Intrathecal Autologous Bone Marrow Derived Mesenchymal Stem Cells for Ischemic Stroke: Short Term Safety and Efficacy Study
American Journal of Bioscience and Bioengineering
Volume 3, Issue 4-1, July 2015, Pages: 1-6
Received: Apr. 1, 2015;
Accepted: Apr. 2, 2015;
Published: May 6, 2015
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Abo Elkheir W, Military Medical Academy, Immunology Department, Cairo, Egypt
Reda M. A., Azhar University, Neurology Department, Cairo, Egypt
Montaser I. A., Azhar University, Neurology Department, Cairo, Egypt
Salem A. E., Azhar University, Neurology Department, Cairo, Egypt
Sakr M. A., Azhar University, Neurology Department, Cairo, Egypt
Background: Preclinical and animal studies provide considerable hope for stem cell therapy in cerebrovascular stroke. This study was designed as a pilot study to explore this provisional data. Autologous bone marrow derived mesenchymal stem cells were chosen due to their proven angiogenic, paracrine and neuroregenerative functions. Subjects and Methods: The present study included 32 patients with ischemic stroke fulfilling the following criteria: Inclusion Criteria: 1. Patients with established stroke in the distribution of the middle cerebral artery territory. 2. Six months at least after the onset of acute ischemic stroke. 3. CT brain at the onset denoting acute ischemic stroke. Exclusion Criteria: 1. Hemorrhagic stroke. 2. Conditions which mimick stroke,e.g., multiple sclerosis, vasculitis, arteriovenous malformations, trauma, tumours. Patients were randomly divided into control group (11 patients) and study group (21 patients) which was further divided according to the time between the onset of the stroke and the beginning of the study into: Group I : onset of the stroke and the beginning of the study :6-12 months( 12 patients: 6 males and 6 females). Group II: onset of stroke and the beginning of the study :13-36 months (9 patients: 5 males and 4 females). Control Group: 11 stroke patients : 6 males and 5 females. Time from onset of stroke to beginning of the study ranged from 6-30 months. Both study and control group were subjected to thorough clinical and laboratory assessment , CT brain, National institutes of Health Stroke Scale (NIHSS) and th Barthel active daily life (ADL) scale at the start of therapy, and at 1,3,6 and 12 months after the start of therapy. Stem Cell Injection: 10 million autologous bone marrow-derived MSCs were injected via lumbar puncture in the study group. Results and Conclusions: Changes in Follow-up Parameters: 1. Changes in NIHSS score: Control group showed non-significant decrease in NIHSS score starting from the 3rd month. On the other hand, study group showed highly significant decrease in NIHSS score starting from 6th month, more in group I. 2. Changes in ADL score: ADL score showed non-significant increase starting from 3rd month in the control group, while it showed a highly significant increase in the study group starting from 6th month, more pronounced in group I. Intrathecal administration of MSCs is safe and enhances regeneration in ischemic stroke patients.
Abo Elkheir W,
Reda M. A.,
Montaser I. A.,
Salem A. E.,
Sakr M. A.,
Intrathecal Autologous Bone Marrow Derived Mesenchymal Stem Cells for Ischemic Stroke: Short Term Safety and Efficacy Study, American Journal of Bioscience and Bioengineering. Special Issue: Stem Cells for Neuro-Regeneration: Where Do We Stand.
Vol. 3, No. 4-1,
2015, pp. 1-6.
Smith H and Gavins F (2012): The potential of stem cell therapy for stroke: is PISCES the sign? FASEB 26(6):2239-225
Mattson MP, Culmsee C, and Yu ZF (2000): Apoptotic and antiapoptotic mechanisms in stroke. Cell Tissue Res 301:173-187.
Gravins FN, Dalli J, Flower RJ, Granger DN andPerretti M (2007): Activation of annexin-1 counter-regulatory circuit affords protection in the mouse brain microcirculation. FASEB 121:1751-1758.
Matsuo Y, Onodera H, Shiga Y, Shozuhara H, Ninomiya M, Kihara T, Tamatani T, Miyasaka M and Kogure K (1994): Role of cell adhesion molecules in brain injury after transient middle cerebral artery occlusion in the rat. Brain Res 656:344-352.
