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Stem Cell Therapy in Cerebrovascular Disease

  • Cerebrovascular Disorders (D Jamieson, Section Editor)
  • Published:
Current Treatment Options in Neurology Aims and scope Submit manuscript

Abstract

Purpose of review

The purpose of this article is to provide a review of state-of-the-art cellular therapy in cerebrovascular diseases by discussing published and ongoing clinical trials.

Recent findings

In spite of the challenge in translating the success of cellular therapy in acute strokes from preclinical models to clinical trials, early phase clinical trial have recently shown promise in overcoming these challenges. Various stem cell types and doses are being studied, different routes of administration are under investigation, as well as defining the optimal time window to intervene. In addition, experimental methods to enhance cellular therapy, such as ischemic preconditioning, are evolving.

Summary

After the failure of neuroprotectants in cerebrovascular diseases, researchers have been keen to provide a way of replacement of damaged brain tissue and to promote recovery in order to achieve better outcomes. The field has progressed from intravenous delivery in the 24- to 36-h time window to later intracerebral administration in chronic stroke in clinical trials. New optimism in acute stroke care fostered by the success of mechanical thrombectomy will hopefully extend into cell therapy to promote recovery.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. Landis SC, Amara SG, Asadullah K, Austin CP, Blumenstein R, Bradley EW, et al. A call for transparent reporting to optimize the predictive value of preclinical research. Nature. 2012;490(7419):187–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Leader B, Baca QJ, Golan DE. Protein therapeutics: a summary and pharmacological classification. Nat Rev Drug Discov. 2008;7(1):21–39.

    Article  CAS  PubMed  Google Scholar 

  3. Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, et al. Neurogenesis in the adult human hippocampus. Nat Med. 1998;4(11):1313–7.

    Article  CAS  PubMed  Google Scholar 

  4. Lee ST, Chu K, Jung KH, Kim SJ, Kim DH, Kang KM, et al. Anti-inflammatory mechanism of intravascular neural stem cell transplantation in haemorrhagic stroke. Brain. 2008;131(Pt 3):616–29.

    Article  PubMed  Google Scholar 

  5. Darsalia V, Heldmann U, Lindvall O, Kokaia Z. Stroke-induced neurogenesis in aged brain. Stroke. 2005;36(8):1790–5.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  7. 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.

    Article  PubMed  Google Scholar 

  8. 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.

    Article  PubMed  Google Scholar 

  9. Lindvall O, Kokaia Z. Stem cell research in stroke: how far from the clinic? Stroke. 2011;42(8):2369–75.

    Article  PubMed  Google Scholar 

  10. 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.

    Article  CAS  PubMed  Google Scholar 

  11. Zou ZZY, Hao L, Wang F, Liu D, Su Y, Sun H. More insight into mesenchymal stem cells and their effects inside the body. Expert Opin Biol Ther. 2010;10(2):215–30.

    Article  CAS  PubMed  Google Scholar 

  12. Chen X, Li Y, Wang L, Katakowski M, Zhang L, Chen J, et al. Ischemic rat brain extracts induce human marrow stromal cell growth factor production. Neuropathology. 2002;22(4):275–9.

    Article  PubMed  Google Scholar 

  13. Li WY, Choi YJ, Lee PH, Huh K, Kang YM, Kim HS, et al. Mesenchymal stem cells for ischemic stroke: changes in effects after ex vivo culturing. Cell Transplant. 2008;17(9):1045–59.

    Article  PubMed  Google Scholar 

  14. 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.

    Article  CAS  PubMed  Google Scholar 

  15. Zhang R, Liu Y, Yan K, Chen L, Chen XR, Li P, et al. Anti-inflammatory and immunomodulatory mechanisms of mesenchymal stem cell transplantation in experimental traumatic brain injury. J Neuroinflammation. 2013;10:106.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Spees JL, Gregory CA, Singh H, Tucker HA, Peister A, Lynch PJ, et al. Internalized antigens must be removed to prepare hypoimmunogenic mesenchymal stem cells for cell and gene therapy. Mol Ther. 2004;9(5):747–56.

    Article  CAS  PubMed  Google Scholar 

  17. Caplan AI. Why are MSCs therapeutic? New data: new insight. J Pathol. 2009;217(2):318–24.

    Article  CAS  PubMed  Google Scholar 

  18. Trounson A, Thakar RG, Lomax G, Gibbons D. Clinical trials for stem cell therapies. BMC Med. 2011;9:52.

    Article  PubMed  PubMed Central  Google Scholar 

  19. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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

    Article  PubMed  Google Scholar 

  21. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Choi YJ, Li WY, Moon GJ, Lee PH, Ahn YH, Lee G, et al. Enhancing trophic support of mesenchymal stem cells by ex vivo treatment with trophic factors. J Neurol Sci. 2010;298(1–2):28–34.

