Autologous Mesenchymal Stem Cells Improve Motor Recovery in Subacute Ischemic Stroke: a Randomized Clinical Trial


While preclinical stroke studies have shown that mesenchymal stem cells (MSCs) promote recovery, few randomized controlled trials (RCT) have assessed cell therapy in humans. In this RCT, we assessed the safety, feasibility, and efficacy of intravenous autologous bone marrow-derived MSCs in subacute stroke. ISIS-HERMES was a single-center, open-label RCT, with a 2-year follow-up. We enrolled patients aged 18–70 years less than 2 weeks following moderate-severe ischemic carotid stroke. Patients were randomized 2:1 to receive intravenous MSCs or not. Primary outcomes assessed feasibility and safety. Secondary outcomes assessed global and motor recovery. Passive wrist movement functional MRI (fMRI) activity in primary motor cortex (MI) was employed as a motor recovery biomarker. We compared “treated” and “control” groups using as-treated analyses. Of 31 enrolled patients, 16 patients received MSCs. Treatment feasibility was 80%, and there were 10 and 16 adverse events in treated patients, and 12 and 24 in controls at 6-month and 2-year follow-up, respectively. Using mixed modeling analyses, we observed no treatment effects on the Barthel Index, NIHSS, and modified-Rankin scores, but significant improvements in motor-NIHSS (p = 0.004), motor-Fugl-Meyer scores (p = 0.028), and task-related fMRI activity in MI-4a (p = 0.031) and MI-4p (p = 0.002). Intravenous autologous MSC treatment following stroke was safe and feasible. Motor performance and task-related MI activity results suggest that MSCs improve motor recovery through sensorimotor neuroplasticity. Identifier NCT 00875654.

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  1. 1.

    Sarraj A, Grotta JC. Stroke: new horizons in treatment. Lancet Neurol. 2014;13(1):2–3.

    PubMed  Article  Google Scholar 

  2. 2.

    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.

    PubMed  Article  Google Scholar 

  3. 3.

    Cunningham CJ, Redondo-Castro E, Allan SM. The therapeutic potential of the mesenchymal stem cell secretome in ischaemic stroke. J Cereb Blood Flow Metab. 2018:271678X18776802.

  4. 4.

    Dhere T, Copland I, Garcia M, Chiang KY, Chinnadurai R, Prasad M, et al. The safety of autologous and metabolically fit bone marrow mesenchymal stromal cells in medically refractory Crohn’s disease—a phase 1 trial with three doses. Aliment Pharmacol Ther. 2016;44(5):471–81.

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Duijvestein M, Vos AC, Roelofs H, Wildenberg ME, Wendrich BB, Verspaget HW, et al. Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn’s disease: results of a phase I study. Gut. 2010;59(12):1662–9.

    PubMed  Article  Google Scholar 

  6. 6.

    Kuriyan AE, Albini TA, Townsend JH, Rodriguez M, Pandya HK, Leonard RE 2nd, et al. Vision loss after intravitreal injection of autologous “stem cells” for AMD. N Engl J Med. 2017;376(11):1047–53.

    PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Gazdic M, Volarevic V, Arsenijevic N, Stojkovic M. Mesenchymal stem cells: a friend or foe in immune-mediated diseases. Stem Cell Rev. 2015;11(2):280–7.

    CAS  Article  Google Scholar 

  8. 8.

    Volarevic V, Markovic BS, Gazdic M, Volarevic A, Jovicic N, Arsenijevic N, et al. Ethical and safety issues of stem cell-based therapy. Int J Med Sci. 2018;15(1):36–45.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

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

    PubMed  Article  Google Scholar 

  10. 10.

    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.

    PubMed  Article  Google Scholar 

  11. 11.

    Moniche F, Gonzalez A, Gonzalez-Marcos JR, Carmona M, Pinero P, Espigado I, et al. Intra-arterial bone marrow mononuclear cells in ischemic stroke: a pilot clinical trial. Stroke. 2012;43(8):2242–4.

    PubMed  Article  Google Scholar 

  12. 12.

    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. 2010;28(6):1099–106.

    PubMed  Article  Google Scholar 

  13. 13.

    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.

    PubMed  Article  Google Scholar 

  14. 14.

