholar
  105. 105.
    Fujiwara Y, Tanaka N, Ishida O, Fujimoto Y, Murakami T, Kajihara H, et al. Intravenously injected neural progenitor cells of transgenic rats can migrate to the injured spinal cord and differentiate into neurons, astrocytes and oligodendrocytes. Neurosci Lett. 2004;366(3):287–91.PubMedCrossRefGoogle Scholar
  106. 106.
    Ourednik J, Ourednik V, Lynch WP, Schachner M, Snyder EY. Neural stem cells display an inherent mechanism for rescuing dysfunctional neurons. Nat Biotechnol. 2002;20(11):1103–10.PubMedCrossRefGoogle Scholar
  107. 107.
    Pluchino S, Quattrini A, Brambilla E, Gritti A. Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature. 2003;422(6933):688.PubMedCrossRefGoogle Scholar
  108. 108.
    Liska MG, Crowley MG, Borlongan CV. Regulated and unregulated clinical trials of stem cell therapies for stroke. Transl Stroke Res. 2017;8(2):293–103.CrossRefGoogle Scholar
  109. 109.
    Aharonowiz M, Einstein O, Fainstein N, Lassmann H, Reubinoff B, Ben-Hur T. Neuroprotective effect of transplanted human embryonic stem cell-derived neural precursors in an animal model of multiple sclerosis. PLoS One. 2008;3(9):e3145.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Ben-Hur T. Immunomodulation by neural stem cells. J Neurol Sci. 2008;265(1):102–4.PubMedCrossRefGoogle Scholar
  111. 111.
    Einstein O, Ben-Hur T. The changing face of neural stem cell therapy in neurologic diseases. Arch Neurol. 2008;65(4):452–6.PubMedCrossRefGoogle Scholar
  112. 112.
    Locatelli F, Bersano A, Ballabio E, Lanfranconi S, Papadimitriou D, Strazzer S, et al. Stem cell therapy in stroke. Cell Mol Life Sci. 2009;66(5):757–72.PubMedCrossRefGoogle Scholar
  113. 113.
    Bacigaluppi M, Pluchino S, Jametti LP, Kilic E, Kilic Ü, Salani G, et al. Delayed post-ischaemic neuroprotection following systemic neural stem cell transplantation involves multiple mechanisms. Brain. 2009;132(8):2239–51.PubMedCrossRefGoogle Scholar
  114. 114.
    Pluchino S, Cusimano M, Bacigaluppi M, Martino G. Remodelling the injured CNS through the establishment of atypical ectopic perivascular neural stem cell niches. Arch Ital Biol. 2010;148(2):173–83.PubMedGoogle Scholar
  115. 115.
    Lee S-T, Chu K, Jung K-H, Kim S-J, Kim D-H, Kang K-M, et al. Anti-inflammatory mechanism of intravascular neural stem cell transplantation in haemorrhagic stroke. Brain. 2007;131(3):616–29.PubMedCrossRefGoogle Scholar
  116. 116.
    Prowse AB, Chong F, Gray PP, Munro TP. Stem cell integrins: implications for ex-vivo culture and cellular therapies. Stem Cell Res. 2011;6(1):1–12.PubMedCrossRefGoogle Scholar
  117. 117.
    Yasuhara T, Hara K, Maki M, Xu L, Yu G, Ali M, et al. Mannitol facilitates neurotrophic factor up-regulation and behavioural recovery in neonatal hypoxic-ischaemic rats with human umbilical cord blood grafts. J Cell Mol Med. 2010;14(4):914–21.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Vendrame M, Gemma C, Pennypacker KR, Bickford PC, Sanberg CD, Sanberg PR, et al. Cord blood rescues stroke-induced changes in splenocyte phenotype and function. Exp Neurol. 2006;199(1):191–200.PubMedCrossRefGoogle Scholar
  119. 119.
    Yang M, Wei X, Li J, Heine LA, Rosenwasser R, Iacovitti L. Changes in host blood factors and brain glia accompanying the functional recovery after systemic administration of bone marrow stem cells in ischemic stroke rats. Cell Transplant. 2010;19(9):1073–84.PubMedCrossRefGoogle Scholar
  120. 120.
    Keirstead HS, Nistor G, Bernal G, Totoiu M, Cloutier F, Sharp K, et al. Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci. 2005;25(19):4694–705.PubMedCrossRefGoogle Scholar
  121. 121.
    Borlongan CV, Hadman M, Sanberg CD, Sanberg PR. Central nervous system entry of peripherally injected umbilical cord blood cells is not required for neuroprotection in stroke. Stroke. 2004;35(10):2385–9.PubMedCrossRefGoogle Scholar
  122. 122.
    Sheikh AM, Nagai A, Wakabayashi K, Narantuya D, Kobayashi S, Yamaguchi S, et al. Mesenchymal stem cell transplantation modulates neuroinflammation in focal cerebral ischemia: contribution of fractalkine and IL-5. Neurobiol Dis. 2011;41(3):717–24.PubMedCrossRefGoogle Scholar
  123. 123.
