Cell Therapy in Stroke—Cautious Steps Towards a Clinical Treatment


In the future, stroke patients may receive stem cell therapy as this has the potential to restore lost functions. However, the development of clinically deliverable therapy has been slower and more challenging than expected. Despite recommendations by STAIR and STEPS consortiums, there remain flaws in experimental studies such as lack of animals with comorbidities, inconsistent approaches to experimental design, and concurrent rehabilitation that might lead to a bias towards positive results. Clinical studies have typically been small, lacking control groups as well as often without clear biological hypotheses to guide patient selection. Furthermore, they have used a wide range of cell types, doses, and delivery methods, and outcome measures. Although some ongoing and recent trial programs offer hints that these obstacles are now being tackled, the Horizon2020 funded RESSTORE trial will be given as an example of inconsistent regulatory requirements and challenges in harmonized cell production, logistic, and clinical criteria in an international multicenter study. The PISCES trials highlight the complex issues around intracerebral cell transplantation. Therefore, a better understanding of translational challenges is expected to pave the way to more successful help for stroke patients.

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  1. 1.

    Hankey GJ. Stroke. Lancet Lond Engl. 2017;389(10069):641–54. https://doi.org/10.1016/S0140-6736(16)30962-X.

    Article  Google Scholar 

  2. 2.

    Wei L, Wei ZZ, Jiang MQ, Mohamad O, Yu SP. Stem cell transplantation therapy for multifaceted therapeutic benefits after stroke. Prog Neurobiol. 2017;157:49–78. https://doi.org/10.1016/j.pneurobio.2017.03.003.

    PubMed  CAS  Article  PubMed Central  Google Scholar 

  3. 3.

    Hicks A, Jolkkonen J. Challenges and possibilities of intravascular cell therapy in stroke. Acta Neurobiol Exp (Wars). 2009;69(1):1–11.

    Google Scholar 

  4. 4.

    Auriat AM, Rosenblum S, Smith TN, Guzman R. Intravascular stem cell transplantation for stroke. Transl Stroke Res. 2011;2(3):250–65. https://doi.org/10.1007/s12975-011-0093-1.

    PubMed  Article  Google Scholar 

  5. 5.

    Janowski M, Wagner D-C, Boltze J. Stem cell-based tissue replacement after stroke: factual necessity or notorious fiction? Stroke. 2015;46(8):2354–63. https://doi.org/10.1161/STROKEAHA.114.007803.

    PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    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. https://doi.org/10.1161/STROKEAHA.109.575993.

    PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Detante O, Valable S, de Fraipont F, Grillon E, Barbier EL, Moisan A, et al. Magnetic resonance imaging and fluorescence labeling of clinical-grade mesenchymal stem cells without impacting their phenotype: study in a rat model of stroke. Stem Cells Transl Med. 2012;1(4):333–41. https://doi.org/10.5966/sctm.2011-0043.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  8. 8.

    Rosado-de-Castro PH, Schmidt F d R, Battistella V, Lopes de Souza SA, Gutfilen B, Goldenberg RC, et al. Biodistribution of bone marrow mononuclear cells after intra-arterial or intravenous transplantation in subacute stroke patients. Regen Med. 2013;8(2):145–55. https://doi.org/10.2217/rme.13.2.

    PubMed  CAS  Article  Google Scholar 

  9. 9.

    Rosenblum S, Wang N, Smith TN, Pendharkar AV, Chua JY, Birk H, et al. Timing of intra-arterial neural stem cell transplantation after hypoxia-ischemia influences cell engraftment, survival, and differentiation. Stroke. 2012;43(6):1624–31. https://doi.org/10.1161/STROKEAHA.111.637884.

    PubMed  CAS  Article  Google Scholar 

  10. 10.

    Mitkari B, Kerkelä E, Nystedt J, Korhonen M, Mikkonen V, Huhtala T, et al. Intra-arterial infusion of human bone marrow-derived mesenchymal stem cells results in transient localization in the brain after cerebral ischemia in rats. Exp Neurol. 2013;239:158–62. https://doi.org/10.1016/j.expneurol.2012.09.018.

    PubMed  CAS  Article  Google Scholar 

  11. 11.

    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. https://doi.org/10.1186/s13287-017-0643-x.

    PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Boltze J, Arnold A, Walczak P, Jolkkonen J, Cui L, Wagner D-C. The dark side of the force - constraints and complications of cell therapies for stroke. Front Neurol. 2015;6:155. https://doi.org/10.3389/fneur.2015.00155.

    PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    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. https://doi.org/10.1111/j.1747-4949.2012.00797.x.

    PubMed  Article  Google Scholar 

  14. 14.

    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. https://doi.org/10.1212/WNL.0000000000000278.

    PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Chen L, Zhang G, Gu Y, Guo X. Meta-analysis and systematic review of neural stem cells therapy for experimental ischemia stroke in preclinical studies. Sci Rep. 2016;6(1):32291. https://doi.org/10.1038/srep32291.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  16. 16.

    Wu Q, Wang Y, Demaerschalk BM, Ghimire S, Wellik KE, Qu W. Bone marrow stromal cell therapy for ischemic stroke: a meta-analysis of randomized control animal trials. Int J Stroke. 2016;1:1747493016676617.

    Google Scholar 

  17. 17.

    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 J Cereb Circ. 2016;47(6):1632–9. https://doi.org/10.1161/STROKEAHA.116.012701.

    Article  Google Scholar 

  18. 18.

    Rosado-de-Castro PH, Pimentel-Coelho PM, da Fonseca LMB, de Freitas GR, Mendez-Otero R. The rise of cell therapy trials for stroke: review of published and registered studies. Stem Cells Dev. 2013;22(15):2095–111. https://doi.org/10.1089/scd.2013.0089.

    PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Jolkkonen J, Kwakkel G. Translational hurdles in stroke recovery studies. Transl Stroke Res. 2016;7(4):331–42. https://doi.org/10.1007/s12975-016-0461-y.

    PubMed  CAS  Article  Google Scholar 

  20. 20.

    Detante O, Moisan A, Hommel M, Jaillard A. Controlled clinical trials of cell therapy in stroke: meta-analysis at six months after treatment. Int J Stroke. 2017;12(7):748–51. https://doi.org/10.1177/1747493017696098.

    PubMed  Article  Google Scholar 

  21. 21.

    Boltze J, Nitzsche F, Jolkkonen J, Weise G, Pösel C, Nitzsche B, et al. Concise review: increasing the validity of cerebrovascular disease models and experimental methods for translational stem cell research. Stem Cells Dayt Ohio. 2017;35(5):1141–53. https://doi.org/10.1002/stem.2595.

  22. 22.

    O’Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW. 1,026 experimental treatments in acute stroke. Ann Neurol. 2006;59(3):467–77. https://doi.org/10.1002/ana.20741.

    PubMed  CAS  Article  Google Scholar 

  23. 23.

    Sena E, van der Worp HB, Howells D, Macleod M. How can we improve the pre-clinical development of drugs for stroke? Trends Neurosci. 2007;30(9):433–9. https://doi.org/10.1016/j.tins.2007.06.009.

    PubMed  CAS  Article  Google Scholar 

  24. 24.

    Minnerup J, Zentsch V, Schmidt A, Fisher M, Schäbitz W-R. Methodological quality of experimental stroke studies published in the stroke journal: time trends and effect of the basic science checklist. Stroke. 2016;47(1):267–72. https://doi.org/10.1161/STROKEAHA.115.011695.

    PubMed  Article  Google Scholar 

  25. 25.

    Thomas A, Detilleux J, Flecknell P, Sandersen C. Impact of stroke therapy academic industry roundtable (STAIR) guidelines on peri-anesthesia care for rat models of stroke: a meta-analysis comparing the years 2005 and 2015. PLoS One. 2017;12(1):e0170243. https://doi.org/10.1371/journal.pone.0170243.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  26. 26.

    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 J Cereb Circ. 2009;40(6):2244–50. https://doi.org/10.1161/STROKEAHA.108.541128.

    Article  Google Scholar 

  27. 27.

    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 J Cereb Circ. 2011;42(3):825–9. https://doi.org/10.1161/STROKEAHA.110.601914.

    Article  Google Scholar 

  28. 28.

