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Stem cells in stroke management
Published online by Cambridge University Press: 21 December 2010
Summary
Stem cells are a potential means of tissue regeneration in the brain that hold promise for treatment of the large number of stroke survivors who have permanent disability. Animal studies with stem cells derived from many different sources indicate that cells can migrate to the site of ischaemic injury in the brain, and that some survive and differentiate into neurones and glia with evidence of electrical function. Cells additionally promote endogenous repair mechanisms, including mobilization of neural stem cells resident within the adult brain. Whether the behavioural benefits seen with stem cell administration in rodent models reflect enhanced endogenous recovery or tissue regeneration is unclear. Production of stem cells to clinical standards and in quantities required for clinical studies is technically challenging. To date only a handful of patients have been involved in preliminary clinical studies of cell therapies for stroke, and there are therefore insufficient data to draw conclusions about either safety or efficacy. Further trials with several cell types are ongoing or planned, including neural stem cells, and bone marrow-derived stem cells and endothelial progenitor cells.
Keywords
- Type
- Clinical geriatrics
- Information
- Copyright
- Copyright © Cambridge University Press 2010
References
1The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995; 333: 1581–87.CrossRefGoogle Scholar
2Wolf, SL, Winstein, CJ, Miller, JP, Thompson, PA, Taub, E, Uswatte, G, Morris, D, Blanton, S, Nichols-Larsen, D, Clark, PC. Retention of upper limb function in stroke survivors who have received constraint-induced movement therapy: the EXCITE randomised trial. Lancet Neuro 2008; 7: 33–40.CrossRefGoogle ScholarPubMed
3Cramer, SC. Repairing the human brain after stroke. II. Restorative therapies. Ann Neurol 2008; 63: 549–60.CrossRefGoogle ScholarPubMed
4Macleod, MR, O'Collins, T, Howells, DW, Donnan, GA. Pooling of animal experimental data reveals influence of study design and publication bias. Stroke 2004; 35: 1203–8.CrossRefGoogle ScholarPubMed
5Crossley, NA, Sena, E, Goehler, J, Horn, J, van der, WB, Bath, PM et al. Empirical evidence of bias in the design of experimental stroke studies. A metaepidemiologic approach. Stroke 2008; 39: 929–34.CrossRefGoogle ScholarPubMed
6Bliss, TM, Andres, RH, Steinberg, GK. Optimizing the success of cell transplantation therapy for stroke. Neurobiol Dis 2010; 37: 275–83.CrossRefGoogle ScholarPubMed
7Hicks, A, Schallert, T, Jolkkonen, J. Cell-based therapies and functional outcome in experimental stroke. Cell Stem Cell 2009; 5: 139–40.CrossRefGoogle ScholarPubMed
8Puceat, M, Ballis, A. Embryonic stem cells: from bench to bedside. Clin Pharmacol Ther 2007; 82: 337–39.CrossRefGoogle ScholarPubMed
9Hoehn, M, Küstermann, E, Blunk, J, Wiedermann, D, Trapp, T, Wecker, S, Föcking, M, Arnold, H, Hescheler, J, Fleischmann, BK, Schwindt, W, Bührle, C. Monitoring of implanted stem cell migration in vivo: a highly resolved in vivo magnetic resonance imaging investigation of experimental stroke in rat. Proc Natl Acad Sci USA 2002; 99: 16267–72.CrossRefGoogle ScholarPubMed