    Article  CAS  PubMed  Google Scholar 

  23. 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.

    Article  CAS  PubMed  Google Scholar 

  24. 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.

    Article  CAS  PubMed  Google Scholar 

  25. 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. 2007;318(5858):1917–20.

    Article  CAS  PubMed  Google Scholar 

  26. Kim JB, Zaehres H, Arauzo-Bravo MJ, Scholer HR. Generation of induced pluripotent stem cells from neural stem cells. Nat Protoc. 2009;4(10):1464–70.

    Article  CAS  PubMed  Google Scholar 

  27. Sterneckert J, Hoing S, Scholer HR. Concise review: Oct4 and more: the reprogramming expressway. Stem Cells. 2012;30(1):15–21.

    Article  CAS  PubMed  Google Scholar 

  28. Han DW, Tapia N, Hermann A, Hemmer K, Hoing S, Arauzo-Bravo MJ, et al. Direct reprogramming of fibroblasts into neural stem cells by defined factors. Cell Stem Cell. 2012;10(4):465–72.

    Article  CAS  PubMed  Google Scholar 

  29. 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.

    Article  CAS  PubMed  Google Scholar 

  30. 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. 2010;30(8):1487–93.

    Article  PubMed  PubMed Central  Google Scholar 

  31. 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.

    Article  PubMed  Google Scholar 

  32. Chang DJ, Lee N, Park IH, 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.

    Article  PubMed  Google Scholar 

  33. 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. 2012;30(6):1120–33.

    Article  CAS  PubMed  Google Scholar 

  34. Mohamad O, Drury-Stewart D, Song M, Faulkner B, Chen D, Yu SP, et al. Vector-free and transgene-free human iPS cells differentiate into functional neurons and enhance functional recovery after ischemic stroke in mice. PLoS One. 2013;8(5):e64160.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Durruthy-Durruthy J, Briggs SF, Awe J, Ramathal CY, Karumbayaram S, Lee PC, et al. Rapid and efficient conversion of integration-free human induced pluripotent stem cells to GMP-grade culture conditions. PLoS One. 2014;9(4):e94231.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Baker EW, Platt SR, Lau VW, Grace HE, Holmes SP, Wang L, et al. Induced pluripotent stem cell-derived neural stem cell therapy enhances recovery in an ischemic stroke pig model. Sci Rep. 2017;7(1):10075.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Platt SR, Holmes SP, Howerth EW, Duberstein KJJ, Dove CR, Kinder HA, et al. Development and characterization of a Yucatan miniature biomedical pig permanent middle cerebral artery occlusion stroke model. Exp Transl Stroke Med. 2014;6(1):5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Lind NM, Moustgaard A, Jelsing J, Vajta G, Cumming P, Hansen AK. The use of pigs in neuroscience: modeling brain disorders. Neurosci Biobehav Rev. 2007;31(5):728–51.

    Article  CAS  PubMed  Google Scholar 

  39. Morizane A, Doi D, Kikuchi T, Okita K, Hotta A, Kawasaki T, et al. Direct comparison of autologous and allogeneic transplantation of iPSC-derived neural cells in the brain of a non-human primate. Stem Cell Reports. 2013;1(4):283–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Nakatsuji N, Nakajima F, Tokunaga K. HLA-haplotype banking and iPS cells. Nat Biotechnol. 2008;26(7):739–40.

    Article  CAS  PubMed  Google Scholar 

  41. Jiang Y, Vaessen B, Lenvik T, Blackstad M, Reyes M, Verfaillie CM. Multipotent progenitor cells can be isolated from postnatal murine bone marrow, muscle, and brain. Exp Hematol. 2002;30(8):896–904.

    Article  CAS  PubMed  Google Scholar 

  42. Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature. 2002;418(6893):41–9.

    Article  CAS  PubMed  Google Scholar 

  43. Burrows GG, Van't Hof W, Newell LF, Reddy A, Wilmarth PA, David LL, et al. Dissection of the human multipotent adult progenitor cell secretome by proteomic analysis. Stem Cells Transl Med. 2013;2(10):745–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Roobrouck VD, Clavel C, Jacobs SA, Ulloa-Montoya F, Crippa S, Sohni A, et al. Differentiation potential of human postnatal mesenchymal stem cells, mesoangioblasts, and multipotent adult progenitor cells reflected in their transcriptome and partially influenced by the culture conditions. Stem Cells. 2011;29(5):871–82.

