Remember Me
Or use your Academic/Social account:


Or use your Academic/Social account:


You have just completed your registration at OpenAire.

Before you can login to the site, you will need to activate your account. An e-mail will be sent to you with the proper instructions.


Please note that this site is currently undergoing Beta testing.
Any new content you create is not guaranteed to be present to the final version of the site upon release.

Thank you for your patience,
OpenAire Dev Team.

Close This Message


Verify Password:
Verify E-mail:
*All Fields Are Required.
Please Verify You Are Human:
fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
Muir, Keith W. (2017)
Publisher: Elsevier
Languages: English
Types: Article
Stem cells of various sources have been investigated in a series of small, safety and feasibility-focused studies over the past 15 years. Understanding of mechanisms of action has evolved and the trial paradigms have become focused on two different approaches – one being an early subacute delivery of cells to reduce acute tissue injury and modify the tissue environment in a direction favourable to reparative processes (for example by being anti-inflammatory, anti-apoptotic, and encouraging endogenous stem cell mobilisation); the other exploring later delivery of cells during the recovery phase after stroke to modulate the local environment in favour of angiogenesis and neurogenesis. The former approach has generally investigated intravenous or intra-arterial delivery of cells with an expected paracrine mode of action and no expected engraftment within the brain. The latter has explored direct intracerebral implantation adjacent to the infarct. Several relevant trials have been conducted, including two controlled trials of intravenously delivered bone marrow-derived cells in the early subacute stage, and two small single-arm phase 1 trials of intracerebrally implanted cells. The findings of these studies and their implications for future trial design are considered.
  • The results below are discovered through our pilot algorithms. Let us know how we are doing!

