Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 May 5;5(5):CD007231.
doi: 10.1002/14651858.CD007231.pub3.

Stem cell transplantation for ischemic stroke

Giorgio Battista Boncoraglio  1 , Michela Ranieri, Anna Bersano, Eugenio A Parati, Cinzia Del Giovane
Affiliations

Stem cell transplantation for ischemic stroke

Giorgio Battista Boncoraglio et al. Cochrane Database Syst Rev. .

Abstract

Background: Stroke is a leading cause of morbidity and mortality worldwide, with very large healthcare and social costs, and a strong demand for alternative therapeutic approaches. Preclinical studies have shown that stem cells transplanted into the brain can lead to functional improvement. However, to date, evidence for the benefits of stem cell transplantation in people with ischemic stroke is lacking. This is the first update of the Cochrane review published in 2010.

Objectives: To assess the efficacy and safety of stem cell transplantation compared with control in people with ischemic stroke.

Search methods: We searched the Cochrane Stroke Group Trials Register (last searched August 2018), CENTRAL (last searched August 2018), MEDLINE (1966 to August 2018), Embase (1980 to August 2018), and BIOSIS (1926 to August 2018). We handsearched potentially relevant conference proceedings, screened reference lists, and searched ongoing trials and research registers (last searched August 2018). We also contacted individuals active in the field and stem cell manufacturers (last contacted August 2018).

Selection criteria: We included randomized controlled trials (RCTs) that recruited people with ischemic stroke, in any phase of the disease (acute, subacute or chronic), and an ischemic lesion confirmed by computerized tomography or magnetic resonance imaging scan. We included all types of stem cell transplantation, regardless of cell source (autograft, allograft, or xenograft; embryonic, fetal, or adult; from brain or other tissues), route of cell administration (systemic or local), and dosage. The primary outcome was efficacy (assessed as neurologic impairment or functional outcome) at longer term follow-up (minimum six months). Secondary outcomes included post-procedure safety outcomes (death, worsening of neurological deficit, infections, and neoplastic transformation).

Data collection and analysis: Two review authors independently applied the inclusion criteria, assessed trial quality and risk of bias, and extracted data. If needed, we contacted study authors for additional information. We performed random effects meta-analyses when two or more RCTs were available for any outcome. We assessed the certainty of the evidence by using the GRADE approach.

Main results: In this updated review, we included seven completed RCTs with 401 participants. All tested adult human non-neural stem cells; cells were transplanted during the acute, subacute, or chronic phase of ischemic stroke; administered intravenously, intra-arterially, intracerebrally, or into the lumbar subarachnoid space. Follow-up ranged from six months to seven years. Efficacy outcomes were measured with the National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), or Barthel Index (BI). Safety outcomes included case fatality, and were measured at the end of the trial.Overall, stem cell transplantation was associated with a better clinical outcome when measured with the NIHSS (mean difference [MD] -1.49, 95% confidence interval [CI] -2.65 to -0.33; five studies, 319 participants; low-certainty evidence), but not with the mRS (MD -0.42, 95% CI -0.86 to 0.02; six studies, 371 participants; very low-certainty evidence), or the BI (MD 14.09, 95% CI -1.94 to 30.13; three studies, 170 participants; very low-certainty evidence). The studies in favor of stem cell transplantation had, on average, a higher risk of bias, and a sample size of 32 or fewer participants.No significant safety concerns associated with stem cell transplantation were raised with respect to death (risk ratio [RR] 0.66, 95% CI 0.39 to 1.14; six studies, participants; low-certainty evidence).We were not able to perform the sensitivity analysis according to the quality of studies, because all of them were at high risk of bias.

Authors' conclusions: Overall, in participants with ischemic stroke, stem cell transplantation was associated with a reduced neurological impairment, but not with a better functional outcome. No obvious safety concerns were raised. However, these conclusions came mostly from small RCTs with high risk of bias, and the certainty of the evidence ranged from low to very low. More well-designed trials are needed.

PubMed Disclaimer

Conflict of interest statement

Giorgio Battista Boncoraglio: none known. Michela Ranieri: none known. Anna Bersano: none known. Eugenio A Parati: none known. Cinzia Del Giovane: none known.