    McGuckin CP, Jurga M, Miller A-M, Sarnowska A, Wiedner M, Boyle NT, et al. Ischemic brain injury: a consortium analysis of key factors involved in mesenchymal stem cell-mediated inflammatory reduction. Arch Biochem Biophys. 2013;534(1):88–97.PubMedCrossRefGoogle Scholar
  124. 124.
    Chang D-J, Lee N, Park I-H, Choi C, Jeon I, Kwon J, et al. Therapeutic potential of human induced pluripotent stem cells in experimental stroke. Cell Transplant. 2013;22(8):1427–40.PubMedCrossRefGoogle Scholar
  125. 125.
    Franco EC, Cardoso MM, Gouvêia A, Pereira A, Gomes-Leal W. Modulation of microglial activation enhances neuroprotection and functional recovery derived from bone marrow mononuclear cell transplantation after cortical ischemia. Neurosci Res. 2012;73(2):122–32.PubMedCrossRefGoogle Scholar
  126. 126.
    Hirko AC, Dallasen R, Jomura S, Xu Y. Modulation of inflammatory responses after global ischemia by transplanted umbilical cord matrix stem cells. Stem Cells. 2008;26(11):2893–901.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Pluchino S, Muzio L, Imitola J, Deleidi M, Alfaro-Cervello C, Salani G, et al. Persistent inflammation alters the function of the endogenous brain stem cell compartment. Brain. 2008:2564–78.Google Scholar
  128. 128.
    Takagi T, Yoshimura S, Sakuma R, Nakano-Doi A, Matsuyama T, Nakagomi T. Novel regenerative therapies based on regionally induced multipotent stem cells in post-stroke brains: their origin, characterization, and perspective. Transl Stroke Res 2017. doi:  https://doi.org/10.1007/s12975-017-0556-0. .
  129. 129.
    Rodríguez-Frutos B, Otero-Ortega L, Gutiérrez-Fernández M, Fuentes B, Ramos-Cejudo J, Díez-Tejedor E. Stem cell therapy and administration routes after stroke. Transl Stroke Res. 2016;7(5):378–87.PubMedCrossRefGoogle Scholar
  130. 130.
    Ikehara S. Grand challenges in stem cell treatments. Front Cell Dev Biol. 2013;1:2.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Delavaran H, Aked J, Sjunnesson H, Lindvall O, Norrving B, Kokaia Z et al. Spontaneous recovery of upper extremity motor impairment after ischemic stroke: implications for stem cell-based therapeutic approaches. Transl Stroke Res 2017:1-11.Google Scholar
  132. 132.
    Karp JM, Teo GSL. Mesenchymal stem cell homing: the devil is in the details. Cell Stem Cell. 2009;4(3):206–16.PubMedCrossRefGoogle Scholar
  133. 133.
    Chang YS, Ahn SY, Sung S, Park WS. Stem cell therapy for neonatal disorders: prospects and challenges. Yonsei Med J. 2017;58(2):266–71.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Sasaki M, Abe R, Fujita Y, Ando S, Inokuma D, Shimizu H. Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type. J Immunol. 2008;180(4):2581–7.PubMedCrossRefGoogle Scholar
  135. 135.
    Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood. 2007;110(10):3499–506.PubMedCrossRefGoogle Scholar
  136. 136.
    Chen J, Li Y, Wang L, Lu M, Zhang X, Chopp M. Therapeutic benefit of intracerebral transplantation of bone marrow stromal cells after cerebral ischemia in rats. J Neurol Sci. 2001;189(1):49–57.PubMedCrossRefGoogle Scholar
  137. 137.
    Chopp M, Li Y. Treatment of neural injury with marrow stromal cells. Lancet Neurol. 2002;1(2):92–100.PubMedCrossRefGoogle Scholar
  138. 138.
    Li Y, Chopp M, Chen J, Wang L, Gautam SC, Y-X X, 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.PubMedCrossRefGoogle Scholar
  139. 139.
    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
  140. 140.
    Vendrame M, Cassady J, Newcomb J, Butler T, Pennypacker KR, Zigova T, et al. Infusion of human umbilical cord blood cells in a rat model of stroke dose-dependently rescues behavioral deficits and reduces infarct volume. Stroke. 2004;35(10):2390–5.PubMedCrossRefGoogle Scholar
  141. 141.
    Yasuhara T, Matsukawa N, Yu G, Xu L, Mays RW, Kovach J, et al. Behavioral and histological characterization of intrahippocampal grafts of human bone marrow-derived multipotent progenitor cells in neonatal rats with hypoxic-ischemic injury. Cell Transplant. 2006;15(3):231–8.PubMedCrossRefGoogle Scholar
  142. 142.
    Schwarz SC, Schwarz J. Translation of stem cell therapy for neurological diseases. Transl Res. 2010;156(3):155–60.PubMedCrossRefGoogle Scholar
  143. 143.