    Macleod MR, van der Worp HB, Sena ES, Howells DW, Dirnagl U, Donnan GA. Evidence for the efficacy of NXY-059 in experimental focal cerebral ischaemia is confounded by study quality. Stroke. 2008;39(10):2824–9. https://doi.org/10.1161/STROKEAHA.108.515957.

    PubMed  Article  Google Scholar 

  29. 29.

    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. https://doi.org/10.1161/hs1101.098367.

    PubMed  CAS  Article  Google Scholar 

  30. 30.

    Zacharek A, Chen J, Cui X, Li A, Li Y, Roberts C, et al. Angiopoietin1/Tie2 and VEGF/Flk1 induced by MSC treatment amplifies angiogenesis and vascular stabilization after stroke. J Cereb Blood Flow Metab. 2007;27(10):1684–91. https://doi.org/10.1038/sj.jcbfm.9600475.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  31. 31.

    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 J Cereb Circ. 2011;42(12):3551–8. https://doi.org/10.1161/STROKEAHA.111.627174.

    Article  Google Scholar 

  32. 32.

    Yan T, Venkat P, Chopp M, Zacharek A, Ning R, Roberts C, et al. Neurorestorative responses to delayed human mesenchymal stromal cells treatment of stroke in type 2 diabetic rats. Stroke. 2016;47(11):2850–8. https://doi.org/10.1161/STROKEAHA.116.014686.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  33. 33.

    Rewell SSJ, Fernandez JA, Cox SF, Spratt NJ, Hogan L, Aleksoska E, et al. Inducing stroke in aged, hypertensive, diabetic rats. J Cereb Blood Flow Metab. 2010;30(4):729–33. https://doi.org/10.1038/jcbfm.2009.273.

    PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Boltze J, Wagner D-C, Barthel H, Gounis MJ. Academic-industry collaborations in translational stroke research. Transl Stroke Res. 2016;7(4):343–53. https://doi.org/10.1007/s12975-016-0475-5.

    PubMed  CAS  Article  Google Scholar 

  35. 35.

    Llovera G, Hofmann K, Roth S, Salas-Pérdomo A, Ferrer-Ferrer M, Perego C, et al. Results of a preclinical randomized controlled multicenter trial (pRCT): anti-CD49d treatment for acute brain ischemia. Sci Transl Med. 2015;7(299):299ra121. https://doi.org/10.1126/scitranslmed.aaa9853.

    PubMed  CAS  Article  Google Scholar 

  36. 36.

    Savitz SI, Cramer SC, Wechsler L. STEPS 3 consortium. Stem cells as an emerging paradigm in stroke 3: enhancing the development of clinical trials. Stroke J Cereb Circ. 2014;45(2):634–9. https://doi.org/10.1161/STROKEAHA.113.003379.

    Article  Google Scholar 

  37. 37.

    Biernaskie J, Corbett D. Enriched rehabilitative training promotes improved forelimb motor function and enhanced dendritic growth after focal ischemic injury. J Neurosci. 2001;21(14):5272–80.

    PubMed  CAS  Article  Google Scholar 

  38. 38.

    Zhao S, Zhao M, Xiao T, Jolkkonen J, Zhao C. Constraint-induced movement therapy overcomes the intrinsic axonal growth-inhibitory signals in stroke rats. Stroke J Cereb Circ. 2013;44(6):1698–705. https://doi.org/10.1161/STROKEAHA.111.000361.

    CAS  Article  Google Scholar 

  39. 39.

    Jones TA, Chu CJ, Grande LA, Gregory AD. Motor skills training enhances lesion-induced structural plasticity in the motor cortex of adult rats. J Neurosci. 1999;19(22):10153–63.

    PubMed  CAS  Article  Google Scholar 

  40. 40.

    Kwakkel G, Veerbeek JM, van Wegen EEH, Wolf SL. Constraint-induced movement therapy after stroke. Lancet Neurol. 2015;14(2):224–34. https://doi.org/10.1016/S1474-4422(14)70160-7.

    PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Mering S, Jolkkonen J. Proper housing conditions in experimental stroke studies-special emphasis on environmental enrichment. Front Neurosci. 2015;9:106. https://doi.org/10.3389/fnins.2015.00106.

    PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    Karelina K, Norman GJ, Zhang N, DeVries AC. Social contact influences histological and behavioral outcomes following cerebral ischemia. Exp Neurol. 2009;220(2):276–82. https://doi.org/10.1016/j.expneurol.2009.08.022.