    Article  CAS  PubMed  Google Scholar 

  45. Aranda P, Agirre X, Ballestar E, Andreu EJ, Roman-Gomez J, Prieto I, et al. Epigenetic signatures associated with different levels of differentiation potential in human stem cells. PLoS One. 2009;4(11):e7809.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Vaes B, Van't Hof W, Deans R, Pinxteren J. Application of MultiStem((R)) allogeneic cells for immunomodulatory therapy: clinical progress and pre-clinical challenges in prophylaxis for graft versus host disease. Front Immunol. 2012;3:345.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Jacobs SA, Pinxteren J, Roobrouck VD, Luyckx A, van't Hof W, Deans R, et al. Human multipotent adult progenitor cells are nonimmunogenic and exert potent immunomodulatory effects on alloreactive T-cell responses. Cell Transplant. 2013;22(10):1915–28.

    Article  PubMed  Google Scholar 

  48. Mora-Lee S, Sirerol-Piquer MS, Gutierrez-Perez M, Gomez-Pinedo U, Roobrouck VD, Lopez T, et al. Therapeutic effects of hMAPC and hMSC transplantation after stroke in mice. PLoS One. 2012;7(8):e43683.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Highfill SL, Kelly RM, O'Shaughnessy MJ, Zhou Q, Xia L, Panoskaltsis-Mortari A, et al. Multipotent adult progenitor cells can suppress graft-versus-host disease via prostaglandin E2 synthesis and only if localized to sites of allopriming. Blood. 2009;114(3):693–701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Yang B HJ, Strong R, Xi X, Mays R, Savitz S. Human multipotential bone marrow stem cells exert immunomodulatory effects, prevent splenic contraction, and enhance functional recovery in a rodent model of ischemic stroke. Stroke; Philadelphia, PA: Lippincott Williams & Wilkins; 2011. p. E67.

  51. Yang B, Hamilton JA, Valenzuela KS, Bogaerts A, Xi X, Aronowski J, et al. Multipotent adult progenitor cells enhance recovery after stroke by modulating the immune response from the spleen. Stem Cells. 2017;35(5):1290–302.

    Article  CAS  PubMed  Google Scholar 

  52. Eglitis MA, Mezey E. Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice. Proc Natl Acad Sci U S A. 1997;94(8):4080–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Lu D, Mahmood A, Wang L, Li Y, Lu M, Chopp M. Adult bone marrow stromal cells administered intravenously to rats after traumatic brain injury migrate into brain and improve neurological outcome. Neuroreport. 2001;12(3):559–63.

    Article  CAS  PubMed  Google Scholar 

  54. 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.

    Article  CAS  PubMed  Google Scholar 

  55. Chen J, Sanberg PR, Li Y, Wang L, Lu M, Willing AE, et al. Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats. Stroke. 2001;32(11):2682–8.

    Article  CAS  PubMed  Google Scholar 

  56. Fischer UM, Harting MT, Jimenez F, Monzon-Posadas WO, Xue H, Savitz SI, et al. Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem Cells Dev. 2009;18(5):683–92.

    Article  CAS  PubMed  Google Scholar 

  57. Hayashi T, Noshita N, Sugawara T, Chan PH. Temporal profile of angiogenesis and expression of related genes in the brain after ischemia. J Cereb Blood Flow Metab. 2003;23(2):166–80.

    Article  CAS  PubMed  Google Scholar 

  58. Keimpema E, Fokkens MR, Nagy Z, Agoston V, Luiten PG, Nyakas C, et al. Early transient presence of implanted bone marrow stem cells reduces lesion size after cerebral ischaemia in adult rats. Neuropathol Appl Neurobiol. 2009;35(1):89–102.

    Article  CAS  PubMed  Google Scholar 

  59. Lappalainen RS, Narkilahti S, Huhtala T, Liimatainen T, Suuronen T, Narvanen A, et al. The SPECT imaging shows the accumulation of neural progenitor cells into internal organs after systemic administration in middle cerebral artery occlusion rats. Neurosci Lett. 2008;440(3):246–50.