Figures

1
1
Results of database searches
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study (green for low risk of bias, yellow for unclear risk of bias, and red for high risk of bias)
1.1
1.1. Analysis
Comparison 1 Stem cell transplantation versus conventional treatments, Outcome 1 Neurologic impairment (measured by NIHSS).
1.2
1.2. Analysis
Comparison 1 Stem cell transplantation versus conventional treatments, Outcome 2 Neurologic impairment (measured by NIHSS, by phase of disease).
1.3
1.3. Analysis
Comparison 1 Stem cell transplantation versus conventional treatments, Outcome 3 Neurologic impairment (measured by NIHSS, by route of administration).
1.4
1.4. Analysis
Comparison 1 Stem cell transplantation versus conventional treatments, Outcome 4 Disability (measured by mRS).
1.5
1.5. Analysis
Comparison 1 Stem cell transplantation versus conventional treatments, Outcome 5 Disability (measured by mRS, by phase of disease).
1.6
1.6. Analysis
Comparison 1 Stem cell transplantation versus conventional treatments, Outcome 6 Disability (measured by mRS, by route of administration).
1.7
1.7. Analysis
Comparison 1 Stem cell transplantation versus conventional treatments, Outcome 7 Dependency (measured by BI).
1.8
1.8. Analysis
Comparison 1 Stem cell transplantation versus conventional treatments, Outcome 8 Dependency (measured by BI, by route of administration).
1.9
1.9. Analysis
Comparison 1 Stem cell transplantation versus conventional treatments, Outcome 9 Any cause of death.
1.10
1.10. Analysis
Comparison 1 Stem cell transplantation versus conventional treatments, Outcome 10 Severe worsening of neurological deficit.
1.11
1.11. Analysis
Comparison 1 Stem cell transplantation versus conventional treatments, Outcome 11 Infections.
1.12
1.12. Analysis
Comparison 1 Stem cell transplantation versus conventional treatments, Outcome 12 Neoplastic transformation of ischemic lesion at longer‐term follow‐up.
See this image and copyright information in PMC

Update of

References

References to studies included in this review

Bang 2005 {published and unpublished data}
    1. Bang OY, Lee JS, Lee PH, Lee G. Autologous mesenchymal stem cell transplantation in stroke patients. Annals of Neurology 2005;57(6):874‐82. - PubMed
Bhatia 2015 {published and unpublished data}
    1. Bhatia V, Gupta V, Khurana D, Sharma RR, Khandelwal N. Randomized assessment of the safety and efficacy of intra‐arterial infusion of autologous stem cells in subacute ischemic stroke. American Journal of Neuroradiology 2018;39(5):899‐904. - PMC - PubMed
    1. Khurana D, Singh R, Gupta V, Sharma R, Khandelwal N. Safety and efficacy of intra‐arterial infusion of bone marrow derived mononuclear cells in subacute ischemic stroke: randomized open labeled clinical trial. European Stroke Journal 2017;2(1S):483.
    1. Singh R, Khurana D, Sharma RR, Gupta V. Safety and clinical outcome of intraarterial infusion of bone marrow derived mononuclear cells in subacute ischemic stroke: randomized open labeled blinded end point clinical pilot trial. European Stroke Journal 2018;3(1S):128.
Chen 2014 {published data only}
    1. Chen DC, Lin SZ, Fan JR, Lin CH, Lee W, Lin CC, et al. Intracerebral implantation of autologous peripheral blood stem cells in stroke patients: a randomized phase II study. Cell Transplantation 2014;23(12):1599‐612. - PubMed
Hess 2014 {published and unpublished data}
    1. Hess DC, Auchus AP, Uchino K, Sila C, Clark WM, Chiu D, et al. Final results of the B01‐02 phase 2 trial testing the safety and efficacy of MultiStem in treatment of ischemic stroke. Stroke 2016;47:A71.
    1. 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. International Journal of Stroke 2014;9(3):381‐6. - PubMed
    1. 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 Neurology 2017;16(5):360‐8. - PubMed
Jin 2016 {published data only}
    1. Jin Y, Ying L, Yu G, Nan G. Analysis of the long‐term effect of bone marrow mononuclear cell transplantation for the treatment of cerebral infarction. International Journal of Clinical and Experimental Medicine 2017;10(2):3059‐68.
Lee 2010 {published data only}
    1. Lee JS, Hong JM, Moon GJ, Lee PH, Ahn YH, Bang OY, STARTING Collaborators. 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
Prasad 2014 {published and unpublished data}
    1. 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. - PubMed