    PubMed  Article  Google Scholar 

  43. 43.

    Venna VR, Xu Y, Doran SJ, Patrizz A, McCullough LD. Social interaction plays a critical role in neurogenesis and recovery after stroke. Transl Psychiatry. 2014;4(1):e351. https://doi.org/10.1038/tp.2013.128.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  44. 44.

    Venna VR, McCullough LD. Role of social factors on cell death, cerebral plasticity and recovery after stroke. Metab Brain Dis. 2015;30(2):497–506. https://doi.org/10.1007/s11011-014-9544-1.

    PubMed  Article  Google Scholar 

  45. 45.

    Kilkenny C, Browne W, Cuthill IC, Emerson M, Altman DG, National Centre for the Replacement, Refinement and Reduction of Animals in Research. Animal research: reporting in vivo experiments—the ARRIVE guidelines. J Cereb Blood Flow Metab. 2011;31(4):991–3. https://doi.org/10.1038/jcbfm.2010.220.

    PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Hicks AU, Hewlett K, Windle V, Chernenko G, Ploughman M, Jolkkonen J, et al. Enriched environment enhances transplanted subventricular zone stem cell migration and functional recovery after stroke. Neuroscience. 2007;146(1):31–40. https://doi.org/10.1016/j.neuroscience.2007.01.020.

    PubMed  CAS  Article  Google Scholar 

  47. 47.

    Hicks AU, Lappalainen RS, Narkilahti S, Suuronen R, Corbett D, Sivenius J, et al. Transplantation of human embryonic stem cell-derived neural precursor cells and enriched environment after cortical stroke in rats: cell survival and functional recovery. Eur J Neurosci. 2009;29(3):562–74. https://doi.org/10.1111/j.1460-9568.2008.06599.x.

    PubMed  Article  Google Scholar 

  48. 48.

    Zhang Y-X, Yuan M-Z, Cheng L, Lin L-Z, Du H-W, Chen R-H, et al. Treadmill exercise enhances therapeutic potency of transplanted bone mesenchymal stem cells in cerebral ischemic rats via anti-apoptotic effects. BMC Neurosci. 2015;16(1):56. https://doi.org/10.1186/s12868-015-0196-9.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  49. 49.

    Sasaki Y, Sasaki M, Kataoka-Sasaki Y, Nakazaki M, Nagahama H, Suzuki J, et al. Synergic effects of rehabilitation and intravenous infusion of mesenchymal stem cells after stroke in rats. Phys Ther. 2016;96(11):1791–8. https://doi.org/10.2522/ptj.20150504.

    PubMed  Article  Google Scholar 

  50. 50.

    Boltze J, Lukomska B, Jolkkonen J, MEMS–IRBI consortium. Mesenchymal stromal cells in stroke: improvement of motor recovery or functional compensation? J Cereb Blood Flow Metab. 2014;34(8):1420–1. https://doi.org/10.1038/jcbfm.2014.94.

    PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Knieling M, Metz GA, Antonow-Schlorke I, Witte OW. Enriched environment promotes efficiency of compensatory movements after cerebral ischemia in rats. Neuroscience. 2009;163(3):759–69. https://doi.org/10.1016/j.neuroscience.2009.07.004.

    PubMed  CAS  Article  Google Scholar 

  52. 52.

    Kitago T, Liang J, Huang VS, Hayes S, Simon P, Tenteromano L, et al. Improvement after constraint-induced movement therapy: recovery of normal motor control or task-specific compensation? Neurorehabil Neural Repair. 2013;27(2):99–109. https://doi.org/10.1177/1545968312452631.

    PubMed  Article  Google Scholar 

  53. 53.

    Braun RG, Andrews EM, Kartje GL. Kinematic analysis of motor recovery with human adult bone marrow-derived somatic cell therapy in a rat model of stroke. Neurorehabil Neural Repair. 2012;26(7):898–906. https://doi.org/10.1177/1545968312446004.

    PubMed  Article  Google Scholar 

  54. 54.

    Muir KW. Clinical trial design for stem cell therapies in stroke: what have we learned? Neurochem Int. 2016;106:108–13. https://doi.org/10.1016/j.neuint.2016.09.011.