    Wang LE, Fink GR, Diekhoff S, Rehme AK, Eickhoff SB, Grefkes C. Noradrenergic enhancement improves motor network connectivity in stroke patients. Ann Neurol. 2011;69(2):375–88.

    PubMed  Article  Google Scholar 

  15. 15.

    Ramsey LE, Siegel JS, Baldassarre A, Metcalf NV, Zinn K, Shulman GL, et al. Normalization of network connectivity in hemispatial neglect recovery. Ann Neurol. 2016;80(1):127–41.

    PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Loubinoux I, Dechaumont-Palacin S, Castel-Lacanal E, De Boissezon X, Marque P, Pariente J, et al. Prognostic value of FMRI in recovery of hand function in subcortical stroke patients. Cereb Cortex. 2007;17(12):2980–7.

    PubMed  Article  Google Scholar 

  17. 17.

    Richards LG, Stewart KC, Woodbury ML, Senesac C, Cauraugh JH. Movement-dependent stroke recovery: a systematic review and meta-analysis of TMS and fMRI evidence. Neuropsychologia. 2008;46(1):3–11.

    PubMed  Article  Google Scholar 

  18. 18.

    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.

    PubMed  Article  Google Scholar 

  19. 19.

    Hannanu FF, Zeffiro TA, Lamalle L, Heck O, Renard F, Thuriot A, et al. Parietal operculum and motor cortex activities predict motor recovery in moderate to severe stroke. NeuroImage Clin. 2017;14:518–29.

    PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Zhao LR, Duan WM, Reyes M, Keene CD, Verfaillie CM, Low WC. Human bone marrow stem cells exhibit neural phenotypes and ameliorate neurological deficits after grafting into the ischemic brain of rats. Exp Neurol. 2002;174(1):11–20.

    PubMed  Article  Google Scholar 

  21. 21.

    Li Y, Chen J, Chopp M. Adult bone marrow transplantation after stroke in adult rats. Cell Transplant. 2001;10(1):31–40.

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Chen J, Li Y, Katakowski M, Chen X, Wang L, Lu D, et al. Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat. J Neurosci Res. 2003;73(6):778–86.

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Brott T, Adams HP Jr, Olinger CP, Marler JR, Barsan WG, Biller J, et al. Measurements of acute cerebral infarction: a clinical examination scale. Stroke. 1989;20(7):864–70.

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Mahoney FI, Barthel DW. Functional evaluation: the Barthel Index. Maryland State Med J. 1965;14:61–5.

    CAS  Google Scholar 

  25. 25.

    van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988;19(5):604–7.

    PubMed  Article  Google Scholar 

  26. 26.

    Sullivan KJ, Tilson JK, Cen SY, Rose DK, Hershberg J, Correa A, et al. Fugl-Meyer assessment of sensorimotor function after stroke: standardized training procedure for clinical practice and clinical trials. Stroke. 2011;42(2):427–32.

    PubMed  Article  Google Scholar 

  27. 27.

    Chollet F, Tardy J, Albucher JF, Thalamas C, Berard E, Lamy C, et al. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial. Lancet Neurol. 2011;10(2):123–30.

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Loubinoux I. Can fMRI measures of brain motor activation add significantly to other variables in the prediction of treatment response? Stroke. 2007;38(7):2032–3.

    PubMed  Article  Google Scholar 

  29. 29.

    Mahdavi A, Azar R, Shoar MH, Hooshmand S, Mahdavi A, Kharrazi HH. Functional MRI in clinical practice: assessment of language and motor for pre-surgical planning. Neuroradiol J. 2015;28(5):468–73.

    PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    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.

    PubMed  Article  Google Scholar 

  31. 31.

    Choudhri AF, Patel RM, Siddiqui A, Whitehead MT, Wheless JW. Cortical activation through passive-motion functional MRI. AJNR Am J Neuroradiol. 2015;36(9):1675–81.

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Blatow M, Reinhardt J, Riffel K, Nennig E, Wengenroth M, Stippich C. Clinical functional MRI of sensorimotor cortex using passive motor and sensory stimulation at 3 Tesla. J Magn Reson Imaging. 2011;34(2):429–37.

    PubMed  Article  Google Scholar 

  33. 33.