References to studies excluded from this review

Banerjee 2014 {published data only}
    1. 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 Translational Medicine 2014;3(11):1322‐30. - PMC - PubMed
Battistella 2011 {published data only}
    1. Battistella V, Freitas GR, Fonseca LM, Mercante D, Gutfilen B, Goldenberg RC, et al. Safety of autologous bone marrow mononuclear cell transplantation in patients with non acute ischemic stroke. Regenerative Medicine 2011;6(1):45‐52. - PubMed
Bhasin 2011 {published data only}
    1. Bhasin A, Srivastava MV, Kumaran SS, Mohanty S, Bhatia R, Bose S, et al. Autologous mesenchymal stem cells in chronic stroke. Cerebrovascular Diseases Extra 2011;1:93–104. - PMC - PubMed
Bhasin 2013 {published data only}
    1. Bhasin A, Srivastava MV, Mohanty S, Bhatia R, Kumaran SS, Bose S. Stem cell therapy: a clinical trial of stroke. Clinical Neurology and Neurosurgery 2013;115(7):1003‐8. - PubMed
CoBIS 2015 {published data only}
    1. Laskowitz DT, Bennett ER, Durham RJ, Volpi JJ, Wiese JR, Frankel M, et al. Allogeneic umbilical cord blood infusion for adults with ischemic stroke: clinical outcomes from a phase 1 safety study. Stem Cells Translational Medicine 2018;7:521–9. - PMC - PubMed
Friedrich 2012 {published data only}
    1. Friedrich MA, 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 Transplantation 2012;21 Suppl 1:S13‐21. - PubMed
Ghali 2016 {published data only}
    1. Ghali AA, Yousef MK, Ragab OA, ElZamarany EA. Intra‐arterial infusion of autologous bone marrow mononuclear stem cells in subacute ischemic stroke patients. Frontiers in Neurology 2016;7:228. - PMC - PubMed
Honmou 2011 {published data only}
    1. 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 2011;134:1790‐807. - PMC - PubMed
ISRCTN15677760 {unpublished data only}
    1. ISRCTN15677760. The therapeutic effect of autologous peripheral blood‐derived stem cell therapy on acute brain infarcts. isrctn.com/ISRCTN15677760 (first received 23 April 2018).
Kondziolka 2000 {published data only (unpublished sought but not used)}
    1. 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. - PubMed
    1. Meltzer CC, Kondziolka D, Villemagne VL, Wechsler L, Goldstein S, Thulborn KR, et al. Serial [18F] fluorodeoxyglucose positron emission tomography after human neuronal implantation for stroke. Neurosurgery 2001;49(3):586‐91. - PubMed
    1. Nelson PT, Kondziolka D, Wechsler L, Goldstein S, Gebel J, DeCesare S, et al. Clonal human (hNT) neuron grafts for stroke therapy: neuropathology in a patient 27 months after implantation. American Journal of Pathology 2002;160(4):1201‐6. - PMC - PubMed
Li 2007 {published data only}
    1. Li JB, Man Y, Shan H, Duan YL. Sterile preparation of umbilical cord derived mesenchymal stem cells with multiple bags: method and effect. Journal of Clinical Rehabilitative Tissue Engineering Research 2007;11(24):4781‐4.
Lin 2008 {published data only}
    1. Lin SZ, Shyu WC, Li H. CD34+ stem cell therapy in chronic stroke patients – Phase I trial. Cell Transplantation 2008;17(4):472.
Lu 2013 {published data only}
    1. Lu W, Li Z, Tian Z, Jia B, Zeng Y. Clinical transplantation of human embryonic neural stem cells for the treatment of cerebral infarction sequelae. Neurosurgery Quarterly 2013;23(1):58‐60.
Man 2006 {published data only}
    1. Man Y, Li J, Yang B, Ma J. Vein transplantation using human umbilical cord blood stem cells in the treatment of stroke sequela. Neural Regeneration Research 2006;1(7):618‐21.
Mendonça 2006 {published data only}
    1. Mendez‐Otero R, Freitas GR, André C, Mendonça ML, Friedrich M, Oliveira‐Filho J. Potential roles of bone marrow stem cells in stroke therapy. Regenerative Medicine 2007;2(4):417‐23. - PubMed