    PubMed  CAS  Article  Google Scholar 

  55. 55.

    Kondziolka D, Wechsler L, Goldstein S, Meltzer C, Thulborn KR, Gebel J, et al. Transplantation of cultured human neuronal cells for patients with stroke. Neurology. 2000;55(4):565–9. https://doi.org/10.1212/WNL.55.4.565.

    PubMed  CAS  Article  Google Scholar 

  56. 56.

    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. https://doi.org/10.3171/jns.2005.103.1.0038.

    PubMed  Article  Google Scholar 

  57. 57.

    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 Basel Switz. 2005;20(2):101–7. https://doi.org/10.1159/000086518.

    Article  Google Scholar 

  58. 58.

    Rabinovich SS, Seledtsov VI, Banul NV, Poveshchenko OV, Senyukov VV, Astrakov SV, et al. Cell therapy of brain stroke. Bull Exp Biol Med. 2005;139(1):126–8. https://doi.org/10.1007/s10517-005-0229-y.

    PubMed  CAS  Article  Google Scholar 

  59. 59.

    Bang OY, Lee JS, Lee PH, Lee G. Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol. 2005;57(6):874–82. https://doi.org/10.1002/ana.20501.

    PubMed  Article  Google Scholar 

  60. 60.

    Lee JS, Hong JM, Moon GJ, Lee PH, Ahn YH, Bang OY, et al. A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells Dayt Ohio. 2010;28(6):1099–106. https://doi.org/10.1002/stem.430.

    Article  Google Scholar 

  61. 61.

    Mendonça MLF, Freitas GR, Silva SA, Manfrim A, Falcão CH, Gonzáles C, et al. Safety of intra-arterial autologous bone marrow mononuclear cell transplantation for acute ischemic stroke. Arq Bras Cardiol. 2006;86(1):52–5.

  62. 62.

    Suárez-Monteagudo C, Hernández-Ramírez P, Alvarez-González L, García-Maeso I, de la Cuétara-Bernal K, Castillo-Díaz L, et al. Autologous bone marrow stem cell neurotransplantation in stroke patients. An open study. Restor Neurol Neurosci. 2009;27(3):151–61. https://doi.org/10.3233/RNN-2009-0483.

    PubMed  Article  Google Scholar 

  63. 63.

    Barbosa da Fonseca LM, Gutfilen B, Rosado de Castro PH, Battistella V, Goldenberg RCS, Kasai-Brunswick T, et al. Migration and homing of bone-marrow mononuclear cells in chronic ischemic stroke after intra-arterial injection. Exp Neurol. 2010;221(1):122–8. https://doi.org/10.1016/j.expneurol.2009.10.010.

    PubMed  Article  Google Scholar 

  64. 64.

    Battistella V, de Freitas GR, da Fonseca LMB, Mercante D, Gutfilen B, Goldenberg RCS, et al. Safety of autologous bone marrow mononuclear cell transplantation in patients with nonacute ischemic stroke. Regen Med. 2011;6(1):45–52. https://doi.org/10.2217/rme.10.97.

    PubMed  CAS  Article  Google Scholar 

  65. 65.

    Savitz SI, Misra V, Kasam M, Juneja H, Cox CS, Alderman S, et al. Intravenous autologous bone marrow mononuclear cells for ischemic stroke. Ann Neurol. 2011;70(1):59–69. https://doi.org/10.1002/ana.22458.

    PubMed  Article  Google Scholar 

  66. 66.

    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 J Neurol. 2011;134(Pt 6):1790–807. https://doi.org/10.1093/brain/awr063.

    Article  Google Scholar 

  67. 67.

    Bhasin A, Srivastava MVP, Kumaran SS, Mohanty S, Bhatia R, Bose S, et al. Autologous mesenchymal stem cells in chronic stroke. Cerebrovasc Dis Extra. 2011;1(1):93–104. https://doi.org/10.1159/000333381.

    PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    Bhasin A, Srivastava MVP, Mohanty S, Bhatia R, Kumaran SS, Bose S. Stem cell therapy: a clinical trial of stroke. Clin Neurol Neurosurg. 2013;115(7):1003–8. https://doi.org/10.1016/j.clineuro.2012.10.015.