    Article  CAS  PubMed  Google Scholar 

  60. Pendharkar AV, Chua JY, Andres RH, Wang N, Gaeta X, Wang H, et al. Biodistribution of neural stem cells after intravascular therapy for hypoxic-ischemia. Stroke. 2010;41(9):2064–70.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Li L, Jiang Q, Ding G, Zhang L, Zhang ZG, Li Q, et al. Effects of administration route on migration and distribution of neural progenitor cells transplanted into rats with focal cerebral ischemia, an MRI study. J Cereb Blood Flow Metab. 2010;30(3):653–62.

    Article  PubMed  Google Scholar 

  62. Ge J, Guo L, Wang S, Zhang Y, Cai T, Zhao RC, et al. The size of mesenchymal stem cells is a significant cause of vascular obstructions and stroke. Stem Cell Rev. 2014;10(2):295–303.

    Article  CAS  PubMed  Google Scholar 

  63. Walczak P, Zhang J, Gilad AA, Kedziorek DA, Ruiz-Cabello J, Young RG, et al. Dual-modality monitoring of targeted intraarterial delivery of mesenchymal stem cells after transient ischemia. Stroke. 2008;39(5):1569–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Aoki H, Onodera H, Yae T, Jian Z, Kogure K. Neural grafting to ischemic CA1 lesions in the rat hippocampus: an autoradiographic study. Neuroscience. 1993;56(2):345–54.

    Article  CAS  PubMed  Google Scholar 

  65. 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.

    Article  PubMed  Google Scholar 

  66. Lin YC, Ko TL, Shih YH, Lin MY, Fu TW, Hsiao HS, et al. Human umbilical mesenchymal stem cells promote recovery after ischemic stroke. Stroke. 2011;42(7):2045–53.

    Article  PubMed  Google Scholar 

  67. Kondziolka D, Steinberg GK, Wechsler L, Meltzer CC, Elder E, Gebel J, et al. Neurotransplantation for patients with subcortical motor stroke: a phase 2 randomized trial. J Neurosurg. 2005;103(1):38–45.

    Article  PubMed  Google Scholar 

  68. Hess DC, Wechsler LR, Clark WM, Savitz SI, Ford GA, Chiu D, et al. Safety and efficacy of multipotent adult progenitor cells in acute ischaemic stroke (MASTERS): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol. 2017;16(5):360–8.This clinical trial provides further clarity on the important immunomodulatory role of MultiStem in treating early stroke patients.

    Article  PubMed  Google Scholar 

  69. Hess DC, Sila CA, Furlan AJ, Wechsler LR, Switzer JA, Mays RW. A double-blind placebo-controlled clinical evaluation of MultiStem for the treatment of ischemic stroke. Int J Stroke. 2014;9(3):381–6.

    Article  PubMed  Google Scholar 

  70. Mays R, Deans R. Adult adherent cell therapy for ischemic stroke: clinical results and development experience using MultiStem. Transfusion. 2016;56(4):6S–8S.

    Article  PubMed  Google Scholar 

  71. 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.This is the first clinical trial of human neural stem cells in stroke patients that showed no major harmful cell-related effects over a period of 2–4 years of folllow-up.

    Article  PubMed  Google Scholar 

  72. Kalladka DSJ, Pollock K, et al. PISCES – A phase I trial of CTX0E03 human neural stem cells in ischemic stroke: final results. Int J Stroke. 2015;10(Suppl 2):10.

    Google Scholar 

  73. Yozbatiran N, Der-Yeghiaian L, Cramer SC. A standardized approach to performing the action research arm test. Neurorehabil Neural Repair. 2008;22(1):78–90.

    Article  PubMed  Google Scholar 

  74. Steinberg GK, Kondziolka D, Wechsler LR, Lunsford LD, Coburn ML, Billigen JB, et al. Clinical Outcomes of Transplanted Modified Bone Marrow-Derived Mesenchymal Stem Cells in Stroke: A Phase 1/2a Study. Stroke. 2016;47(7):1817–24. This clinical trial demonstrated safety of SB632 and motor-function improvement in treating chronic stroke patients.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Mimura T, Dezawa M, Kanno H, Yamamoto I. Behavioral and histological evaluation of a focal cerebral infarction rat model transplanted with neurons induced from bone marrow stromal cells. J Neuropathol Exp Neurol. 2005;64(12):1108–17.

    Article  PubMed  Google Scholar 

  76. Kenmuir CLRV, Mountz J, et al. Changes in FDG-PET activity following intracranial injection of SB623 cells in patients with stable ischemic strokes. Stroke. 2015;46(Suppl):AWMP93.