Saver JL, Fonarrow GC, Smith EE, Reeves MJ, Grau-Sepulveda MV, Pan W, Oslon DM, Hernandez AF, Peterson ED, Schwamm LH (2013): Time to treatment with intravenous tissue plasminogen activator and outcome from acute ischemic stroke. JAMA 309(23):2480-2488.
Morris GF, Bullock R, Marshall SB, Marmarou A, Maas A, and Marshall F (1999): Failure of the competitive N-methyl-D-aspartate antagonist selfotel (CGS19755) in the treatment of severe head injury: results of two phase III clinical trials. The selfotel investigaors. J.Neurosurg 91:737-743.
Olsson SB (2003): Stroke prevention with the oral direct thrombin inhibitor zimelagatran compared with warfarin in patients with non-valvular atrial fibritllation (SPORTIF III): randomied controlled trial. Lancet 362:1691-169
EAST (2001): Use of anti-ICAM-1 therapy in ischemic stroke: results of the Enlimornab Acute Stroke Trial. Neurology 57:1428-1434.
Holloway PM, Smith HK, Renshaw D, Flower RJ, Getting SJ and Gavins FN (2011): Targeting the melanocortin receptor system for anti-stroke therapy. Trends Pharmacol. Sci 32:90-98.
Stankowski JN and Gupta R (2010): Therapeutic Targets for Neuroprotection in Acute Ischemic Stroke: Lost in Translation? AntioxidRedox Signal 14(10):1841-1851.
Zheng Z and Chopp M (2009): Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic. Lancet Neurol 8(5): 491-500.
Joyce N, Annett G, Wirthlin L, Oslon S, Bauer G and Nolta (2010): Mesenchymal stem cells for the treament of neurodegenerative disease. Regen Med 5(6):933-946.
Jiang Q, Zhang ZG, Ding GL, Zhang L, Ewing JR, Wang L, Zhang R, Li L Lu M, Meng H, Arbab AS, Hu J, LiQ (2005): Investigation of neural progenitor cell induced angiogenesis after embolic stroke in rat using MRI. Neuroimage 28:698-70
Heo JS, Choi SM, Kim HO, Kim EH, You J, Park T, Kim E, Kim HS (2013): Neural transdifferentiation of human bone marrow mesenchymal stem cells on hydrophobic polymer-modified surface and therapeutic effects in an animal model of ischemic stroke. Neuroscience 15:238-305.
Wang L, Zhang ZG, Zhang RL, Gregg SR, Hozeska-Solgot A, LeTourneau Y, Wang Y , Chopp M (2006): Matrix metalloproteinase 2 (MMP2) and MMP9 secreted by erythropoeitin-activated endothelial cells promote neural progenitor cell migration. J Neurosci 26:5996-6003.
Roitbak T, Li L, Cunningham LA (2008): Neural stm/progenitor cells promote endothelial cell morphogenesis and protect endothelial cells against ischemia via HIF-1-alpha-regulated VEGF signaling. J Cereb Blood Flow Metab. 28:1530-42.
Shen LH, Li Y, Chen J, Zacharek A, Gao Q, Kapke A, Lu M, Raginski K, Vanguri P, Smith A, Chopp M (2007): Therapeutic benefit of bone marrow stromal cells administered 1 month after stroke. J Cereb Blood Flow Metab 27:6-13.
Chen J, Li Y, Katakowski M, Chen X, Wang L, Lu D, Lu M, Gautam SC, Chopp M (2003): Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat. J Neurosci Res 73:778-86.
Wang Y, Deng Y, Zhou GQ (2008): SDF-1 alpha/CXCR4-mediated migration of systemically transplanted bone marrow stromal cells towards ischemic brain lesion in a rat model. Brain Res 1195:104-1
Bang OY, Lee JS, Lee PH, Lee G (2005): Autologous mesenchymal stem cell transplantation in
Verma A, Verma N (2011): Induced pluripotent stem cells and promises of neuroregenerative medicine. Neurol India 59(4):555-7.
Zivin JA (2009): Acute stroke therapy with tissue plasminogen activator (tPA) since it was approved by the U.S. Food and Drug Administration (FDA). Ann Neurol 66(1):6-10.