    Weiller C, Juptner M, Fellows S, Rijntjes M, Leonhardt G, Kiebel S, et al. Brain representation of active and passive movements. NeuroImage. 1996;4(2):105–10.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Loubinoux I, Carel C, Alary F, Boulanouar K, Viallard G, Manelfe C, et al. Within-session and between-session reproducibility of cerebral sensorimotor activation: a test–retest effect evidenced with functional magnetic resonance imaging. J Cereb Blood Flow Metab. 2001;21(5):592–607.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Tombari D, Loubinoux I, Pariente J, Gerdelat A, Albucher JF, Tardy J, et al. A longitudinal fMRI study: in recovering and then in clinically stable sub-cortical stroke patients. NeuroImage. 2004;23(3):827–39.

    PubMed  Article  Google Scholar 

  36. 36.

    Wilkinson L, Task Force on Statistical Inference. Statistical methods in psychology journals: guidelines and explanations. Am Psychol. 1999;54:594–604.

    Article  Google Scholar 

  37. 37.

    Middlemiss W, Granger DA, Goldberg WA. Response to “let’s help parents help themselves: a letter to the editor supporting the safety of behavioural sleep techniques”. Early Hum Dev. 2013;89(1):41–2.

    PubMed  Article  Google Scholar 

  38. 38.

    Cohen J. Statistical power analysis for the behavioral science. 2nd ed. New York: Lawrence Erlbaum Associate; 1988.

    Google Scholar 

  39. 39.

    Lakens D. Calculating and reporting effect sizes to facilitate cumulative science: a practical primer for t-tests and ANOVAs. Front Psychol. 2013;4:863.

    PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Cheng J, Edwards LJ, Maldonado-Molina MM, Komro KA, Muller KE. Real longitudinal data analysis for real people: building a good enough mixed model. Stat Med. 2010;29(4):504–20.

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    Maas CJM, Snijders TAB. The multilevel approach to repeated measures for complete and incomplete data. Qual Quant. 2003;37(1):71–89.

    Article  Google Scholar 

  42. 42.

    Burton P, Gurrin L, Sly P. Extending the simple linear regression model to account for correlated responses: an introduction to generalized estimating equations and multi-level mixed modelling. Stat Med. 1998;17(11):1261–91.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Steyerberg EW, Harrell FE, Borsboom GJ, Eijkemans MJ, Vergouwe Y, Habbema JD. Internal validation of predictive models: efficiency of some procedures for logistic regression analysis. J Clin Epidemiol. 2001;54(8):774–81.

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Veldema J, Bosl K, Nowak DA. Motor recovery of the affected hand in subacute stroke correlates with changes of contralesional cortical hand motor representation. Neural Plasticity. 2017;2017:6171903.

    PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Hommel M, Detante O, Favre I, Touze E, Jaillard A. How to measure recovery? Revisiting concepts and methods for stroke studies. Transl Stroke Res. 2016;7(5):388–94.

    PubMed  Article  Google Scholar 

  46. 46.

    Rehme AK, Volz LJ, Feis DL, Eickhoff SB, Fink GR, Grefkes C. Individual prediction of chronic motor outcome in the acute post-stroke stage: behavioral parameters versus functional imaging. Hum Brain Mapp. 2015;36(11):4553–65.

    PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Carey LM, Abbott DF, Egan GF, Bernhardt J, Donnan GA. Motor impairment and recovery in the upper limb after stroke: behavioral and neuroanatomical correlates. Stroke. 2005;36(3):625–9.

    PubMed  Article  Google Scholar 

  48. 48.

    Loubinoux I, Carel C, Pariente J, Dechaumont S, Albucher JF, Marque P, et al. Correlation between cerebral reorganization and motor recovery after subcortical infarcts. NeuroImage. 2003;20(4):2166–80.

    PubMed  Article  Google Scholar 

  49. 49.

    Rehme AK, Eickhoff SB, Rottschy C, Fink GR, Grefkes C. Activation likelihood estimation meta-analysis of motor-related neural activity after stroke. NeuroImage. 2012;59(3):2771–82.

    PubMed  Article  Google Scholar 

  50. 50.

    Geyer S, Ledberg A, Schleicher A, Kinomura S, Schormann T, Burgel U, et al. Two different areas within the primary motor cortex of man. Nature. 1996;382(6594):805–7.

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Rathelot J-A, Strick PL. Subdivisions of primary motor cortex based on cortico-motoneuronal cells. Proc Natl Acad Sci. 2009;106(3):918–23.

