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01-10-2020 | Stroke | Original Article

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

Authors: Assia Jaillard, Marc Hommel, Anaick Moisan, Thomas A. Zeffiro, Isabelle M. Favre-Wiki, Marianne Barbieux-Guillot, Wilfried Vadot, Sebastien Marcel, Laurent Lamalle, Sylvie Grand, Olivier Detante, (for the ISIS-HERMES Study Group)

Published in: Translational Stroke Research | Issue 5/2020

Abstract

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.

ClinicalTrials.gov Identifier NCT 00875654.

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

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

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.

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.PubMed

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

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.PubMedPubMedCentral

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.

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.PubMedPubMedCentral

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

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

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

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

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

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

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.PubMedPubMedCentral

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

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

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

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.PubMedPubMedCentral

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

21.

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

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.PubMed

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.PubMed

24.

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

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

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

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.PubMed

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

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.PubMedPubMedCentral

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

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.PubMed

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

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.PubMed

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.PubMed

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

36.

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

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

38.

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

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.PubMedPubMedCentral

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.PubMedPubMedCentral

41.

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

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.PubMed

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.PubMed

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.PubMedPubMedCentral

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

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.PubMedPubMedCentral

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

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

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

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.PubMed

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.PubMed

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.PubMed

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.PubMed

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.PubMedPubMedCentral

55.

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

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

Title: Autologous Mesenchymal Stem Cells Improve Motor Recovery in Subacute Ischemic Stroke: a Randomized Clinical Trial
Authors: Assia Jaillard
Marc Hommel
Anaick Moisan
Thomas A. Zeffiro
Isabelle M. Favre-Wiki
Marianne Barbieux-Guillot
Wilfried Vadot
Sebastien Marcel
Laurent Lamalle
Sylvie Grand
Olivier Detante
(for the ISIS-HERMES Study Group)
Publication date: 01-10-2020
Publisher: Springer US
Keywords: Stroke
Biomarkers
Published in: Translational Stroke Research / Issue 5/2020
Print ISSN: 1868-4483
Electronic ISSN: 1868-601X
DOI: https://doi.org/10.1007/s12975-020-00787-z

At a glance: The STEP trials

Springer Medicine

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

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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