(Stroke. 2001;32:1005.)
© 2001 American Heart Association, Inc.
Original Contributions |
Therapeutic Benefit of Intravenous Administration of Bone Marrow Stromal Cells After Cerebral Ischemia in Rats
From Henry Ford Health Sciences Center, Department of Neurology (J.C., Y.L., L.W., Z.Z., M.C.), Neurosurgery (D.L.), and Biostatistics and Research Epidemiology (M.L.), Detroit, Mich; and Oakland University, Department of Physics (M.C.), Rochester, Mich.
Correspondence to Michael Chopp, PhD, Henry Ford Hospital, Neurology Department, 2799 W Grand Blvd, Detroit, MI 48202. E-mail chopp{at}neuro.hfh.edu
Background and Purpose—We tested the hypothesis that intravenous infusion of bone marrow derived–marrow stromal cells (MSCs) enter the brain and reduce neurological functional deficits after stroke in rats.
Methods—Rats (n=32) were subjected to 2 hours of middle cerebral artery occlusion (MCAO). Test groups consisted of MCAO alone (group 1, n=6); intravenous infusion of 1x106 MSCs at 24 hours after MCAO (group 2, n=6); or infusion of 3x106 MSCs (group 3, n=7). Rats in groups 1 to 3 were euthanized at 14 days after MCAO. Group 4 consisted of MCAO alone (n=6) and group 5, intravenous infusion of 3x106 MSCs at 7 days after MCAO (n=7). Rats in groups 4 and 5 were euthanized at 35 days after MCAO. For cellular identification, MSCs were prelabeled with bromodeoxyuridine. Behavioral tests (rotarod, adhesive-removal, and modified Neurological Severity Score [NSS]) were performed before and at 1, 7, 14, 21, 28, and 35 days after MCAO. Immunohistochemistry was used to identify MSCs or cells derived from MSCs in brain and other organs.
Results—Significant recovery of somatosensory behavior and Neurological Severity Score (P<0.05) were found in animals infused with 3x106 MSCs at 1 day or 7 days compared with control animals. MSCs survive and are localized to the ipsilateral ischemic hemisphere, and a few cells express protein marker phenotypic neural cells.
Conclusions—MSCs delivered to ischemic brain tissue through an intravenous route provide therapeutic benefit after stroke. MSCs may provide a powerful autoplastic therapy for stroke.
Key Words: bone marrow transplantation • middle cerebral artery occlusion • neuronal plasticity • stroke, experimental • stromal cells • rats
This article has been cited by other articles:
 |
|
 |
|
  K. Karki, R. A. Knight, Y. Han, D. Yang, J. Zhang, K. A. Ledbetter, M. Chopp, and D. M. Seyfried Simvastatin and Atorvastatin Improve Neurological Outcome After Experimental Intracerebral Hemorrhage Stroke, October 1, 2009; 40(10): 3384 - 3389. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
The STEPS Participants 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, February 1, 2009; 40(2): 510 - 515. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Liu, Y. Li, X. Zhang, S. Savant-Bhonsale, and M. Chopp Contralesional Axonal Remodeling of the Corticospinal System in Adult Rats After Stroke and Bone Marrow Stromal Cell Treatment Stroke, September 1, 2008; 39(9): 2571 - 2577. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Knight, Y. Han, T. N. Nagaraja, P. Whitton, J. Ding, M. Chopp, and D. M. Seyfried Temporal MRI Assessment of Intracerebral Hemorrhage in Rats Stroke, September 1, 2008; 39(9): 2596 - 2602. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. D. Muller, K. M. Hanumanthiah, K. Diederich, S. Schwab, W.-R. Schabitz, and C. Sommer Brain-Derived Neurotrophic Factor But Not Forced Arm Use Improves Long-Term Outcome After Photothrombotic Stroke and Transiently Upregulates Binding Densities of Excitatory Glutamate Receptors in the Rat Brain Stroke, March 1, 2008; 39(3): 1012 - 1021. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Shi, T. Kazui, X. Jiang, N. Washiyama, K. Yamashita, H. Terada, and A. H. M. Bashar Therapeutic Benefit of Intrathecal Injection of Marrow Stromal Cells on Ischemia-Injured Spinal Cord Ann. Thorac. Surg., April 1, 2007; 83(4): 1484 - 1490. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. De Becker, P. Van Hummelen, M. Bakkus, I. Vande Broek, J. De Wever, M. De Waele, and I. Van Riet Migration of culture-expanded human mesenchymal stem cells through bone marrow endothelium is regulated by matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-3 Haematologica, April 1, 2007; 92(4): 440 - 449. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Buhnemann, A. Scholz, C. Bernreuther, C. Y. Malik, H. Braun, M. Schachner, K. G. Reymann, and M. Dihne Neuronal differentiation of transplanted embryonic stem cell-derived precursors in stroke lesions of adult rats Brain, December 1, 2006; 129(12): 3238 - 3248. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Sprigg, P. M. Bath, L. Zhao, M. R. Willmot, L. J. Gray, M. F. Walker, M. S. Dennis, and N. Russell Granulocyte-Colony-Stimulating Factor Mobilizes Bone Marrow Stem Cells in Patients With Subacute Ischemic Stroke: The Stem Cell Trial of Recovery EnhanceMent After Stroke (STEMS) Pilot Randomized, Controlled Trial (ISRCTN 16784092) Stroke, December 1, 2006; 37(12): 2979 - 2983. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Liu, O. Honmou, K. Harada, K. Nakamura, K. Houkin, H. Hamada, and J. D. Kocsis Neuroprotection by PlGF gene-modified human mesenchymal stem cells after cerebral ischaemia Brain, October 1, 2006; 129(10): 2734 - 2745. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Pacary, H. Legros, S. Valable, P. Duchatelle, M. Lecocq, E. Petit, O. Nicole, and M. Bernaudin Synergistic effects of CoCl2 and ROCK inhibition on mesenchymal stem cell differentiation into neuron-like cells J. Cell Sci., July 1, 2006; 119(13): 2667 - 2678. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Shi, T. Kazui, X. Jiang, N. Washiyama, K. Yamashita, H. Terada, and A. H. M. Bashar Intrathecal Injection of Bone Marrow Stromal Cells Attenuates Neurologic Injury After Spinal Cord Ischemia Ann. Thorac. Surg., June 1, 2006; 81(6): 2227 - 2234. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Y. Khakoo, S. Pati, S. A. Anderson, W. Reid, M. F. Elshal, I. I. Rovira, A. T. Nguyen, D. Malide, C. A. Combs, G. Hall, et al. Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi's sarcoma J. Exp. Med., May 15, 2006; 203(5): 1235 - 1247. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Sheridan, D. Rice, P. S. Hiscott, D. Wong, and D. L. Kent The Presence of AC133-Positive Cells Suggests a Possible Role of Endothelial Progenitor Cells in the Formation of Choroidal Neovascularization. Invest. Ophthalmol. Vis. Sci., April 1, 2006; 47(4): 1642 - 1645. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Zhang, R. L. Zhang, Y. Wang, C. Zhang, Z. G. Zhang, H. Meng, and M. Chopp Functional Recovery in Aged and Young Rats After Embolic Stroke: Treatment With a Phosphodiesterase Type 5 Inhibitor Stroke, April 1, 2005; 36(4): 847 - 852. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Hanabusa, N. Nagaya, T. Iwase, T. Itoh, S. Murakami, Y. Shimizu, W. Taki, K. Miyatake, and K. Kangawa Adrenomedullin Enhances Therapeutic Potency of Mesenchymal Stem Cells After Experimental Stroke in Rats Stroke, April 1, 2005; 36(4): 853 - 858. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Chen, A. Zacharek, C. Zhang, H. Jiang, Y. Li, C. Roberts, M. Lu, A. Kapke, and M. Chopp Endothelial Nitric Oxide Synthase Regulates Brain-Derived Neurotrophic Factor Expression and Neurogenesis after Stroke in Mice J. Neurosci., March 2, 2005; 25(9): 2366 - 2375. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Lindvall and Z. Kokaia Recovery and Rehabilitation in Stroke: Stem Cells Stroke, November 1, 2004; 35(11_suppl_1): 2691 - 2694. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W.-C. Shyu, S.-Z. Lin, H.-I Yang, Y.-S. Tzeng, C.-Y. Pang, P.-S. Yen, and H. Li Functional Recovery of Stroke Rats Induced by Granulocyte Colony-Stimulating Factor-Stimulated Stem Cells Circulation, September 28, 2004; 110(13): 1847 - 1854. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W.