    PubMed  Article  Google Scholar 

  69. 69.

    Prasad K, Mohanty S, Bhatia R, Srivastava MVP, Garg A, Srivastava A, et al. Autologous intravenous bone marrow mononuclear cell therapy for patients with subacute ischaemic stroke: a pilot study. Indian J Med Res. 2012;136(2):221–8.

    PubMed  PubMed Central  Google Scholar 

  70. 70.

    Moniche F, Montaner J, Gonzalez-Marcos J-R, Carmona M, Piñero P, Espigado I, et al. Intra-arterial bone marrow mononuclear cell transplantation correlates with GM-CSF, PDGF-BB, and MMP-2 serum levels in stroke patients: results from a clinical trial. Cell Transplant. 2014;23(Suppl 1):S57–64.

    PubMed  Article  Google Scholar 

  71. 71.

    Friedrich MAG, Martins MP, Araújo MD, Klamt C, Vedolin L, Garicochea B, et al. Intra-arterial infusion of autologous bone marrow mononuclear cells in patients with moderate to severe middle cerebral artery acute ischemic stroke. Cell Transplant. 2012;21(Suppl 1):S13–21.

    PubMed  Article  Google Scholar 

  72. 72.

    Li Z-M, Zhang Z-T, Guo C-J, Geng F-Y, Qiang F, Wang L-X. Autologous bone marrow mononuclear cell implantation for intracerebral hemorrhage-a prospective clinical observation. Clin Neurol Neurosurg. 2013;115(1):72–6. https://doi.org/10.1016/j.clineuro.2012.04.030.

    PubMed  Article  Google Scholar 

  73. 73.

    Chen D-C, Lin S-Z, Fan J-R, Lin C-H, Lee W, Lin C-C, et al. Intracerebral implantation of autologous peripheral blood stem cells in stroke patients: a randomized phase II study. Cell Transplant. 2014;23(12):1599–612. https://doi.org/10.3727/096368914X678562.

    PubMed  Article  Google Scholar 

  74. 74.

    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. https://doi.org/10.1161/STROKEAHA.114.007028.

    PubMed  CAS  Article  Google Scholar 

  75. 75.

    Banerjee S, Bentley P, Hamady M, Marley S, Davis J, Shlebak A, et al. Intra-arterial immunoselected CD34+ stem cells for acute ischemic stroke. Stem Cells Transl Med. 2014;3(11):1322–30. https://doi.org/10.5966/sctm.2013-0178.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  76. 76.

    Sharma A, Sane H, Nagrajan A, Gokulchandran N, Badhe P, Paranjape A, et al. Autologous bone marrow mononuclear cells in ischemic cerebrovascular accident paves way for neurorestoration: a case report. Case Rep Med. 2014;2014:530239. https://doi.org/10.1155/2014/530239.

    PubMed  PubMed Central  Article  Google Scholar 

  77. 77.

    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. https://doi.org/10.1089/scd.2015.0160.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  78. 78.

    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. https://doi.org/10.1161/STROKEAHA.116.012995.

    PubMed  PubMed Central  Article  Google Scholar 

  79. 79.

    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 Lond Engl. 2016;388(10046):787–96. https://doi.org/10.1016/S0140-6736(16)30513-X.

    Article  Google Scholar 

  80. 80.

    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. https://doi.org/10.1016/S1474-4422(17)30046-7.

    PubMed  Article  Google Scholar 

  81. 81.

    Pollock K, Stroemer P, Patel S, Stevanato L, Hope A, Miljan E, et al. A conditionally immortal clonal stem cell line from human cortical neuroepithelium for the treatment of ischemic stroke. Exp Neurol. 2006;199(1):143–55. https://doi.org/10.1016/j.expneurol.2005.12.011.

    PubMed  Article  Google Scholar 

  82. 82.

    Kalladka D, Muir KW. Stem cell therapy in stroke: designing clinical trials. Neurochem Int. 2011;59(3):367–70. https://doi.org/10.1016/j.neuint.2011.03.016.

    PubMed  CAS  Article  Google Scholar 

  83. 83.

    George AJT, Collet C, Carr AJ, Holm S, Bale C, Burton S, et al. When should placebo surgery as a control in clinical trials be carried out. Bull R Coll Surg Engl. 2016;98(2):75–9. https://doi.org/10.1308/rcsbull.2016.75.