    Janowski M, Lyczek A, Engels C, Xu J, Lukomska B, Bulte JW, et al. Cell size and velocity of injection are major determinants of the safety of intracarotid stem cell transplantation. J Cereb Blood Flow Metab. 2013;33(6):921–7.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Chen C, Lee Y, Chiu S, Shyu W, Lee M, Huang S, et al. The application of stem cells in the treatment of ischemic diseases. Histol Histopathol. 2006;21(10/12):1209.PubMedGoogle Scholar
  145. 145.
    Newcomb JD, Ajmo Jr CT, Sanberg CD, Sanberg PR, Pennypacker KR, Willing AE. Timing of cord blood treatment after experimental stroke determines therapeutic efficacy. Cell Transplant. 2006;15(3):213–23.PubMedCrossRefGoogle Scholar
  146. 146.
    Savitz SI, Dinsmore J, Wu J, Henderson GV, Stieg P, Caplan LR. Neurotransplantation of fetal porcine cells in patients with basal ganglia infarcts: a preliminary safety and feasibility study. Cerebrovasc Dis. 2005;20(2):101–7.PubMedCrossRefGoogle Scholar
  147. 147.
    Lindvall O, Kokaia Z. Stem cells for the treatment of neurological disorders. Nature. 2006;441(7097):1094.PubMedCrossRefGoogle Scholar
  148. 148.
    Smith EJ, Stroemer RP, Gorenkova N, Nakajima M, Crum WR, Tang E, et al. Implantation site and lesion topology determine efficacy of a human neural stem cell line in a rat model of chronic stroke. Stem Cells. 2012;30(4):785–96.PubMedCrossRefGoogle Scholar
  149. 149.
    Barbash IM, Chouraqui P, Baron J, Feinberg MS, Etzion S, Tessone A, et al. Systemic delivery of bone marrow–derived mesenchymal stem cells to the infarcted myocardium. Circulation. 2003;108(7):863–8.PubMedCrossRefGoogle Scholar
  150. 150.
    Aslam M, Baveja R, Liang OD, Fernandez-Gonzalez A, Lee C, Mitsialis SA, et al. Bone marrow stromal cells attenuate lung injury in a murine model of neonatal chronic lung disease. Am J Respir Crit Care Med. 2009;180(11):1122–30.PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Ishizaka S, Horie N, Satoh K, Fukuda Y, Nishida N, Nagata I. Intra-arterial cell transplantation provides timing-dependent cell distribution and functional recovery after stroke. Stroke. 2013;44(3):720–6.PubMedCrossRefGoogle Scholar
  152. 152.
    Chua JY, Pendharkar AV, Wang N, Choi R, Andres RH, Gaeta X, et al. Intra-arterial injection of neural stem cells using a microneedle technique does not cause microembolic strokes. J Cereb Blood Flow Metab. 2011;31(5):1263–71.PubMedCrossRefGoogle Scholar
  153. 153.
    Danielyan L, Schäfer R, von Ameln-Mayerhofer A, Buadze M, Geisler J, Klopfer T, et al. Intranasal delivery of cells to the brain. Eur J Cell Biol. 2009;88(6):315–24.PubMedCrossRefGoogle Scholar
  154. 154.
    Savitz SI, Rosenbaum DM, Dinsmore JH, Wechsler LR, Caplan LR. Cell transplantation for stroke. Ann Neurol. 2002;52(3):266–75.PubMedCrossRefGoogle Scholar
  155. 155.
    Hadani M, Freeman T, Munsiff A, Young W, Flamm E. Fetal cortical cells survive in focal cerebral infarct after permanent occlusion of the middle cerebral artery in adult rats. J Neurotrauma. 1992;9(2):107–12.PubMedCrossRefGoogle Scholar
  156. 156.
    Veizovic T, Beech JS, Stroemer RP, Watson WP, Hodges H. Resolution of stroke deficits following contralateral grafts of conditionally immortal neuroepithelial stem cells. Stroke. 2001;32(4):1012–9.PubMedCrossRefGoogle Scholar
  157. 157.
    Back SA, Han BH, Luo NL, Chricton CA, Xanthoudakis S, Tam J, et al. Selective vulnerability of late oligodendrocyte progenitors to hypoxia–ischemia. J Neurosci. 2002;22(2):455–63.PubMedGoogle Scholar
  158. 158.
    Plate KH. Mechanisms of angiogenesis in the brain. J Neuropathol Exp Neurol. 1999;58(4):313–20.PubMedCrossRefGoogle Scholar
  159. 159.
    Krupinski J, Kaluza J, Kumar P, Kumar S, Wang JM. Role of angiogenesis in patients with cerebral ischemic stroke. Stroke. 1994;25(9):1794–8.PubMedCrossRefGoogle Scholar
  160. 160.
    Wei L, Erinjeri JP, Rovainen CM, Woolsey TA. Collateral growth and angiogenesis around cortical stroke. Stroke. 2001;32(9):2179–84.PubMedCrossRefGoogle Scholar
  161. 161.