    1. Mendonça ML, Freitas GR, Silva SA, Manfrim A, Falcão CH, Gonzáles C, et al. Intra‐arterial autologous bone marrow mononuclear cell transplantation for acute ischemic stroke. Arquivos Brasileiros de Cardiologia 2006;86(1):52‐5. - PubMed
Meng 2009 {published data only}
    1. Meng X‐G, Zhu S‐W, Gao H, Li Z, Shi Q, Hou H‐S, et al. Treatment of cerebral infarction using autologous marrow mesenchymal stem cells transplantation: a six‐month follow‐up. Journal of Clinical Rehabilitative Tissue Engineering Research 2009; Vol. 13, issue 32:6374‐8.
Mohamed Ibrahim 2016 {published data only}
    1. Mohamed Ibrahim N, Tan H, Chin S, Law Z, Ismail N, Cheong S, et al. BM‐MSC accelerates acute stroke recovery in a randomized placebo‐controlled clinical phase II/III study. Cytotherapy 2016;18(6 Supplement):S8.
Moniche 2012 {published data only}
    1. Moniche F, Gonzalez A, Gonzalez‐Marcos JR, Carmona M, Piñero 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
    1. Moniche F, Montaner J, Gonzalez‐Marcos JR, 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 Transplantation 2014;23 Suppl 1:S57‐64. - PubMed
Napgal 2016 {published data only}
    1. Nagpal A, Kremer KL, Hamilton‐Bruce MA, Kaidonis X, Milton AG, Levi C, et al. TOOTH (The Open study Of dental pulp stem cell Therapy in Humans): study protocol for evaluating safety and feasibility of autologous human adult dental pulp stem cell therapy in patients with chronic disability after stroke. International Journal of Stroke 2016;11(5):575‐85. - PubMed
NCT01297413 {unpublished data only}
    1. NCT01297413. A study of allogeneic mesenchymal bone marrow cells in subjects with ischemic stroke. clinicalTrials.gov/show/NCT01297413 (first received 16 February 2011).
NCT02397018 {unpublished data only}
    1. NCT02397018. Cord blood infusion for ischemic stroke. clinicalTrials.gov/show/NCT02397018 (first received 24 March 2015).
NCT02795052 {unpublished data only}
    1. NCT02795052. Neurologic Stem cell Treatment study (NEST). clinicalTrials.gov/show/NCT02795052 (first received 9 June 2016).
NCT03296618 {unpublished data only}
    1. NCT03296618. Intracerebral transplantation of neural stem cells for the treatment of ischemic stroke. clinicaltrials.gov/show/NCT03296618 (first received 28 September 2017).
NCT03384433 {unpublished data only}
    1. NCT03384433. Allogenic mesenchymal stem cell derived exosome in patients with acute ischemic stroke. clinicaltrials.gov/show/NCT03384433 (first received 27 December 2017).
PISCES 2016 {published data only}
    1. 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. - PubMed
    1. Muir KW. Neural stem cells in ischaemic stroke: from bench‐to‐bedside. Journal of Neurology 2012;259 Suppl 1:S109.
PISCES II 2017 {published data only}
    1. Bulters D, Wilmot M, Sprigg N, Dixit A, Ward N, Tyrrell P, et al. Ctx human stem cells in stroke recovery: 6 month outcomes of the pilot investigation of stem cells in stroke phase 2 efficacy (PISCES II) study. European Stroke Journal 2017;2(1S):484.
Prasad 2012 {published data only}
    1. Prasad K, Mohanty S, Bhatia R, Srivastava MV, Garg A, Srivastava A, et al. Autologous intravenous bone marrow mononuclear cell therapy for patients with subacute ischaemic stroke: a pilot study. Indian Journal of Medical Research 2012;136(2):221‐8. - PMC - PubMed
Qiao 2014 {published data only}
    1. Qiao L, Huang F, Zhao M, Xie J, Shi J, Wang J, et al. A two‐year follow‐up study of cotransplantation with neural stem/progenitor cells and mesenchymal stromal cells in ischemic stroke patients. Cell Transplantation 2014; Vol. 23 Suppl 1:S65–72. - PubMed
Rabinovich 2005 {published data only}