Doeppner TR and Hermann DM (2014): Stem cell-based treatments against stroke: observations from human proof-of-concept studies and considerations regarding clinical applicability. Front Cell Neurosci 8:35
Banajeree S, Williamson D, Habib N, Chataway J (2012): The potential benefit of stem cell therapy after stroke: an update. Vascular Health and Risk Management 8:569-580.
STEPS Participants (2009): Stem Cell Therapies as an Emerging Paradigm in Stroke (STEPS) Bridging Basic and Clinical Science for Cellular and Neurogenic Factor Therapy in Treating Stroke. Stroke 40:510-515.
Kurozumi K, Nakamura K, Tamiya T, Kawano Y, Ishii K, Kobune M, Hirai S, Uchida H, Sasaki K, Ito Y, Kato K, Honmou O, Houkin K, Date I, Hamada H (2005): Mesenchymal stem cells that produce neurotrophic factors reduce ischemic damage in the rat middle cerebral artery occlusion model. Mol Ther 1:96-10
Sheikh AM, Nagai A, Wakabayashi K, Narantuya D, Kobayashi S, Yamaguchi S, Kim SU (2011): Mesenchymal stem cell transplantation modulates neuroinflammation in focal cerebral ischemia: contribution of fractalkine and IL-Neurobiol Dis 41:717-724.
Lee JS, Hong JM, Moon GJ, Lee PH, Ahn YH, Bang OY, STARTING collaborators (2010): A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells 28(6):1099-106.
El-Kheir WA, Gabr H, Awad MR, Ghannam O, Barakat Y, Farghali HA, El Maadawi ZM, Ewes I, Sabaawy HE. (2014): Autologous bone marrow-derived cell therapy combined with physical therapy induces functional improvement in chronic spinal cord injury patients. Cell Transplant 23(6):729-45.
Bang OY, Lee JS, Lee PH and Lee G (2005): Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol 57(6):874-82.
Bhasin A, Srivastava MV, Kumaran SS, Mohanty S, Bhatia R, Bose S, Gaikwad S, GArg A, Airan B (2011): Autologous mesenchymal stem cells in chronic stroke. Cerebrovasc. Dis. Extra 1:93-104.
Bhasin A, Srivastava MV, Mohanty S, Bhatia R, Kumaran SS, Bose S( 2013): Stem Cell therapy a clinical trial of stroke. Clin Neurol Neurosurg 115:1003-1008.
Honmou O, Houkin K, Matsunaga T, Niitsu Y, Ishiai S, Onodera R, Waxman SG, Kocis JD (2011): Intravenous administration of auto serum-expanded autologous mesenchymal stem cells in stroke. Brain 134:1790-1807.
Savitz SI, Misra V, Kasam M, Juneia H, Cox CS Jr, Alderman S, Aisiku I, Kar S, Gee A, Grota JC (2011): Intravenous autologous bone marrow mononuclear cells for ischemic stroke. Ann Neurol 70:59-69.
Barbosa da Fonesca LM, Gutfilen B, Rosado de Castro PH, Battistella V, Goldenberg RC, Kasai-Brunswick T, Chagas CL, Wainberg E, Maiolino A, Salles Xavier S, Andre C, Mendez-Otero R, de Freitas GR (2010): Migration and homing of bone-marrow mononuclear cells in chroic ischemic stroke after intra-arterial injection. Exp Neurol 221, 122-128.
Suarez-Monteagudo C, Hernandez-Ramirez P, Alvarez-Gonzalez L, Garcia-Maeso I, de la Cuetara-Bernal K, Castillo-Diaz L, Bringas-Vega ML, Martinez-Aching G, Morales-Chacon LM, Baez-Martin MM, Sanchez-Catasus C, Carballo-Barreda M, Rodriguez-Rojas R, Gomez-fernandez L, Alberti-Amador E, Macias-Abraham C, Balea ED, Rosales LC, Del Valle Perez L, Ferrer BB, Gonzalez RM, Bergado JA (2009): Autologous bone marrow stem cell neurotransplantation in sgroke patients. Restor Neurol Neurosci 27:151-161.
Rabinovich SS, Seledtsov VI, Banul NV, Poveshchenko OV, Senvukov VV, Astrakov SV, Samarin DM, Taraban VY (2005): Cell therapy of brain stroke. Bull Exp Biol Med 139:126-128.