10Hayashi, J, Takagi, Y, Fukuda, H, Imazato, T, Nishimura, M, Fujimoto, M, Takahashi, J, Hashimoto, N, Nozaki, K. Primate embryonic stem cell-derived neuronal progenitors transplanted into ischemic brain. J Cereb Blood Flow Metab 2006; 26: 906–14.CrossRefGoogle ScholarPubMed
11Erdö, F, Bührle, C, Blunk, J, Hoehn, M, Xia, Y, Fleischmann, B, Föcking, M, Küstermann, E, Kolossov, E, Hescheler, J, Hossmann, KA, Trapp, T. Host-dependent tumorigenesis of embryonic stem cell transplantation in experimental stroke. J Cereb Blood Flow Metab 2003; 23: 780–5.CrossRefGoogle ScholarPubMed
12Keirstead, HS, Nistor, G, Bernal, G, Totoiu, M, Cloutier, F, Sharp, K, Steward, O. Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci 2005; 25: 4694–705.CrossRefGoogle ScholarPubMed
13Okita, K, Ichisaka, T, Yamanaka, S. Generation of germline-competent induced pluripotent stem cells. Nature 2007; 448: 313–17.CrossRefGoogle ScholarPubMed
14Yu, J, Vodyanik, MA, Smuga-Otto, K, Antosiewicz-Bourget, J, Frane, JL, Tian, S, Nie, J, Jonsdottir, GA, Ruotti, V, Stewart, R, Slukvin, II, Thomson, JA. Induced pluripotent stem cell lines derived from human somatic cells. Science 2007; 318: 1917–20.CrossRefGoogle ScholarPubMed
15Okita, K, Nakagawa, M, Hyenjong, H, Ichisaka, T, Yamanaka, S. Generation of mouse induced pluripotent stem cells without viral vectors. Science 2008; 322: 949–53.CrossRefGoogle ScholarPubMed
16Leeper, NJ, Hunter, AL, Cooke, JP. Stem cell therapy for vascular regeneration: adult, embryonic, and induced pluripotent stem cells. Circulation 2010; 122: 517–26.CrossRefGoogle ScholarPubMed
17Miura, K, Okada, Y, Aoi, T, Okada, A, Takahashi, K, Okita, K, Nakagawa, M, Koyanagi, M, Tanabe, K, Ohnuki, M, Ogawa, D, Ikeda, E, Okano, H, Yamanaka, S. Variation in the safety of induced pluripotent stem cell lines. Nat Biotechnol 2009; 27: 743–45.CrossRefGoogle ScholarPubMed
18Tsuji, O, Miura, K, Okada, Y, Fujiyoshi, K, Mukaino, M, Nagoshi, N, Kitamura, K, Kumagai, G, Nishino, M, Tomisato, S, Higashi, H, Nagai, T, Katoh, H, Kohda, K, Matsuzaki, Y, Yuzaki, M, Ikeda, E, Toyama, Y, Nakamura, M, Yamanaka, S, Okano, H. Therapeutic potential of appropriately evaluated safe-induced pluripotent stem cells for spinal cord injury. Proc Natl Acad Sci USA 2010; 107: 12704–9.CrossRefGoogle ScholarPubMed
19Bacigaluppi, M, Pluchino, S, Martino, G, Kilic, E, Hermann, DM. Neural stem/precursor cells for the treatment of ischemic stroke. J Neurol Sci 2008; 265: 73–77.CrossRefGoogle ScholarPubMed
20Borlongan, CV, Tajima, Y, Trojanowski, JQ, Lee, VM, Sanberg, PR. Transplantation of cryopreserved human embryonal carcinoma-derived neurons (NT2N cells) promotes functional recovery in ischemic rats. Exp Neurol 1998; 149: 310–21.CrossRefGoogle ScholarPubMed
21Cacci, E, Villa, A, Parmar, M, Cavallaro, M, Mandahl, N, Lindvall, O, Martinez-Serrano, A, Kokaia, Z. Generation of human cortical neurons from a new immortal fetal neural stem cell line. Exp Cell Res 2007; 313: 588–601.CrossRefGoogle ScholarPubMed