    1. Rabinovich SS, Seledtsov VI, Banul NV, Poveshchenko OV, Senyukov VV, Astrakov SV, et al. Cell therapy of brain stroke. Bulletin of Experimental Biology and Medicine 2005;139(1):126‐8. - PubMed
Savitz 2005 {published data only}
    1. 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. Cerebrovascular Diseases 2005;20(2):101‐7. - PubMed
Savitz 2011 {published data only}
    1. Savitz SI, Misra V, Kasam M, Juneja H, Cox CS Jr, Alderman S, et al. Intravenous autologous bone marrow mononuclear cells for ischemic stroke. Annals of Neurology 2011; Vol. 70:59–69. - PubMed
Sharma 2014 {published data only}
    1. Sharma A, Sane H, Gokulchandran N, Khopkar D, Paranjape A, Sundaram J, et al. Autologous bone marrow mononuclear cells intrathecal transplantation in chronic stroke. Stroke Research and Treatment 2014; Vol. 2014:234095. - PMC - PubMed
Sinden 2009 {published data only}
    1. Sinden J. ReN001, a stem cell therapy for stroke disability. Cell Transplantation 2009;18(2):234.
Steinberg 2014 {published data only}
    1. Steinberg GK, Kondziolka D, Schwartz NE, Wechsler L, Lunsford D, Coburn ML, et al. A novel phase 1/2A study of intraparenchymal transplantation of human modified bone marrow‐derived cells in patients with stable ischemic stroke. Cell Transplantation 2014;23(6):784.
    1. 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. - PMC - PubMed
Suarez‐Monteagudo 2009 {published data only}
    1. Suárez‐Monteagudo C, Hernández‐Ramírez P, Alvarez‐González L, García‐Maeso I, Cuétara‐Bernal K, Castillo‐Díaz L, et al. Autologous bone marrow stem cell neurotransplantation in stroke patients. An open study. Restorative Neurology and Neuroscience 2009;27(3):151‐61. - PubMed
Taguchi 2015 {published data only}
    1. 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 and Development 2015; Vol. 24, issue 19:2207‐18. - PMC - PubMed
Vahidy 2012 {published data only}
    1. Vahidy F, Kar S, Aisiku I, Juneja H, Lee D, Garret J, et al. Safety of intravenous mononuclear cells for acute stroke (SIVMAS) trial. Cell Transplantation 2012; Vol. 21 Suppl 1:795.
Wanamaker 2015 {published data only}
    1. Wanamaker CP, Fakhran S, Alhilali LM. Qualitative and quantitative analysis of MR imaging findings in patients with middle cerebral artery stroke implanted with mesenchymal stem cells. American Journal of Neuroradiology 2015;36(6):1063‐8. - PMC - PubMed
Wang 2007 {published data only}
    1. Wang YC, Zhang CQ, Wang LZ, Wen H, Yin ZM, Wang L, et al. Autologous bone marrow‐derived mononuclear cell transplant for treatment of nervous system damage and degenerative disease: a report of 42 cases. Journal of Clinical Rehabilitative Tissue Engineering Research 2007;11(20):3994‐7.
Wang 2013 {published data only}
    1. Wang L, Ji H, Li M, Zhou J, Bai W, Zhong Z, et al. Intrathecal administration of autologous CD34 positive cells in patients with past cerebral infarction: a safety study. ISRN Neurology 2013;2013:128591. - PMC - PubMed
Yang 2005 {published data only}
    1. Yang QC, Zhang XD, Liang CC, Du Y, Li HW. Functional evaluation of stroke patients 6 months after intrathecal injection of neural stem cells. Chinese Journal of Clinical Rehabilitation 2005;9(9):208‐10.
Yang 2007 {published data only}
    1. Yang QC, Liang CC, Li MX, Zhang XD, Ma DF. Neural stem cell transplantation for treating stroke sequela in 59 cases. Journal of Clinical Rehabilitative Tissue Engineering Research 2007;11(20):4033‐5.
Zhang 2006 {published data only}
    1. Zhang RY, Zheng YR, Hu SS, Cheng HB, An YH. Clinical analysis of neural stem cells for treatment of sequela in 50 stroke patients. Chinese Journal of Clinical Rehabilitation 2006;10(9):138‐9.