    Google Scholar 

  77. Stem Cell Therapies as an Emerging Paradigm in Stroke P. Stem Cell Therapies as an Emerging Paradigm in Stroke (STEPS): bridging basic and clinical science for cellular and neurogenic factor therapy in treating stroke. Stroke. 2009;40(2):510–5.

  78. Savitz SI, Chopp M, Deans R, Carmichael T, Phinney D, Wechsler L, et al. Stem Cell Therapy as an Emerging Paradigm for Stroke (STEPS) II. Stroke. 2011;42(3):825–9.

    Article  PubMed  Google Scholar 

  79. Savitz SI, Cramer SC, Wechsler L, Consortium S. Stem cells as an emerging paradigm in stroke 3: enhancing the development of clinical trials. Stroke. 2014;45(2):634–9.

    Article  PubMed  Google Scholar 

  80. Fisher M, Feuerstein G, Howells DW, Hurn PD, Kent TA, Savitz SI, et al. Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke. 2009;40(6):2244–50.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Saver JL, Albers GW, Dunn B, Johnston KC, Fisher M, Consortium SV. Stroke Therapy Academic Industry Roundtable (STAIR) recommendations for extended window acute stroke therapy trials. Stroke. 2009;40(7):2594–600.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Albers GW, Goldstein LB, Hess DC, Wechsler LR, Furie KL, Gorelick PB, et al. Stroke Treatment Academic Industry Roundtable (STAIR) recommendations for maximizing the use of intravenous thrombolytics and expanding treatment options with intra-arterial and neuroprotective therapies. Stroke. 2011;42(9):2645–50.

    Article  PubMed  Google Scholar 

  83. Webb RL, Kaiser EE, Jurgielewicz BJ, Spellicy S, Scoville SL, Thompson TA, et al. Human Neural Stem Cell Extracellular Vesicles Improve Recovery in a Porcine Model of Ischemic Stroke. Stroke. 2018;49(5):1248–56.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Lener T, Gimona M, Aigner L, Borger V, Buzas E, Camussi G, et al. Applying extracellular vesicles based therapeutics in clinical trials - an ISEV position paper. J Extracell Vesicles. 2015;4:30087.

    Article  PubMed  CAS  Google Scholar 

  85. Basso M, Bonetto V. Extracellular Vesicles and a Novel Form of Communication in the Brain. Front Neurosci. 2016;10:127.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013;200(4):373–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Wiklander OP, Nordin JZ, O'Loughlin A, Gustafsson Y, Corso G, Mager I, et al. Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. J Extracell Vesicles. 2015;4:26316.

    Article  PubMed  Google Scholar 

  88. Doeppner TR, Herz J, Gorgens A, Schlechter J, Ludwig AK, Radtke S, et al. Extracellular Vesicles Improve Post-Stroke Neuroregeneration and Prevent Postischemic Immunosuppression. Stem Cells Transl Med. 2015;4(10):1131–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Webb RL, Kaiser EE, Scoville SL, Thompson TA, Fatima S, Pandya C, et al. Human Neural Stem Cell Extracellular Vesicles Improve Tissue and Functional Recovery in the Murine Thromboembolic Stroke Model. Transl Stroke Res. 2017.

  90. Prasad K, Sharma A, Garg A, Mohanty S, Bhatnagar S, Johri S, et al. Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke: a multicentric, randomized trial. Stroke. 2014;45(12):3618–24.

    Article  CAS  PubMed  Google Scholar 

  91. Yavagal DRHD, Graffagnino C, et al. Intra-arterial delivery of autologous ALDBHR cells in ischemic stroke: final 1-year results of the RECOVER-Stroke trial. Int J Stroke. 2015;10(Suppl 2):13.

    Google Scholar 

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Acknowledgments

We thank Coby Polonsky M.S., Department of Medical Illustration at Augusta University for creating the figure artwork.

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Authors and Affiliations

  1. Department of Neurology, Medical College of Georgia at Augusta University, Augusta, GA, USA

    Michael I. Nahhas MD & David C. Hess MD

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  1. Michael I. Nahhas MD
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Correspondence to David C. Hess MD.

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Conflict of Interest

Dr. David C. Hess has a patent on MultiStem in Neurological Disease with Athersys, Inc.

Dr. David C. Hess reports grants from ARUNA.

Dr. Michael I. Nahhas declares that he has no conflict of interest.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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This article is part of the Topical Collection on Cerebrovascular Disorders

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Nahhas, M.I., Hess, D.C. Stem Cell Therapy in Cerebrovascular Disease. Curr Treat Options Neurol 20, 49 (2018). https://doi.org/10.1007/s11940-018-0532-3

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