    • 1. Krishnamurthi RV, Feigin VL, Forouzanfar MH, et al. Global and regional burden of first-ever ischaemic and haemorrhagic stroke during 1990-2010: findings from the Global Burden of Disease Study 2010. Lancet Glob Health 2013; 1(5): e259-81.
    • 2. Emberson J, Lees KR, Lyden P, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet 2014; 384(9958): 1929-35.
    • 3. Goyal M, Menon BK, van Zwam WH, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet 2016; 387(10029): 1723-31.
    • 4. Morris S, Hunter RM, Ramsay AI, et al. Impact of centralising acute stroke services in English metropolitan areas on mortality and length of hospital stay: difference-in-differences analysis. BMJ 2014; 349: g4757.
    • 5. Kalladka D, Muir KW. Stem cell therapy in stroke: designing clinical trials. Neurochem Int 2011; 59(3): 367-70.
    • 6. Savitz SI. Developing Cellular Therapies for Stroke. Stroke 2015; 46(7): 2026-31.
    • 7. Koch P, Kokaia Z, Lindvall O, Brustle O. Emerging concepts in neural stem cell research: autologous repair and cell-based disease modelling. Lancet Neurol 2009; 8(9): 819-29.
    • 8. Lindvall O, Kokaia Z. Stem cells for the treatment of neurological disorders. Nature 2006; 441(7097): 1094-6.
    • 9. Saver JL. Time is brain--quantified. Stroke 2006; 37(1): 263-6.
    • 10. Muir KW, Tyrrell P, Sattar N, Warburton E. Inflammation and ischaemic stroke. Current Opinion in Neurology 2007; 20(3): 334-42.
    • 11. Emsley HC, Smith CJ, Georgiou RF, et al. Correlation of systemic inflammatory response with infarct volume in acute ischemic stroke patients. Stroke 2005; 36(2): 228-9; author reply -9.
    • 12. Carmichael ST. Emergent properties of neural repair: elemental biology to therapeutic concepts. Ann Neurol 2016; 79(6): 895-906.
    • 13. Carmichael ST, Archibeque I, Luke L, Nolan T, Momiy J, Li S. Growth-associated gene expression after stroke: evidence for a growth-promoting region in peri-infarct cortex. Exp Neurol 2005; 193(2): 291-311.
    • 14. Stroemer RP, Kent TA, Hulsebosch CE. Neocortical neural sprouting, synaptogenesis, and behavioral recovery after neocortical infarction in rats. Stroke 1995; 26(11): 2135-44.
    • 15. Nih LR, Carmichael ST, Segura T. Hydrogels for brain repair after stroke: an emerging treatment option. Curr Opin Biotechnol 2016; 40: 155-63.
    • 16. Lam J, Lowry WE, Carmichael ST, Segura T. Delivery of iPS-NPCs to the Stroke Cavity within a Hyaluronic Acid Matrix Promotes the Differentiation of Transplanted Cells. Adv Funct Mater 2014; 24(44): 7053-62.
    • 17. Lees JS, Sena ES, Egan KJ, et al. Stem cell-based therapy for experimental stroke: a systematic review and meta-analysis. International journal of stroke : official journal of the International Stroke Society 2012; 7(7): 582-8.
    • 18. 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.
    • 19. 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 2016; 47(6): 1632-9.
    • 20. Sinden JD, Vishnubhatla I, Muir KW, Dunnett S, Bjorklund A. Prospects for stem cell-derived therapy in stroke. Functional Neural Transplantation Iii Primary and Stem Cell Therapies For Brain Repair, Pt Ii; 2012: 119-67.
    • 21. Detante O, Moisan A, Dimastromatteo J, et al. Intravenous administration of 99mTcHMPAO-labeled human mesenchymal stem cells after stroke: in vivo imaging and biodistribution. Cell Transplant 2009; 18(12): 1369-79.
    • 22. Pendharkar AV, Chua JY, Andres RH, et al. Biodistribution of neural stem cells after intravascular therapy for hypoxic-ischemia. Stroke 2010; 41(9): 2064-70.
    • 23. Lee RH, Pulin AA, Seo MJ, et al. Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell 2009; 5(1): 54-63.
    • 24. Rosado-de-Castro PH, Schmidt Fda R, Battistella V, 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.
    • 25. Sahota P, Vahidy F, Nguyen C, et al. Changes in spleen size in patients with acute ischemic stroke: a pilot observational study. International journal of stroke : official journal of the International Stroke Society 2013; 8(2): 60-7.
    • 26. Golden JE, Shahaduzzaman M, Wabnitz A, et al. Human umbilical cord blood cells alter blood and spleen cell populations after stroke. Transl Stroke Res 2012; 3(4): 491-9.
    • 27. Bang OY, Lee JS, Lee PH, Lee G. Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol 2005; 57(6): 874-82.
    • 28. Lee JS, Hong JM, Moon GJ, 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.
    • 29. Bhasin A, Srivastava MV, Kumaran SS, et al. Autologous mesenchymal stem cells in chronic stroke. Cerebrovasc Dis Extra 2011; 1(1): 93-104.
    • 30. Honmou O, Houkin K, Matsunaga T, et al. Intravenous administration of auto serumexpanded autologous mesenchymal stem cells in stroke. Brain 2011; 134(Pt 6): 1790-807.
    • 31. Banerjee S, Bentley P, Hamady M, et al. Intra-Arterial Immunoselected CD34+ Stem Cells for Acute Ischemic Stroke. Stem Cells Translational Medicine 2014; 3(11): 1322-30.
    • 32. Moniche F, Gonzalez A, Gonzalez-Marcos JR, et al. Intra-arterial bone marrow mononuclear cells in ischemic stroke: a pilot clinical trial. Stroke 2012; 43(8): 2242-4.