References to studies awaiting assessment

ChiCTR‐INR‐16008908 {unpublished data only}
    1. ChiCTR‐INR‐16008908. Allogenic bone marrow‐derived mesenchymal stem cells transplantation in severe cerebral infarction patients: a randomized controlled clinical trial. www.chictr.org.cn/showprojen.aspx?proj=14716 (first received 25 July 2016).
Kondziolka 2005 {published data only}
    1. 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. Journal of Neurosurgery 2005;103(1):38‐45. - PubMed
    1. Stilley CS, Ryan CM, Kondziolka D, Bender A, DeCesare S, Wechsler L. Changes in cognitive function after neuronal cell transplantation for basal ganglia stroke. Neurology 2004;63(7):1320‐2. - PubMed
NCT01310114 {unpublished data only}
    1. NCT01310114. Study of human placenta‐derived cells (PDA001) to evaluate the safety and effectiveness for patients with ischemic stroke. clinicaltrials.gov/show/NCT01310114 (first received 8 March 2011).
NCT01468064 {unpublished data only}
    1. NCT01468064. Autologous bone marrow stromal cell and endothelial progenitor cell transplantation in ischemic stroke (AMETIS). clinicaltrials.gov/show/NCT01468064 (first received 9 November 2011).
NCT01518231 {unpublished data only}
    1. NCT01518231. Autologous hematopoietic stem cell transplantation in ischemic stroke (AHSCTIS). clinicaltrials.gov/show/NCT01518231 (first received 25 January 2012).
NCT02378974 {unpublished data only}
    1. NCT02378974. Evaluation of the safety and potential therapeutic effects after intravenous transplantation of Cordstem‐ST in patients with cerebral infarction. clinicaltrials.gov/show/NCT02378974 (first received 4 March 2015).
NCT02564328 {unpublished data only}
    1. NCT02564328. Autologous bone marrow mesenchymal stem cell transplantation for chronic ischemic stroke. clinicaltrials.gov/show/NCT02564328 (first received 30 September 2015).
NCT02605707 {unpublished data only}
    1. NCT02605707. Autologous endothelial progenitor cells transplantation for chronic ischemic stroke. clinicaltrials.gov/show/NCT02605707 (first received 16 November 2015).
NCT03176498 {unpublished data only}
    1. NCT03176498. Human umbilical cord mesenchymal stem cell therapy for cerebral infarction patients in convalescent period. clinicaltrials.gov/show/NCT03176498 (first received 5 June 2017).
NCT03186456 {unpublished data only}
    1. NCT03186456. The safety and efficacy of human umbilical cord mesenchymal stem cells in the treatment of acute cerebral infarction. clinicaltrials.gov/show/NCT03186456 (first received 14 June 2017).
Sych 2012 {published data only}
    1. Sych N, Klunnyk M, lvankova O, Matiyaschuk I. Cognitive functions and S‐100 protein in acute brain infarction after fetal stem cells. 8th World Stroke Congress; 2012 Oct 10‐13; Brasilia (Brazil). 2012.
Yavagal 2015 {published data only}
    1. Atchaneeyasakul K, Dharmadhikari S, Sidani C, Ramdas K, Guada L, Pafford R, et al. Intra‐arterial ALD401 cell therapy is associated with reduction in stroke volume at 90 days in a subset of the RECOVER‐stroke trial. Stroke 2016;47:ATMP32.
    1. Yavagal DR, Huang DY, Graffagnino C, Rappard G, Budzik R, Likosky W, et al. Intra‐arterial delivery of autologous ALDHbr cells in ischemic stroke: final 1‐year results of the recover‐stroke trial. International Journal of Stroke 2015;10 Suppl 2:1–76.