22Pollock, K, Stroemer, P, Patel, S, Stevanato, L, Hope, A, Miljan, E, Dong, Z, Hodges, H, Price, J, Sinden, JD. A conditionally immortal clonal stem cell line from human cortical neuroepithelium for the treatment of ischemic stroke. Exp Neurol 2006; 199: 143–55.CrossRefGoogle ScholarPubMed
23Joannides, A, Gaughwin, P, Schwiening, C, Majed, H, Sterling, J, Compston, A, Chandran, S. Efficient generation of neural precursors from adult human skin: astrocytes promote neurogenesis from skin-derived stem cells. Lancet 2004; 364: 172–78.CrossRefGoogle ScholarPubMed
24Modo, M, Stroemer, RP, Tang, E, Patel, S, Hodges, H. Effects of implantation site of stem cell grafts on behavioral recovery from stroke damage. Stroke 2002; 33: 2270–78.CrossRefGoogle ScholarPubMed
25Chu, K, Kim, M, Park, KI, Jeong, SW, Park, HK, Jung, KH, Lee, ST, Kang, L, Lee, K, Park, DK, Kim, SU, Roh, JK. Human neural stem cells improve sensorimotor deficits in the adult rat brain with experimental focal ischemia. Brain Res 2004; 1016: 145–53.CrossRefGoogle ScholarPubMed
26Ishibashi, S, Sakaguchi, M, Kuroiwa, T, Yamasaki, M, Kanemura, Y, Shizuko, I, Shimazaki, T, Onodera, M, Okano, H, Mizusawa, H. Human neural stem/progenitor cells, expanded in long-term neurosphere culture, promote functional recovery after focal ischemia in Mongolian gerbils. J Neurosci Res 2004; 78: 215–23.CrossRefGoogle ScholarPubMed
27Jiang, Q, Zhang, ZG, Ding, GL, Silver, B, Zhang, L, Meng, H, Lu, M, Pourabdillah-Nejed-D, S, Wang, L, Savant-Bhonsale, S, Li, L, Bagher-Ebadian, H, Hu, J, Arbab, AS, Vanguri, P, Ewing, JR, Ledbetter, KA, Chopp, M. MRI detects white matter reorganization after neural progenitor cell treatment of stroke. Neuroimage 2006; 32: 1080–89.CrossRefGoogle ScholarPubMed
28Wei, L, Cui, L, Snider, BJ, Rivkin, M, Yu, SS, Lee, CS, Adams, LD, Gottlieb, DI, Johnson, EM Jr, Yu, SP, Choi, DW. Transplantation of embryonic stem cells overexpressing Bcl-2 promotes functional recovery after transient cerebral ischemia. Neurobiol Dis 2005; 19: 183–93.CrossRefGoogle ScholarPubMed
29Veizovic, T, Beech, JS, Stroemer, RP, Watson, WP, Hodges, H. Resolution of stroke deficits following contralateral grafts of conditionally immortal neuroepithelial stem cells. Stroke 2001; 32: 1012–19.CrossRefGoogle ScholarPubMed
30Modo, M, Cash, D, Mellodew, K, Williams, SC, Fraser, SE, Meade, TJ, Price, J, Hodges, H. Tracking transplanted stem cell migration using bifunctional, contrast agent-enhanced, magnetic resonance imaging. Neuroimage 2002; 17: 803–11.CrossRefGoogle ScholarPubMed
31Kelly, S, Bliss, TM, Shah, AK, Sun, GH, Ma, M, Foo, WC, Masel, J, Yenari, MA, Weissman, IL, Uchida, N, Palmer, T, Steinberg, GK. Transplanted human fetal neural stem cells survive, migrate, and differentiate in ischemic rat cerebral cortex. Proc Natl Acad Sci USA 2004; 101: 11839–44.CrossRefGoogle ScholarPubMed
32Chu, K, Kim, M, Chae, SH, Jeong, SW, Kang, KS, Jung, KH, Kim, J, Kim, YJ, Kang, L, Kim, SU, Yoon, BW. Distribution and in situ proliferation patterns of intravenously injected immortalized human neural stem-like cells in rats with focal cerebral ischemia. Neurosci Res 2004; 50: 459–65.CrossRefGoogle ScholarPubMed
33Modo, M, Beech, JS, Meade, TJ, Williams, SC, Price, J. A chronic 1 year assessment of MRI contrast agent-labelled neural stem cell transplants in stroke. Neuroimage 2008; 47 (suppl 2): T133–42.CrossRefGoogle ScholarPubMed