    Article  Google Scholar 

  84. 84.

    Hommel M, Detante O, Favre I, Touzé E, Jaillard A. How to measure recovery? Revisiting concepts and methods for stroke studies. Transl Stroke Res. 2016;7(5):388–94. https://doi.org/10.1007/s12975-016-0488-0.

    PubMed  Article  Google Scholar 

  85. 85.

    Kidwell CS, Liebeskind DS, Starkman S, Saver JL. Trends in acute ischemic stroke trials through the 20th century. Stroke. 2001;32(6):1349–59. https://doi.org/10.1161/01.STR.32.6.1349.

    PubMed  CAS  Article  Google Scholar 

  86. 86.

    Muir KW, Teal PA. Why have neuro-protectants failed?: lessons learned from stroke trials. J Neurol. 2005;252(9):1011–20. https://doi.org/10.1007/s00415-005-0933-6.

    PubMed  CAS  Article  Google Scholar 

  87. 87.

    Kwakkel G, Lannin NA, Borschmann K, English C, Ali M, Churilov L, et al. Standardized measurement of sensorimotor recovery in stroke trials: consensus-based core recommendations from the stroke recovery and rehabilitation roundtable. Int J Stroke. 2017;12(5):451–61. https://doi.org/10.1177/1747493017711813.

    PubMed  Article  Google Scholar 

  88. 88.

    Wolf SL, Winstein CJ, Miller JP, Taub E, Uswatte G, Morris D, et al. Effect of constraint-induced movement therapy on upper extremity function 3 to 9 months after stroke: the EXCITE randomized clinical trial. JAMA. 2006;296(17):2095–104. https://doi.org/10.1001/jama.296.17.2095.

    PubMed  CAS  Article  Google Scholar 

  89. 89.

    Wilson JTL, Hareendran A, Grant M, Baird T, Schulz UGR, Muir KW, et al. Improving the assessment of outcomes in stroke: use of a structured interview to assign grades on the modified Rankin Scale. Stroke. 2002;33(9):2243–6. https://doi.org/10.1161/01.STR.0000027437.22450.BD.

    PubMed  Article  Google Scholar 

  90. 90.

    Wilson JTL, Hareendran A, Hendry A, Potter J, Bone I, Muir KW. Reliability of the modified Rankin Scale across multiple raters: benefits of a structured interview. Stroke. 2005;36(4):777–81. https://doi.org/10.1161/01.STR.0000157596.13234.95.

    PubMed  Article  Google Scholar 

  91. 91.

    Quinn TJ, McArthur K, Dawson J, Walters MR, Lees KR. Reliability of structured modified Rankin scale assessment. Stroke. 2010;41(12):e602; author reply e603. https://doi.org/10.1161/STROKEAHA.110.590547.

    PubMed  Article  Google Scholar 

  92. 92.

    McArthur K, Fan Y, Pei Z, Quinn T. Optimising outcome assessment to improve quality and efficiency of stroke trials. Expert Rev Pharmacoecon Outcomes Res. 2014;14(1):101–11. https://doi.org/10.1586/14737167.2014.870479.

    PubMed  Article  Google Scholar 

  93. 93.

    McArthur KS, Johnson PCD, Quinn TJ, Higgins P, Langhorne P, Walters MR, et al. Improving the efficiency of stroke trials: feasibility and efficacy of group adjudication of functional end points. Stroke. 2013;44(12):3422–8. https://doi.org/10.1161/STROKEAHA.113.002266.

    PubMed  Article  Google Scholar 

  94. 94.

    Bushnell C, Bettger JP, Cockroft KM, Cramer SC, Edelen MO, Hanley D, et al. Chronic stroke outcome measures for motor function intervention trials: expert panel recommendations. Circ Cardiovasc Qual Outcomes. 2015;8(6 Suppl 3):S163–9. https://doi.org/10.1161/CIRCOUTCOMES.115.002098.

    PubMed  PubMed Central  Article  Google Scholar 

  95. 95.

    Svensson J, Ghatnekar O, Lindgren A, Lindvall O, Norrving B, Persson U, et al. Societal value of stem cell therapy in stroke—a modeling study. Cerebrovasc Dis Basel Switz. 2012;33(6):532–9. https://doi.org/10.1159/000337765.