References to ongoing studies

Bhasin 2016 {published data only}
    1. Bhasin A, Srivastava MV, Mohanty S, Vivekanandhan S, Sharma S, Kumaran S, et al. Paracrine mechanisms of intravenous bone marrow‐derived mononuclear stem cells in chronic ischemic stroke. Cerebrovascular Diseases Extra 2016;6(3):107‐19. - PMC - PubMed
    1. Bhasin A, Srivastava P, Mohanty S, Subramaniyam V, Kumaran S, Bhatia R. Intravenous bone marrow derived mononuclear stem cells in chronic ischemic stroke‐paracrine mechanisms of recovery. Stroke 2016;47 Suppl 1:47 (AWP146). - PMC - PubMed
Detante 2013 {published data only}
    1. Detante O, Jaillard A, Moisan A, Favre I, Barbieux M, Garambois K, et al. Intravenous injection of autologous mesenchymal stem cells after ischemic stroke (ISIS/HERMES): protocol and progress. Cerebrovascular Diseases 2013; Vol. 35 Suppl 3:852.
Diez‐Tejedor 2014 {published data only}
    1. Díez‐Tejedor E, Gutiérrez‐Fernández M, Martínez‐Sánchez P, Rodríguez‐Frutos B, Ruiz‐Ares G, Lara ML, et al. Reparative therapy for acute ischemic stroke with allogeneic mesenchymal stem cells from adipose tissue: a safety assessment: a phase II randomized, double‐blind, placebo‐controlled, single‐center, pilot clinical trial. Journal of Stroke and Cerebrovascular Diseases 2014;23(10):2694‐700. - PubMed
Honmou 2016 {published data only}
    1. Honmou O. Phase III clinical trial using autologous mesenchymal stem cells for stroke patients. Nihon Rinsho 2016;74(4):649‐54. - PubMed
Kim 2013 {published data only}
    1. Kim SJ, Moon GJ, Chang WH, Kim YH, Bang OY, STARTING‐2 (STem cell Application Researches and Trials In NeuroloGy‐2) collaborators. Intravenous transplantation of mesenchymal stem cells preconditioned with early phase stroke serum: current evidence and study protocol for a randomized trial. Trials 2013;14:317. - PMC - PubMed
Moniche 2015 {published data only}
    1. Moniche F, Escudero I, Zapata‐Arriaza E, Usero‐Ruiz M, Prieto‐León M, Torre J, et al. Intra‐arterial bone marrow mononuclear cells (BM‐MNCs) transplantation in acute ischemic stroke (IBIStrial): protocol of a phase II, randomised, dose‐finding, controlled multicenter trial. International Journal of Stroke 2015;10(7):1149‐52. - PubMed
NCT02448641 {unpublished data only}
    1. NCT02448641. Study of modified stem cells (SB623) in patients with chronic motor deficit from ischemic stroke (ACTIsSIMA). clinicaltrials.gov/ct2/show/NCT02448641 (first received 19 May 2015).
NCT02580019 {unpublished data only}
    1. NCT02580019. Umbilical cord derived mesenchymal stem cells treatment in ischemic stroke. clinicaltrials.gov/ct2/show/NCT02580019 (first received 20 October 2015).
NCT03004976 {unpublished data only}
    1. NCT03004976. Study of allogeneic umbilical cord blood infusion for adults with ischemic stroke (CoBIS 2). clinicaltrials.gov/show/NCT03004976 (first received 29 December 2016).
NCT03545607 {unpublished data only}
    1. NCT03545607. MultiStem® administration for stroke treatment and enhanced recovery study (MASTERS‐2). clinicaltrials.gov/show/NCT03545607 (first received 4 June 2018).
RESSTORE 2015 {unpublished data only}
    1. REgenerative Stem cell therapy for STroke in Europe. www.resstore.eu/about‐resstore.
TREASURE 2018 {published data only}
    1. Osanai T, Houkin K, Uchiyama S, Minematsu K, Taguchi A, Terasaka S. Treatment evaluation of acute stroke for using in regenerative cell elements (TREASURE) trial: rationale and design. International Journal of Stroke 2018;13(4):444‐8. - PubMed