    Rafii S, Lyden D. Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nat Med. 2003;9(6):702–12.PubMedCrossRefGoogle Scholar
  162. 162.
    Thored P, Wood J, Arvidsson A, Cammenga J, Kokaia Z, Lindvall O. Long-term neuroblast migration along blood vessels in an area with transient angiogenesis and increased vascularization after stroke. Stroke. 2007;38(11):3032–9.PubMedCrossRefGoogle Scholar
  163. 163.
    Teng H, Zhang ZG, Wang L, Zhang RL, Zhang L, Morris D, et al. Coupling of angiogenesis and neurogenesis in cultured endothelial cells and neural progenitor cells after stroke. J Cereb Blood Flow Metab. 2008;28(4):764–71.PubMedCrossRefGoogle Scholar
  164. 164.
    Caplan AI, Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell Biochem. 2006;98(5):1076–84.PubMedCrossRefGoogle Scholar
  165. 165.
    Spaggiari GM, Capobianco A, Abdelrazik H, Becchetti F, Mingari MC, Moretta L. Mesenchymal stem cells inhibit natural killer–cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2, 3-dioxygenase and prostaglandin E2. Blood. 2008;111(3):1327–33.PubMedCrossRefGoogle Scholar
  166. 166.
    Van Sandwijk M, Bemelman F, Ten Berge I. Immunosuppressive drugs after solid organ transplantation. Neth J Med. 2013;71(6):281–9.PubMedGoogle Scholar
  167. 167.
    Carson CT, Aigner S, Gage FH. Stem cells: the good, bad and barely in control. Nat Med. 2006;12(11):1237–8.PubMedCrossRefGoogle Scholar
  168. 168.
    Erdö F, Bührle 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.PubMedCrossRefGoogle Scholar
  169. 169.
    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.PubMedCrossRefGoogle Scholar
  170. 170.
    Lepore A, Neuhuber B, Connors T, Han S, Liu Y, Daniels M, et al. Long-term fate of neural precursor cells following transplantation into developing and adult CNS. Neuroscience. 2006;142(1):287–304.PubMedCrossRefGoogle Scholar
  171. 171.
    Hess PG. Risk of tumorigenesis in first-in-human trials of embryonic stem cell neural derivatives: ethics in the face of long-term uncertainty. Account Res. 2009;16(4):175–98.PubMedCrossRefGoogle Scholar
  172. 172.
    Low CB, Liou YC, Tang BL. Neural differentiation and potential use of stem cells from the human umbilical cord for central nervous system transplantation therapy. J Neurosci Res. 2008;86(8):1670–9.PubMedCrossRefGoogle Scholar
  173. 173.
    Gruen L, Grabel L. Concise review: scientific and ethical roadblocks to human embryonic stem cell therapy. Stem Cells. 2006;24(10):2162–9.PubMedCrossRefGoogle Scholar
  174. 174.
    Chen J, Ye X, Yan T, Zhang C, Yang X-P, Cui X, et al. Adverse effects of bone marrow stromal cell treatment of stroke in diabetic rats. Stroke. 2011;42(12):3551–8.PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Popa-Wagner A, Buga A-M, Doeppner TR, Hermann DM. Stem cell therapies in preclinical models of stroke associated with aging. Front Cell Neurosci. 2014;8Google Scholar
  176. 176.
    Li F, Guo X, Chen SY. Function and therapeutic potential of mesenchymal stem cells in atherosclerosis. Frontiers Cardiovasc Med. 2017;4(32):1–10.Google Scholar
  177. 177.
    Angelini A, Castellani C, Ravara B, Franzin C, Pozzobon M, Tavano R, et al. Stem-cell therapy in an experimental model of pulmonary hypertension and right heart failure: role of paracrine and neurohormonal milieu in the remodeling process. J Heart and Lung Transplant. 2011;30(11):1281–93.CrossRefGoogle Scholar
  178. 178.
    Kim H, Cooke MJ, Shoichet MS. Creating permissive microenvironments for stem cell transplantation into the central nervous system. Trends Biotechnol. 2012;30(1):55–63.PubMedCrossRefGoogle Scholar
  179. 179.
    Dooley D, Vidal P, Hendrix S. Immunopharmacological intervention for successful neural stem cell therapy: new perspectives in CNS neurogenesis and repair. Pharmacol Ther. 2014;141(1):21–31.PubMedCrossRefGoogle Scholar
  180. 180.
    Wei L, Fraser JL, Z-Y L, Hu X, Yu SP. Transplantation of hypoxia preconditioned bone marrow mesenchymal stem cells enhances angiogenesis and neurogenesis after cerebral ischemia in rats. Neurobiol Dis. 2012;46(3):635–45.PubMedPubMedCentralCrossRefGoogle Scholar
  181. 181.
    SP Y, Wei Z, Wei L. Preconditioning strategy in stem cell transplantation therapy. Transl Stroke Res. 2013;4(1):76–88.CrossRefGoogle Scholar
  182. 182.