-R. Schabitz, C. Berger, R. Kollmar, M. Seitz, E. Tanay, M. Kiessling, S. Schwab, and C. Sommer Effect of Brain-Derived Neurotrophic Factor Treatment and Forced Arm Use on Functional Motor Recovery After Small Cortical Ischemia Stroke, April 1, 2004; 35(4): 992 - 997. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-W. Jeong, K. Chu, K.-H. Jung, S. U. Kim, M. Kim, and J.-K. Roh Human Neural Stem Cell Transplantation Promotes Functional Recovery in Rats With Experimental Intracerebral Hemorrhage Stroke, September 1, 2003; 34(9): 2258 - 2263. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. M. Barbash, P. Chouraqui, J. Baron, M. S. Feinberg, S. Etzion, A. Tessone, L. Miller, E. Guetta, D. Zipori, L. H. Kedes, et al. Systemic Delivery of Bone Marrow-Derived Mesenchymal Stem Cells to the Infarcted Myocardium: Feasibility, Cell Migration, and Body Distribution Circulation, August 19, 2003; 108(7): 863 - 868. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Saito, J.-Q. Kuang, C. C. H. Lin, and R. C.-J. Chiu Transcoronary implantation of bone marrow stromal cells ameliorates cardiac function after myocardial infarction J. Thorac. Cardiovasc. Surg., July 1, 2003; 126(1): 114 - 122. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Zhang, Z. G. Zhang, R. L. Zhang, M. Lu, M. Krams, and M. Chopp Effects of a Selective CD11b/CD18 Antagonist and Recombinant Human Tissue Plasminogen Activator Treatment Alone and in Combination in a Rat Embolic Model of Stroke Stroke, July 1, 2003; 34(7): 1790 - 1795. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Wehner, M. Bontert, I. Eyupoglu, K. Prass, M. Prinz, F. F. Klett, M. Heinze, I. Bechmann, R. Nitsch, F. Kirchhoff, et al. Bone Marrow-Derived Cells Expressing Green Fluorescent Protein under the Control of the Glial Fibrillary Acidic Protein Promoter Do Not Differentiate into Astrocytes In Vitro and In Vivo J. Neurosci., June 15, 2003; 23(12): 5004 - 5011. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Zhang, Z. G. Zhang, R. Zhang, D. Morris, M. Lu, B. S. Coller, and M. Chopp Adjuvant Treatment With a Glycoprotein IIb/IIIa Receptor Inhibitor Increases the Therapeutic Window for Low-Dose Tissue Plasminogen Activator Administration in a Rat Model of Embolic Stroke Circulation, June 10, 2003; 107(22): 2837 - 2843. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Chen, Z. G. Zhang, Y. Li, L. Wang, Y. X. Xu, S. C. Gautam, M. Lu, Z. Zhu, and M. Chopp Intravenous Administration of Human Bone Marrow Stromal Cells Induces Angiogenesis in the Ischemic Boundary Zone After Stroke in Rats Circ. Res., April 4, 2003; 92(6): 692 - 699. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Rempe and T. A. Kent Using bone marrow stromal cells for treatment of stroke Neurology, August 27, 2002; 59(4): 486 - 486. [Full Text] [PDF]
|
|
|
|
|
|
Y. Li, J. Chen, X. G. Chen, L. Wang, S. C. Gautam, Y. X. Xu, M. Katakowski, L. J. Zhang, M. Lu, N. Janakiraman, et al. Human marrow stromal cell therapy for stroke in rat: Neurotrophins and functional recovery Neurology, August 27, 2002; 59(4): 514 - 523. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Gladstone, S. E. Black, and A. M. Hakim Toward Wisdom From Failure: Lessons From Neuroprotective Stroke Trials and New Therapeutic Directions Stroke, August 1, 2002; 33(8): 2123 - 2136. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Saito, J.-Q. Kuang, B. Bittira, A. Al-Khaldi, and R. C.-J. Chiu Xenotransplant cardiac chimera: immune tolerance of adult stem cells Ann. Thorac. Surg., July 1, 2002; 74(1): 19 - 24. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. C. Hess, W. D. Hill, A. Martin-Studdard, J. Carroll, J. Brailer, and J. Carothers Bone Marrow as a Source of Endothelial Cells and NeuN-Expressing Cells After Stroke Stroke, May 1, 2002; 33(5): 1362 - 1368. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Chen, P. R. Sanberg, Y. Li, L. Wang, M. Lu, A. E. Willing, J. Sanchez-Ramos, and M. Chopp Intravenous Administration of Human Umbilical Cord Blood Reduces Behavioral Deficits After Stroke in Rats Stroke, November 1, 2001; 32(11): 2682 - 2688. [Abstract] [Full Text] [PDF]
|
|