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Heddings AA, Friel KM, Plautz EJ, Barbay S, Nudo RJ. Factors contributing to motor impairment and recovery after stroke. Neurorehabil Neural Repair. 2000;14(4):301–10.

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Nudo RJ, Plautz EJ, Frost SB. Role of adaptive plasticity in recovery of function after damage to motor cortex. Muscle Nerve. 2001;24(8):1000–19.

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    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.

    PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Mays RW, Savitz SI. Intravenous cellular therapies for acute ischemic stroke. Stroke. 2018;49(5):1058–65.

    PubMed  Article  Google Scholar 

  56. 56.

    Foley N, McClure JA, Meyer M, Salter K, Bureau Y, Teasell R. Inpatient rehabilitation following stroke: amount of therapy received and associations with functional recovery. Disabil Rehabil. 2012;34(25):2132–8.

    PubMed  Article  Google Scholar 

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We thank the other members of the ISIS-HERMES Study group (listed in alphabetical order): S. Achard, P. Antoine, E. L. Barbier C.E. Bulabois, L. Carey, A. Chrispin, M. Cucherat, P. Davoine, F. de Fraipont, C. Delon-Martin, C. Dubray, H. Egelhofer, M.C. Favrot, K. Garambois, P. Garnier, J. Gere, N. Gonnet, I Goundous, F.F. Hannanu, O. Heck, A.V. Jaillard, A. Krainik, J.F. Le Bas, S. Miguel, A. B. Naegele, A. Paris, D. Perennou, P. Pernot, C. Remy, F. Renard, M.J. Richard, G. Rodier, E. Schir A. Thuriot, I. Tropres, and J. Warnking.

Trial Registration, number NCT00875654.


French ISIS RCT and satellite MRI HERMES protocols are available on demand.


This trial was funded by an academic grant from the French Health Ministry: PHRCI Grant numbers: ISIS-2007PHR04 and HERMES-2007-A00853-50. The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. MRI data acquisition was performed at the IRMaGe MRI platform, which gratefully acknowledge financial support from France Life Imaging network through the grant “ANR-11-INBS-0006.” Data monitoring was performed by the Clinical Investigation Center (CIC) INSERM UMS 002 CHU Grenoble Alpes. Data analysis was partly supported by RESSTORE project ( funded by the European Commission under the H2020 program (Grant Number 681044).

Author information





Dr. Jaillard had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the analysis. Concept and design: A. Jaillard, M. Hommel, and O. Detante. Acquisition of data. Recruitment and/or clinical follow-up: O. Detante, I. Favre-Wiki, M. Barbieux-Guillot, W. Vadot, and S. Marcel. MRI data acquisition: A. Jaillard, M. Hommel, L. Lamalle, and S. Grand. Analysis or interpretation of data: A. Jaillard, M. Hommel, T. A. Zeffiro, and O. Detante. Drafting of the manuscript: A. Jaillard, O. Detante, M. Hommel, T.A. Zeffiro, and A. Moisan. Critical revision of the manuscript for important intellectual content: A. Jaillard, T.A. Zeffiro, M. Hommel, and O. Detante. Statistical analysis: A. Jaillard and M. Hommel. Obtaining funding: A. Jaillard and O. Detante. Administrative, technical, or material support: A. Jaillard, M. Hommel, O. Detante, L. Lamalle (MRI calibration), and A. Moisan (Autologous mesenchymal stem cell preparation). Study supervision: O. Detante (ISIS) and A. Jaillard (HERMES).

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Correspondence to Assia Jaillard.

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The authors declare that they have no conflict of interest.

Ethical Approval

All patients gave written informed consent. The trial and the amendments were approved by the local ethics committee (“Comité de Protection des Personnes”). ISIS was monitored by an independent data and safety monitoring board (DSMB).

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Jaillard, A., Hommel, M., Moisan, A. et al. Autologous Mesenchymal Stem Cells Improve Motor Recovery in Subacute Ischemic Stroke: a Randomized Clinical Trial. Transl. Stroke Res. (2020).

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  • Stroke
  • Mesenchymal stem cell
  • Motor recovery
  • fMRI
  • Biomarker
  • Cell therapy
  • Neuroimaging
  • Motor
  • Recovery
  • Motor activation