Additional references

Borlongan 2016
    1. Borlongan CV. Age of PISCES: stem‐cell clinical trials in stroke. Lancet 2016;388(10046):736‐8. - PubMed
de Los Rios la Rosa 2012
    1. Ríos la Rosa F, Khoury J, Kissela BM, Flaherty ML, Alwell K, Moomaw CJ, et al. Eligibility for intravenous recombinant tissue‐type plasminogen activator within a population: the effect of the European Cooperative Acute Stroke Study (ECASS) III trial. Stroke 2012;43(6):1591‐5. - PMC - PubMed
Goldman 2016
    1. Goldman SA. Stem and progenitor cell‐based therapy of the central nervous system: hopes, hype, and wishful thinking. Cell Stem Cell 2016;18(2):174‐88. - PMC - PubMed
GRADE Working Group 2004
    1. GRADE Working Group. Grading quality of evidence and strength of recommendations. BMJ 2004;328(7454):1490‐4. - PMC - PubMed
GRADEpro GDT [Computer program]
    1. McMaster University (developed by Evidence Prime). GRADEpro GDT. Version (accessed 1 October 2018). Hamilton (ON): McMaster University (developed by Evidence Prime), 2015.
Hankey 2017
    1. Hankey GJ. Stroke. Lancet 2017;389(10069):641‐54. - PubMed
Higgins 2011
    1. Higgins JPT, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
Janowski 2015
    1. Janowski M, Wagner DC, Boltze J. Stem cell‐based tissue replacement after stroke: factual necessity or notorious fiction?. Stroke 2015;46(8):2354‐63. - PMC - PubMed
Kim 2017
    1. Kim JT, Fonarow GC, Smith EE, Reeves MJ, Navalkele DD, Grotta JC, et al. Treatment with tissue plasminogen activator in the golden hour and the shape of the 4.5‐hour time‐benefit curve in the National United States Get With The Guidelines‐Stroke Population. Circulation 2017;135(2):128‐39. - PubMed
Muir 2016
    1. Muir KW. Clinical trial design for stem cell therapies in stroke: what have we learned?. Neurochemistry International 2017;106:108‐13. - PubMed
Nagpal 2017
    1. 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 Research and Therapy 2017;8(1):191. - PMC - PubMed
Powers 2018
    1. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, American Heart Association Stroke Council. 2018 guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2018;49(3):e46‐110. - PubMed
PRISMA 2009
    1. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta‐analyses: the PRISMA statement. BMJ 2009;339:b2535. - PMC - PubMed
RevMan 2014 [Computer program]
    1. Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager 5 (RevMan 5). Version 5.3. Copenhagen: Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
STEPS 3 2014
    1. 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 2014;45(2):634‐9. - PMC - PubMed
Zhang 2009
    1. Zhang ZG, Chopp M. Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic. Lancet Neurology 2009;8(5):491‐500. - PMC - PubMed

References to other published versions of this review

Boncoraglio 2008
    1. Boncoraglio GB, Bersano A, Candelise L, Reynolds BA, Parati EA. Stem cell transplantation for ischemic stroke. Cochrane Database of Systematic Reviews 2008, Issue 3. [DOI: 10.1002/14651858.CD007231] - DOI - PubMed
Boncoraglio 2010
    1. Boncoraglio GB, Bersano A, Candelise L, Reynolds BA, Parati EA. Stem cell transplantation for ischemic stroke. Cochrane Database of Systematic Reviews 2010, Issue 9. [DOI: 10.1002/14651858.CD007231.pub2] - DOI - PubMed

Publication types