34Modo, M, Mellodew, K, Cash, D, Fraser, SE, Meade, TJ, Price, J, Williams, SC. Mapping transplanted stem cell migration after a stroke: a serial, in vivo magnetic resonance imaging study. Neuroimage 2004; 21: 311–17.CrossRefGoogle ScholarPubMed
35Sykova, E, Jendelova, P. In vivo tracking of stem cells in brain and spinal cord injury. Prog Brain Res 2007; 161: 367–83.CrossRefGoogle ScholarPubMed
36Bühnemann, C, Scholz, A, Bernreuther, C, Malik, CY, Braun, H, Schachner, M, Reymann, KG, Dihné, M. Neuronal differentiation of transplanted embryonic stem cell-derived precursors in stroke lesions of adult rats. Brain 2006; 129: 3238–48.CrossRefGoogle ScholarPubMed
37Darsalia, V, Kallur, T, Kokaia, Z. Survival, migration and neuronal differentiation of human fetal striatal and cortical neural stem cells grafted in stroke-damaged rat striatum. Eur J Neurosci 2007; 26: 605–14.CrossRefGoogle ScholarPubMed
38Roitberg, BZ, Mangubat, E, Chen, EY, Sugaya, K, Thulborn, KR, Kordower, JH, Pawar, A, Konecny, T, Emborg, ME. Survival and early differentiation of human neural stem cells transplanted in a nonhuman primate model of stroke. J Neurosurg 2006; 105: 96–102.CrossRefGoogle Scholar
39Borlongan, CV, Tajima, Y, Trojanowski, JQ, Lee, VM, Sanberg, PR. Cerebral ischemia and CNS transplantation: differential effects of grafted fetal rat striatal cells and human neurons derived from a clonal cell line. NeuroReport 1998; 9: 3703–9.CrossRefGoogle ScholarPubMed
40Chu, K, Park, KI, Lee, ST, Jung, KH, Ko, SY, Kang, L, Sinn, DI, Lee, YS, Kim, SU, Kim, M, Roh, JK. Combined treatment of vascular endothelial growth factor and human neural stem cells in experimental focal cerebral ischemia. Neurosci Res 2005; 53: 384–90.CrossRefGoogle ScholarPubMed
41Modo, M, Rezaie, P, Heuschling, P, Patel, S, Male, DK, Hodges, H. Transplantation of neural stem cells in a rat model of stroke: assessment of short-term graft survival and acute host immunological response. Brain Res 2002; 958: 70–82.CrossRefGoogle Scholar
42Prockop, DJ. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 1997; 276: 71–74.CrossRefGoogle ScholarPubMed
43Dominici, M, Le Blanc, K, Mueller, I, Slaper-Cortenbach, I, Marini, F, Krause, D, Deans, R, Keating, A, Prockop, DJ, Horwitz, E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8: 315–17.CrossRefGoogle ScholarPubMed
44Li, Y, Chen, J, Chopp, M. Adult bone marrow transplantation after stroke in adult rats. Cell Transplant 2001; 10: 31–40.CrossRefGoogle ScholarPubMed
45Zhao, 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: 11–20.CrossRefGoogle ScholarPubMed
46Eglitis, MA, Dawson, D, Park, KW, Mouradian, MM. Targeting of marrow-derived astrocytes to the ischemic brain. NeuroReport 1999; 10: 1289–92.CrossRefGoogle Scholar
47Li, Y, Chen, J, Wang, L, Lu, M, Chopp, M. Treatment of stroke in rat with intracarotid administration of marrow stromal cells. Neurology 2001; 56: 1666–72.CrossRefGoogle ScholarPubMed
48Chen, J, Li, Y, Wang, L, Zhang, Z, Lu, D, Lu, M, Chopp, M. Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke 2001; 32: 1005–11.CrossRefGoogle ScholarPubMed
