Stem Cell Therapy in Cerebrovascular Disease

  • Michael I. Nahhas
  • David C. HessEmail author
Cerebrovascular Disorders (D Jamieson, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Cerebrovascular Disorders


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.


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.


Stem cells Ischemic stroke Cell therapy Exosomes 



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

Compliance With Ethical Standards

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.

Human and Animal Rights and Informed Consent

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.

References and Recommended Reading

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

  1. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Leader B, Baca QJ, Golan DE. Protein therapeutics: a summary and pharmacological classification. Nat Rev Drug Discov. 2008;7(1):21–39.PubMedCrossRefGoogle Scholar
  3. 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.CrossRefPubMedGoogle Scholar
  4. 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.PubMedCrossRefGoogle Scholar
  5. 5.
    Darsalia V, Heldmann U, Lindvall O, Kokaia Z. Stroke-induced neurogenesis in aged brain. Stroke. 2005;36(8):1790–5.PubMedCrossRefGoogle 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.CrossRefPubMedGoogle Scholar
  7. 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.CrossRefPubMedGoogle Scholar
  8. 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.PubMedCrossRefGoogle Scholar
  9. 9.
    Lindvall O, Kokaia Z. Stem cell research in stroke: how far from the clinic? Stroke. 2011;42(8):2369–75.PubMedCrossRefGoogle Scholar
  10. 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.PubMedCrossRefGoogle Scholar
  11. 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.PubMedCrossRefGoogle Scholar
  12. 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.PubMedCrossRefGoogle Scholar
  13. 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.PubMedCrossRefGoogle Scholar
  14. 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.PubMedCrossRefGoogle Scholar
  15. 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.PubMedPubMedCentralGoogle Scholar
  16. 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.PubMedCrossRefGoogle Scholar
  17. 17.
    Caplan AI. Why are MSCs therapeutic? New data: new insight. J Pathol. 2009;217(2):318–24.PubMedCrossRefGoogle Scholar
  18. 18.
    Trounson A, Thakar RG, Lomax G, Gibbons D. Clinical trials for stem cell therapies. BMC Med. 2011;9:52.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 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):2385–9PubMedCrossRefGoogle Scholar
  21. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 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.PubMedCrossRefGoogle Scholar
  23. 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.CrossRefPubMedGoogle Scholar
  24. 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.CrossRefPubMedGoogle Scholar
  25. 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.CrossRefPubMedGoogle Scholar
  26. 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.PubMedCrossRefGoogle Scholar
  27. 27.
    Sterneckert J, Hoing S, Scholer HR. Concise review: Oct4 and more: the reprogramming expressway. Stem Cells. 2012;30(1):15–21.PubMedCrossRefGoogle Scholar
  28. 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.CrossRefPubMedGoogle Scholar
  29. 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.PubMedCrossRefGoogle Scholar
  30. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 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.PubMedCrossRefGoogle Scholar
  32. 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.PubMedCrossRefGoogle Scholar
  33. 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.PubMedCrossRefGoogle Scholar
  34. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 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.PubMedCrossRefGoogle Scholar
  39. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Nakatsuji N, Nakajima F, Tokunaga K. HLA-haplotype banking and iPS cells. Nat Biotechnol. 2008;26(7):739–40.PubMedCrossRefGoogle Scholar
  41. 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.PubMedCrossRefGoogle Scholar
  42. 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.CrossRefPubMedGoogle Scholar
  43. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 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.PubMedCrossRefGoogle Scholar
  45. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 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.PubMedCrossRefGoogle Scholar
  48. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 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.Google Scholar
  51. 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.PubMedCrossRefGoogle Scholar
  52. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 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.PubMedCrossRefGoogle Scholar
  54. 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.PubMedCrossRefGoogle Scholar
  55. 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.CrossRefPubMedGoogle Scholar
  56. 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.PubMedCrossRefGoogle Scholar
  57. 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.PubMedCrossRefGoogle Scholar
  58. 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.PubMedCrossRefGoogle Scholar
  59. 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.PubMedCrossRefGoogle Scholar
  60. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 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.PubMedCrossRefGoogle Scholar
  62. 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.PubMedCrossRefGoogle Scholar
  63. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 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.PubMedCrossRefGoogle Scholar
  65. 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.PubMedCrossRefGoogle Scholar
  66. 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.PubMedCrossRefGoogle Scholar
  67. 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.PubMedCrossRefGoogle Scholar
  68. 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.PubMedCrossRefGoogle Scholar
  69. 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.PubMedCrossRefGoogle Scholar
  70. 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.PubMedCrossRefGoogle Scholar
  71. 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.PubMedCrossRefGoogle Scholar
  72. 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. 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.PubMedCrossRefGoogle Scholar
  74. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 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.PubMedCrossRefGoogle Scholar
  76. 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. 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.Google Scholar
  78. 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.PubMedCrossRefGoogle Scholar
  79. 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.PubMedCrossRefGoogle Scholar
  80. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 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.PubMedCrossRefGoogle Scholar
  83. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 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.PubMedCrossRefGoogle Scholar
  85. 85.
    Basso M, Bonetto V. Extracellular Vesicles and a Novel Form of Communication in the Brain. Front Neurosci. 2016;10:127.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013;200(4):373–83.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 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.CrossRefPubMedGoogle Scholar
  88. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 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.Google Scholar
  90. 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.PubMedCrossRefGoogle Scholar
  91. 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

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of NeurologyMedical College of Georgia at Augusta UniversityAugustaUSA

Personalised recommendations