    Zhang J, Chen G, Wang Y, Zhao J, Duan H, Liao L, et al. Hydrogen peroxide preconditioning enhances the therapeutic efficacy of Wharton’s Jelly mesenchymal stem cells after myocardial infarction. Chin Med J. 2012;125(19):3472–8.PubMedGoogle Scholar
  183. 183.
    Feng Y, Huang W, Meng W, Jegga AG, Wang Y, Cai W, et al. Heat shock improves Sca-1+ stem cell survival and directs ischemic cardiomyocytes toward a prosurvival phenotype via exosomal transfer: a critical role for HSF1/miR-34a/HSP70 pathway. Stem Cells. 2014;32(2):462–72.PubMedPubMedCentralCrossRefGoogle Scholar
  184. 184.
    Rosenblum S, Smith TN, Wang N, Chua JY, Westbroek E, Wang K, et al. BDNF pretreatment of human embryonic-derived neural stem cells improves cell survival and functional recovery after transplantation in hypoxic-ischemic stroke. Cell Transplant. 2015;24(12):2449–61.PubMedCrossRefGoogle Scholar
  185. 185.
    Petridis AK, El Maarouf A. Brain-derived neurotrophic factor levels influence the balance of migration and differentiation of subventricular zone cells, but not guidance to the olfactory bulb. J Clin Neurosci. 2011;18(2):265–70.PubMedCrossRefGoogle Scholar
  186. 186.
    Doeppner TR, Ewert TA, Tönges L, Herz J, Zechariah A, El Ali A, et al. Transduction of neural precursor cells with TAT-heat shock protein 70 chaperone: therapeutic potential against ischemic stroke after intrastriatal and systemic transplantation. Stem Cells. 2012;30(6):1297–310.PubMedCrossRefGoogle Scholar
  187. 187.
    McGinley LM, McMahon J, Stocca A, Duffy A, Flynn A, O'Toole D, et al. Mesenchymal stem cell survival in the infarcted heart is enhanced by lentivirus vector-mediated heat shock protein 27 expression. Hum Gene Ther. 2013;24(10):840–51.PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Bruey J-M, Ducasse C, Bonniaud P, Ravagnan L, Susin SA, Diaz-Latoud C, et al. Hsp27 negatively regulates cell death by interacting with cytochrome c. Nat Cell Biol. 2000;2(9):645.PubMedCrossRefGoogle Scholar
  189. 189.
    Hino M, Kurogi K, Okubo M-A, Murata-Hori M, Hosoya H. Small heat shock protein 27 (HSP27) associates with tubulin/microtubules in HeLa cells. Biochem Biophys Res Commun. 2000;271(1):164–9.PubMedCrossRefGoogle Scholar
  190. 190.
    Lavoie JN, Hickey E, Weber LA, Landry J. Modulation of actin microfilament dynamics and fluid phase pinocytosis by phosphorylation of heat shock protein 27. J Biol Chem. 1993;268(32):24210–4.PubMedGoogle Scholar
  191. 191.
    Perng MD, Cairns L, van den lJssel P, Prescott A, Hutcheson AM, Quinlan RA. Intermediate filament interactions can be altered by HSP27 and alphaB-crystallin. J Cell Sci. 1999;112(13):2099–112.PubMedGoogle Scholar
  192. 192.
    Ni X, Ou C, Guo J, Liu B, Zhang J, Wu Z, et al. Lentiviral vector-mediated co-overexpression of VEGF and Bcl-2 improves mesenchymal stem cell survival and enhances paracrine effects in vitro. Int J Mol Med. 2017;40(2):418–26.PubMedPubMedCentralGoogle Scholar
  193. 193.
    Haider HK, Jiang S, Idris NM, Ashraf M. IGF-1–overexpressing mesenchymal stem cells accelerate bone marrow stem cell mobilization via paracrine activation of SDF-1α/CXCR4 signaling to promote myocardial repair. Circ Res. 2008;103(11):1300–8.PubMedCrossRefGoogle Scholar
  194. 194.
    Fiedler J, Brill C, Blum WF, Brenner RE. IGF-I and IGF-II stimulate directed cell migration of bone-marrow-derived human mesenchymal progenitor cells. Biochem Biophys Res Commun. 2006;345(3):1177–83.PubMedCrossRefGoogle Scholar
  195. 195.
    Song H, Song B-W, Cha M-J, Choi I-G, Hwang K-C. Modification of mesenchymal stem cells for cardiac regeneration. Expert Opin Biol Ther. 2010;10(3):309–19.PubMedCrossRefGoogle Scholar
  196. 196.
    Brunt KR, Wu J, Chen Z, Poeckel D, Dercho RA, Melo LG, et al. Ex vivo Akt/HO-1 gene therapy to human endothelial progenitor cells enhances myocardial infarction recovery. Cell Transplant. 2012;21(7):1443–61.PubMedCrossRefGoogle Scholar
  197. 197.