49Detante, O, Moisan, A, Dimastromatteo, J, Richard, MJ, Riou, L, Grillon, E, Barbier, E, Desruet, MD, De Fraipont, F, Segebarth, C, Jaillard, A, Hommel, M, Ghezzi, C, Remy, C. Intravenous administration of 99mTc-HMPAO-labeled human mesenchymal stem cells after stroke: in vivo imaging and biodistribution. Cell Transplant 2009; 18: 1369–79.CrossRefGoogle ScholarPubMed
50Shen, LH, Li, Y, Chen, J, Cui, Y, Zhang, C, Kapke, A, Lu, M, Savant-Bhonsale, S, Chopp, M. One-year follow-up after bone marrow stromal cell treatment in middle-aged female rats with stroke. Stroke 2007; 38: 2150–56.CrossRefGoogle ScholarPubMed
51Li, Y, McIntosh, K, Chen, J, Zhang, C, Gao, Q, Borneman, J, Raginski, K, Mitchell, J, Shen, L, Zhang, J, Lu, D, Chopp, M. Allogeneic bone marrow stromal cells promote glial-axonal remodeling without immunologic sensitization after stroke in rats. Exp Neurol 2006; 198: 313–25.CrossRefGoogle ScholarPubMed
52Zhang, R, Zhang, Z, Wang, L, Wang, Y, Gousev, A, Zhang, L, Ho, KL, Morshead, C, Chopp, M. Activated neural stem cells contribute to stroke-induced neurogenesis and neuroblast migration toward the infarct boundary in adult rats. J Cereb Blood Flow Metab 2004; 24: 441–48.CrossRefGoogle ScholarPubMed
53Chen, J, Li, Y, Zhang, R, Katakowski, M, Gautam, SC, Xu, Y, Lu, M, Zhang, Z, Chopp, M. Combination therapy of stroke in rats with a nitric oxide donor and human bone marrow stromal cells enhances angiogenesis and neurogenesis. Brain Res 2004; 1005: 21–28.CrossRefGoogle ScholarPubMed
54Chen, J, Li, Y, Katakowski, M, Chen, X, Wang, L, Lu, D, Lu, M, Gautam, SC, Chopp, M. Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat. J Neurosci Res 2003; 73: 778–86.CrossRefGoogle ScholarPubMed
55Chen, J, Zhang, ZG, Li, Y, Wang, L, Xu, YX, Gautam, SC, Lu, M, Zhu, Z, Chopp, M. Intravenous administration of human bone marrow stromal cells induces angiogenesis in the ischemic boundary zone after stroke in rats. Circ Res 2003; 92: 692–99.CrossRefGoogle ScholarPubMed
56Li, Y, Chen, J, Chen, XG, Wang, L, Gautam, SC, Xu, YX, Katakowski, M, Zhang, LJ, Lu, M, Janakiraman, N, Chopp, M. Human marrow stromal cell therapy for stroke in rat: neurotrophins and functional recovery. Neurology 2002; 59: 514–23.CrossRefGoogle ScholarPubMed
57Shen, LH, Li, Y, Chen, J, Zacharek, A, Gao, Q, Kapke, A, Lu, M, Raginski, K, Vanguri, P, Smith, A, Chopp, M. Therapeutic benefit of bone marrow stromal cells administered 1 month after stroke. J Cereb Blood Flow Metab 2007; 27: 6–13.CrossRefGoogle ScholarPubMed
58Bang, OY, Lee, JS, Lee, PH, Lee, G. Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol 2005; 57: 874–82.CrossRefGoogle ScholarPubMed
59Hentschke, S, Hentschke, M, Hummel, K, Salwender, HJ, Braumann, D, Stang, A. Bilateral thalamic infarction after reinfusion of DMSO-preserved autologous stem-cells. Leuk Lymphoma 2006; 47: 2418–20.CrossRefGoogle ScholarPubMed
60Strauer, BE, Brehm, M, Zeus, T, Köstering, M, Hernandez, A, Sorg, RV, Kögler, G, Wernet, P. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 2002; 106: 1913–18.CrossRefGoogle ScholarPubMed
61Yousef, M, Schannwell, CM, Kostering, M, Zeus, T, Brehm, M, Strauer, BE. The BALANCE Study: clinical benefit and long-term outcome after intracoronary autologous bone marrow cell transplantation in patients with acute myocardial infarction. J Am Coll Cardiol 2009; 53: 2262–69.CrossRefGoogle ScholarPubMed