    Article  Google Scholar 

  96. 96.

    Winstein CJ, Wolf SL, Dromerick AW, Lane CJ, Nelsen MA, Lewthwaite R, et al. Effect of a task-oriented rehabilitation program on upper extremity recovery following motor stroke: the ICARE randomized clinical trial. JAMA. 2016;315(6):571–81. https://doi.org/10.1001/jama.2016.0276.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  97. 97.

    AVERT Trial Collaboration Group, Bernhardt J, Langhorne P, Lindley RI, Thrift AG, Ellery F, et al. Efficacy and safety of very early mobilisation within 24 h of stroke onset (AVERT): a randomised controlled trial. Lancet Lond Engl. 2015;386(9988):46–55.

    Article  Google Scholar 

  98. 98.

    Favre I, Zeffiro TA, Detante O, Krainik A, Hommel M, Jaillard A. Upper limb recovery after stroke is associated with ipsilesional primary motor cortical activity: a meta-analysis. Stroke. 2014;45(4):1077–83. https://doi.org/10.1161/STROKEAHA.113.003168.

    PubMed  Article  Google Scholar 

  99. 99.

    Feydy A, Carlier R, Roby-Brami A, Bussel B, Cazalis F, Pierot L, et al. Longitudinal study of motor recovery after stroke: recruitment and focusing of brain activation. Stroke. 2002;33(6):1610–7. https://doi.org/10.1161/01.STR.0000017100.68294.52.

    PubMed  CAS  Article  Google Scholar 

  100. 100.

    Mitkari B, Kerkelä E, Nystedt J, Korhonen M, Jolkkonen J. Unexpected complication in a rat stroke model: exacerbation of secondary pathology in the thalamus by subacute intraarterial administration of human bone marrow-derived mesenchymal stem cells. J Cereb Blood Flow Metab. 2015;35(3):363–6. https://doi.org/10.1038/jcbfm.2014.235.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  101. 101.

    Stinear CM, Barber PA, Petoe M, Anwar S, Byblow WD. The PREP algorithm predicts potential for upper limb recovery after stroke. Brain J Neurol. 2012;135(Pt 8):2527–35. https://doi.org/10.1093/brain/aws146.

    Article  Google Scholar 

  102. 102.

    Stinear CM, Byblow WD, Ackerley SJ, Smith M-C, Borges VM, Barber PA. Proportional motor recovery after stroke: implications for trial design. Stroke. 2017;48(3):795–8. https://doi.org/10.1161/STROKEAHA.116.016020.

    PubMed  Article  Google Scholar 

  103. 103.

    Stinear CM, Byblow WD, Ackerley SJ, Barber PA, Smith M-C. Predicting recovery potential for individual stroke patients increases rehabilitation efficiency. Stroke. 2017;48(4):1011–9. https://doi.org/10.1161/STROKEAHA.116.015790.

    PubMed  Article  Google Scholar 

  104. 104.

    Nagpal A, Juttner C, Hamilton-Bruce MA, Rolan P, Koblar SA. Stem cell therapy clinical research: a regulatory conundrum for academia. Adv Drug Deliv Rev. 2016; https://doi.org/10.1016/j.addr.2016.10.001.

  105. 105.

    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;8(4):351–61. https://doi.org/10.1007/s12975-017-0523-9.

    PubMed  PubMed Central  Article  Google Scholar 

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This work was supported by RESSTORE project (www.resstore.eu) funded by the European Commission under the H2020 program (grant number 681044).

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Correspondence to Jukka Jolkkonen.

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Conflict of Interest

Dr. Keith Muir is chief Investigator for PISCES 1 and PISCES 2 trials, funded by ReNeuron Ltd. He participated in advisory boards for ReNeuron. No other authors have a conflict of interest.

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Detante, O., Muir, K. & Jolkkonen, J. Cell Therapy in Stroke—Cautious Steps Towards a Clinical Treatment. Transl. Stroke Res. 9, 321–332 (2018). https://doi.org/10.1007/s12975-017-0587-6

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  • Cell therapy
  • Cerebrovascular diseases
  • Experimental studies
  • Clinical trials
  • Translation