    Zimmermann W-H, Melnychenko I, Eschenhagen T. Engineered heart tissue for regeneration of diseased hearts. Biomater. 2004;25(9):1639–47.CrossRefGoogle Scholar
  198. 198.
    Jin J, Jeong SI, Shin YM, Lim KS, Lee YM, Koh HC, et al. Transplantation of mesenchymal stem cells within a poly (lactide-co-ɛ-caprolactone) scaffold improves cardiac function in a rat myocardial infarction model. Eur J Heart Fail. 2009;11(2):147–53.PubMedPubMedCentralCrossRefGoogle Scholar
  199. 199.
    Rustad KC, Wong VW, Sorkin M, Glotzbach JP, Major MR, Rajadas J, et al. Enhancement of mesenchymal stem cell angiogenic capacity and stemness by a biomimetic hydrogel scaffold. Biomater. 2012;33(1):80–90.CrossRefGoogle Scholar
  200. 200.
    McCreedy D, Wilems T, Xu H, Butts J, Brown C, Smith A, et al. Survival, differentiation, and migration of high-purity mouse embryonic stem cell-derived progenitor motor neurons in fibrin scaffolds after sub-acute spinal cord injury. Biomater Sci. 2014;2(11):1672–82.PubMedPubMedCentralCrossRefGoogle Scholar
  201. 201.
    Feng J-F, Liu J, Zhang L, Jiang J-Y, Russell M, Lyeth BG, et al. Electrical guidance of human stem cells in the rat brain. Stem Cell Rep. 2017;9(1):177–89.CrossRefGoogle Scholar
  202. 202.
    Won Y-W, Patel AN, Bull DA. Cell surface engineering to enhance mesenchymal stem cell migration toward an SDF-1 gradient. Biomaterials. 2014;35(21):5627–35.PubMedCrossRefGoogle Scholar
  203. 203.
    Landázuri N, Tong S, Suo J, Joseph G, Weiss D, Sutcliffe DJ, et al. Magnetic targeting of human mesenchymal stem cells with internalized superparamagnetic iron oxide nanoparticles. Small. 2013;9(23):4017–26.PubMedCrossRefGoogle Scholar
  204. 204.
    Takada Y, Ye X, Simon S. The integrins. Genome Biol. 2007;8(5):215.PubMedPubMedCentralCrossRefGoogle Scholar
  205. 205.
    Liu H, Liu S, Li Y, Wang X, Xue W, Ge G, et al. The role of SDF-1-CXCR4/CXCR7 axis in the therapeutic effects of hypoxia-preconditioned mesenchymal stem cells for renal ischemia/reperfusion injury. PLoS One. 2012;7(4):e34608.PubMedPubMedCentralCrossRefGoogle Scholar
  206. 206.
    Wang Z, Wang Y, Wang Z, Gutkind JS, Wang Z, Wang F, et al. Engineered mesenchymal stem cells with enhanced tropism and paracrine secretion of cytokines and growth factors to treat traumatic brain injury. Stem Cells. 2015;33(2):456–67.PubMedCrossRefGoogle Scholar
  207. 207.
    Daadi MM, Klausner JQ, Bajar B, Goshen I, Lee-Messer C, Lee SY, et al. Optogenetic stimulation of neural grafts enhances neurotransmission and downregulates the inflammatory response in experimental stroke model. Cell Transplant. 2016;25(7):1371–80.PubMedCrossRefGoogle Scholar
  208. 208.
    Modo M, Beech J, Meade T, Williams S, Price JA. A chronic 1 year assessment of MRI contrast agent-labelled neural stem cell transplants in stroke. NeuroImage. 2009;47(02):T133–42.PubMedCrossRefGoogle Scholar
  209. 209.
    Bulte JW. In vivo MRI cell tracking: clinical studies. Am J Roentgenol. 2009;193(2):314–25.CrossRefGoogle Scholar
  210. 210.
    Gu E, Chen W-Y, Gu J, Burridge P, Wu JC. Molecular imaging of stem cells: tracking survival, biodistribution, tumorigenicity, and immunogenicity. Theranostics. 2012;2(4):335.PubMedPubMedCentralCrossRefGoogle Scholar
  211. 211.
    Wang Y-XJ. Superparamagnetic iron oxide based MRI contrast agents: current status of clinical application. Quant Imaging in Med Surg. 2011;1(1):35.Google Scholar
  212. 212.
    Sutton EJ, Boddington SE, Nedopil AJ, Henning TD, Demos SG, Baehner R, et al. An optical imaging method to monitor stem cell migration in a model of immune-mediated arthritis. Opt Express. 2009;17(26):24403–13.PubMedPubMedCentralCrossRefGoogle Scholar
  213. 213.
    Cen P, Chen J, Hu C, Fan L, Wang J, Li L. Noninvasive in-vivo tracing and imaging of transplanted stem cells for liver regeneration. Stem Cell Res Ther. 2016;7(1):143.PubMedPubMedCentralCrossRefGoogle Scholar
  214. 214.