    • 33. Savitz SI, Misra V, Kasam M, et al. Intravenous autologous bone marrow mononuclear cells for ischemic stroke. Ann Neurol 2011; 70(1): 59-69.
    • 34. Barbosa da Fonseca LM, Gutfilen B, Rosado de Castro PH, 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.
    • 35. Prasad K, Mohanty S, Bhatia R, 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.
    • 36. Battistella V, de Freitas GR, da Fonseca LM, et al. Safety of autologous bone marrow mononuclear cell transplantation in patients with nonacute ischemic stroke. Regen Med 2011; 6(1): 45-52.
    • 37. Prasad K, Sharma A, Garg A, et al. Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke: a multicentric, randomized trial. Stroke 2014; 45(12): 3618-24.
    • 38. Hess DC, Clark WD, Chiu D, et al. Results of the double-blind, randomized, placebo controlled, phase 2 safety and efficacy trial of MULTISTEM (R) in adults with ischemic stroke. International Journal of Stroke 2015; 10: 8-.
    • 39. Hess DC, Sila CA, Furlan AJ, Wechsler LR, Switzer JA, Mays RW. A double-blind placebocontrolled clinical evaluation of MultiStem for the treatment of ischemic stroke. International Journal of Stroke 2014; 9(3): 381-6.
    • 40. Detante O, Jaillard A, Moisan A, et al. Intravenous injection of autologous mesenchymal stem cells after ischemic stroke (ISIS / HERMES): protocol and progress. Cerebrovascular Diseases 2013; 35(Supplement 3): 852-.
    • 41. Kondziolka D, Steinberg GK, Wechsler L, et al. Neurotransplantation for patients with subcortical motor stroke: a phase 2 randomized trial. J Neurosurg 2005; 103(1): 38-45.
    • 42. Kondziolka D, Wechsler L, Goldstein S, et al. Transplantation of cultured human neuronal cells for patients with stroke. Neurology 2000; 55(4): 565-9.
    • 43. 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 2005; 20(2): 101-7.
    • 44. Kalladka D, Sinden J, Pollock K, et al. Pilot Investigation of Human Neural Stem Cells in Chronic Ischaemic Stroke Patients (PISCES): A Phase 1, First-in-Man Study. Lancet 2016.
    • 45. Sinden JD, Muir KW. Stem cells in stroke treatment: the promise and the challenges. International journal of stroke : official journal of the International Stroke Society 2012; 7(5): 426-34.
    • 46. Stroemer P, Patel S, Hope A, Oliveira C, Pollock K, Sinden J. The neural stem cell line CTX0E03 promotes behavioral recovery and endogenous neurogenesis after experimental stroke in a dosedependent fashion. Neurorehabilitation and neural repair 2009; 23(9): 895-909.
    • 47. Steinberg GK, Kondziolka D, Wechsler LR, 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.
    • 48. Grigoriadis N, Lourbopoulos A, Lagoudaki R, et al. Variable behavior and complications of autologous bone marrow mesenchymal stem cells transplanted in experimental autoimmune encephalomyelitis. Exp Neurol 2011; 230(1): 78-89.
    • 49. Snyder EY. The risk of putting something where it does not belong: mesenchymal stem cells produce masses in the brain. Exp Neurol 2011; 230(1): 75-7.
    • 50. George AJT, Collett C, Carr AJ, et al. When should placebo surgery as a control in clinical trials be carried out? The Bulletin of the Royal College of Surgeons of England 2016; 98(2): 75-9.
    • 51. Muir KW, Sinden J, Miljan E, Dunn L. Intracranial Delivery of Stem Cells. Translational Stroke Research 2011; 2(3): 266-71.
    • 52. Li L, Jiang Q, Ding GL, et al. Effects of administration route on migration and distribution of neural progenitor cells transplanted into rats with focal cerebral ischemia, an MRI study. Journal of Cerebral Blood Flow and Metabolism 2010; 30(3): 653-62.
    • 53. Vahidy FS, Alderman S, Savitz SI. Challenges enrolling patients with acute ischemic stroke into cell therapy trials. Stem cells and development 2013; 22(1): 27-30.
    • 54. Krams M, Lees KR, Hacke W, et al. Acute Stroke Therapy by Inhibition of Neutrophils (ASTIN): an adaptive dose-response study of UK-279,276 in acute ischemic stroke. Stroke 2003; 34(11): 2543- 8.
    • 55. Klamroth-Marganska V, Blanco J, Campen K, et al. Three-dimensional, task-specific robot therapy of the arm after stroke: a multicentre, parallel-group randomised trial. Lancet Neurol 2014; 13(2): 159-66.
    • 56. Bushnell C, Bettger JP, Cockroft KM, 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.
    • 57. Wolf SL, Winstein CJ, Miller JP, et al. Effect of constraint-induced movement therapy on upper extremity function 3 to 9 months after stroke: the EXCITE randomized clinical trial. Journal of the American Medical Association 2006; 296(17): 2095-104.
    • 58. Lo AC, Guarino PD, Richards LG, et al. Robot-assisted therapy for long-term upper-limb impairment after stroke. The New England journal of medicine 2010; 362(19): 1772-83.
    • 59. Stinear C. Prediction of recovery of motor function after stroke. The Lancet Neurology 2010; 9(12): 1228-32.
    • 60. Garcia-Alias G, Barkhuysen S, Buckle M, Fawcett JW. Chondroitinase ABC treatment opens a window of opportunity for task-specific rehabilitation. Nature neuroscience 2009; 12(9): 1145-51.
    • 61. 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.
  • No related research data.
  • No similar publications.

Share - Bookmark

Download from

Cite this article