    Kitchener Wilson JY, Lee A, Wu JC. In vitro and in vivo bioluminescence reporter gene imaging of human embryonic stem cells. J Visualized Experiments: JOVE. 2008;14Google Scholar
  215. 215.
    Shah K, Hingtgen S, Kasmieh R, Figueiredo JL, Garcia-Garcia E, Martinez-Serrano A, et al. Bimodal viral vectors and in vivo imaging reveal the fate of human neural stem cells in experimental glioma model. J Neurosci. 2008;28(17):4406–13.PubMedPubMedCentralCrossRefGoogle Scholar
  216. 216.
    Shanthly N, Aruva M, Zhang K, Mathew B, Thakur M. Stem cells: a regenerative pharmaceutical. Q J Nuc Med Mol Imaging. 2006;50(3):205.Google Scholar
  217. 217.
    Hong H, Yang Y, Zhang Y, Cai W. Non-invasive imaging of human embryonic stem cells. Curr Pharm Biotechnol. 2010;11(6):685–92.PubMedPubMedCentralCrossRefGoogle Scholar
  218. 218.
    Massoud TF, Gambhir SS. Molecular imaging in living subjects: seeing fundamental biological processes in a new light. Genes Dev. 2003;17(5):545–80.PubMedCrossRefGoogle Scholar
  219. 219.
    Nguyen PK, Riegler J, Wu JC. Stem cell imaging: from bench to bedside. Cell Stem Cell. 2014;14(4):431–44.PubMedPubMedCentralCrossRefGoogle Scholar
  220. 220.
    Bang OY. Clinical trials of adult stem cell therapy in patients with ischemic stroke. J Clin Neurol. 2016;12(1):14–20.PubMedCrossRefGoogle Scholar
  221. 221.
    Honmou O, Houkin K, Matsunaga T, Niitsu Y, Ishiai S, Onodera R, et al. Intravenous administration of auto serum-expanded autologous mesenchymal stem cells in stroke. Brain. 2011;134(6):1790–807.PubMedPubMedCentralCrossRefGoogle Scholar
  222. 222.
    Sharma A, Sane H, Gokulchandran N, Khopkar D, Paranjape A, Sundaram J et al. Autologous bone marrow mononuclear cells intrathecal transplantation in chronic stroke. Stroke Res Treat 2014;2014.Google Scholar
  223. 223.
    Taguchi A, Sakai C, Soma T, Kasahara Y, Stern DM, Kajimoto K, et al. Intravenous autologous bone marrow mononuclear cell transplantation for stroke: phase1/2a clinical trial in a homogeneous group of stroke patients. Stem Cells Dev. 2015;24(19):2207–18.PubMedPubMedCentralCrossRefGoogle Scholar
  224. 224.
    Vu Q, Xie K, Eckert M, Zhao W, Cramer SC. Meta-analysis of preclinical studies of mesenchymal stromal cells for ischemic stroke. Neurology. 2014;82(14):1277–86.PubMedPubMedCentralCrossRefGoogle Scholar
  225. 225.
    Jeong H, Yim HW, Cho Y-S, Kim Y-I, Jeong S-N, Kim H-B, et al. Efficacy and safety of stem cell therapies for patients with stroke: a systematic review and single arm meta-analysis. Int J Stem Cells. 2014;7(2):63.PubMedPubMedCentralCrossRefGoogle Scholar
  226. 226.
    Kalladka D, Sinden J, Pollock K, Haig C, McLean J, Smith W, et al. Human neural stem cells in patients with chronic ischaemic stroke (PISCES): a phase 1, first-in-man study. Lancet. 2016;388(10046):787–96.PubMedCrossRefGoogle Scholar
  227. 227.
    Cassidy JM, Cramer SC. Spontaneous and therapeutic-induced mechanisms of functional recovery after stroke. Transl Stroke Res. 2017;8(1):33–46.PubMedCrossRefGoogle Scholar
  228. 228.
    Xin H, Li Y, Liu Z, Wang X, Shang X, Cui Y, et al. MiR-133b promotes neural plasticity and functional recovery after treatment of stroke with multipotent mesenchymal stromal cells in rats via transfer of exosome-enriched extracellular particles. Stem Cells. 2013;31(12):2737–46.PubMedPubMedCentralCrossRefGoogle Scholar
  229. 229.
    Xin H, Li Y, Chopp M. Exosomes/miRNAs as mediating cell-based therapy of stroke. Front Cell Neurosci. 2014;8:337.Google Scholar
  230. 230.
    Gong M, Yu B, Wang J, Wang Y, Liu M, Paul C et al. Mesenchymal stem cells release exosomes that transfer miRNAs to endothelial cells and promote angiogenesis. Oncotarget 2017;5.Google Scholar
  231. 231.
    Anderson JD, Johansson HJ, Graham CS, Vesterlund M, Pham MT, Bramlett CS, et al. Comprehensive proteomic analysis of mesenchymal stem cell exosomes reveals modulation of angiogenesis via nuclear factor-KappaB signaling. Stem Cells. 2016;34(3):601–13.PubMedCrossRefGoogle Scholar
  232. 232.
    Xin H, Li Y, Cui Y, Yang JJ, Zhang ZG, Chopp M. Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J Cereb Blood Flow Metab. 2013;33(11):1711–5.PubMedPubMedCentralCrossRefGoogle Scholar
  233. 233.
    Doeppner TR, Traut V, Heidenreich A, Kaltwasser B, Bosche B, Bähr M, et al. Conditioned medium derived from neural progenitor cells induces long-term post-ischemic neuroprotection, sustained neurological recovery, neurogenesis, and angiogenesis. Mol Neurobiol. 2017;54(2):1531–40.PubMedCrossRefGoogle Scholar
  234. 234.
    Zhao Q, Hu J, Xiang J, Gu Y, Jin P, Hua F, et al. Intranasal administration of human umbilical cord mesenchymal stem cells-conditioned medium enhances vascular remodeling after stroke. Brain Res. 2015;1624:489–96.PubMedCrossRefGoogle Scholar
  235. 235.
    Cui X, Chopp M, Shehadah A, Zacharek A, Kuzmin-Nichols N, Sanberg CD, et al. Therapeutic benefit of treatment of stroke with simvastatin and human umbilical cord blood cells: neurogenesis, synaptic plasticity, and axon growth. Cell Transplant. 2012;21(5):845–56.PubMedPubMedCentralCrossRefGoogle Scholar
  236. 236.
    dela Peña I, Borlongan CV. Translating G-CSF as an adjunct therapy to stem cell transplantation for stroke. Transl Stroke Res. 2015;6(6):421–9.PubMedCrossRefGoogle Scholar
  237. 237.
    Venkat P, Shen Y, Chopp M, Chen J. Cell-based and pharmacological neurorestorative therapies for ischemic stroke. Neuropharmacology 2017.Google Scholar
  238. 238.
    Chan HH, Wathen CA, Ni M, Zhuo S. Stem cell therapies for ischemic stroke: current animal models, clinical trials and biomaterials. RSC Adv. 2017;7(30):18668–80.CrossRefGoogle Scholar
  239. 239.
    Boisserand LS, Kodama T, Papassin J, Auzely R, Moisan A, Rome C et al. Biomaterial applications in cell-based therapy in experimental stroke. Stem Cells Int 2016;2016.Google Scholar
  240. 240.
    Osanai T. Role of biomaterials as scaffolding in cell therapy for stroke. Cell Against Cereb Stroke. Springer; 2017. p. 87-99.Google Scholar
  241. 241.
    Yu H, Cao B, Feng M, Zhou Q, Sun X, Wu S, et al. Combinated transplantation of neural stem cells and collagen type I promote functional recovery after cerebral ischemia in rats. Anat Rec. 2010;293(5):911–7.CrossRefGoogle Scholar
  242. 242.
    Bible E, Chau DY, Alexander MR, Price J, Shakesheff KM, Modo M. The support of neural stem cells transplanted into stroke-induced brain cavities by PLGA particles. Biomaterials. 2009;30(16):2985–94.PubMedCrossRefGoogle Scholar
  243. 243.
    Jin K, Mao X, Xie L, Galvan V, Lai B, Wang Y, et al. Transplantation of human neural precursor cells in Matrigel scaffolding improves outcome from focal cerebral ischemia after delayed postischemic treatment in rats. J Cereb Blood Flow Metab. 2010;30(3):534–44.PubMedCrossRefGoogle Scholar
  244. 244.
    Osanai T, Kuroda S, Yasuda H, Chiba Y, Maruichi K, Hokari M, et al. Noninvasive transplantation of bone marrow stromal cells for ischemic stroke: preliminary study with a thermoreversible gelation polymer hydrogel. Neurosurgery. 2010;66(6):1140–7.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Deepaneeta Sarmah
    • 1
  • Harpreet Kaur
    • 1
  • Jackson Saraf
    • 1
  • Kanta Pravalika
    • 1
  • Avirag Goswami
    • 2
  • Kiran Kalia
    • 1
  • Anupom Borah
    • 3
  • Xin Wang
    • 4
  • Kunjan R. Dave
    • 2
  • Dileep R. Yavagal
    • 2
  • Pallab Bhattacharya
    • 1
    • 5
  1. 1.Department of Pharmacology and ToxicologyNational Institute of Pharmaceutical Education and Research (NIPER) AhmedabadGandhinagarIndia
  2. 2.Department of NeurologyUniversity of Miami Miller School of MedicineMiamiUSA
  3. 3.Cellular and Molecular Neurobiology Laboratory, Department of Life Science and BioinformaticsAssam UniversitySilcharIndia
  4. 4.Department of NeurosurgeryBrigham and Women’s Hospital, Harvard Medical SchoolBostonUSA
  5. 5.Department of NeurosurgeryBoston Children’s Hospital, Harvard Medical SchoolBostonUSA

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