62Tateishi-Yuyama, E, Matsubara, H, Murohara, T, Ikeda, U, Shintani, S, Masaki, H, Amano, K, Kishimoto, Y, Yoshimoto, K, Akashi, H, Shimada, K, Iwasaka, T, Imaizumi, T. Therapeutic Angiogenesis using Cell Transplantation (TACT) Study Investigators. Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial. Lancet 2002; 360: 427–35.CrossRefGoogle Scholar
63Jiang, Y, Jahagirdar, BN, Reinhardt, RL, Schwartz, RE, Keene, CD, Ortiz-Gonzalez, XR, Reyes, M, Lenvik, T, Lund, T, Blackstad, M, Du, J, Aldrich, S, Lisberg, A, Low, WC, Largaespada, DA, Verfaillie, CM. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002; 418: 41–49.CrossRefGoogle ScholarPubMed
64Kovacsovics-Bankowski, M, Mauch, K, Raber, A, Streeter, PR, Deans, RJ, Maziarz, RT, Van't Hof, W. Pre-clinical safety testing supporting clinical use of allogeneic multipotent adult progenitor cells. Cytotherapy 2008; 10: 730–42.CrossRefGoogle ScholarPubMed
65Boozer, S, Lehman, N, Lakshmipathy, U, Love, B, Raber, A, Maitra, A, Deans, R, Rao, MS, Ting, AE. Global characterization and genomic stability of human multistem, a multipotent adult progenitor cell. J Stem Cells 2009; 4: 17–28.Google ScholarPubMed
66Yasuhara, T, Hara, K, Maki, M, Mays, RW, Deans, RJ, Hess, DC, Carroll, JE, Borlongan, CV. Intravenous grafts recapitulate the neurorestoration afforded by intracerebrally delivered multipotent adult progenitor cells in neonatal hypoxic-ischemic rats. J Cereb Blood Flow Metab 2008; 28: 1804–10.CrossRefGoogle ScholarPubMed
67Asahara, T, Murohara, T, Sullivan, A, Silver, M, van der Zee, R, Li, T, Witzenbichler, B, Schatteman, G, Isner, JM. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997; 275: 964–67.CrossRefGoogle ScholarPubMed
68Chu, K, Jung, KH, Lee, ST, Park, HK, Sinn, DI, Kim, JM, Kim, DH, Kim, JH, Kim, SJ, Song, EC, Kim, M, Lee, SK, Roh, JK. Circulating endothelial progenitor cells as a new marker of endothelial dysfunction or repair in acute stroke. Stroke 2008; 39: 1441–47.CrossRefGoogle ScholarPubMed
69Fan, Y, Shen, F, Frenzel, T, Zhu, W, Ye, J, Liu, J, Chen, Y, Su, H, Young, WL, Yang, GY. Endothelial progenitor cell transplantation improves long-term stroke outcome in mice. Ann Neurol 2010; 67: 488–97.CrossRefGoogle ScholarPubMed
70Dunac, A, Frelin, C, Popolo-Blondeau, M, Chatel, M, Mahagne, MH, Philip, PJ. Neurological and functional recovery in human stroke are associated with peripheral blood CD34+ cell mobilization. J Neurol 2007; 254: 327–32.CrossRefGoogle ScholarPubMed
71Paczkowska, E, Kucia, M, Koziarska, D, Halasa, M, Safranow, K, Masiuk, M, Karbicka, A, Nowik, M, Nowacki, P, Ratajczak, MZ, Machalinski, B. Clinical evidence that very small embryonic-like stem cells are mobilized into peripheral blood in patients after stroke. Stroke 2009; 40: 1237–44.CrossRefGoogle ScholarPubMed
72Paczkowska, E, Larysz, B, Rzeuski, R, Karbicka, A, Jałowiński, R, Kornacewicz-Jach, Z, Ratajczak, MZ, Machaliński, B. Human hematopoietic stem/progenitor-enriched CD34(+) cells are mobilized into peripheral blood during stress related to ischemic stroke or acute myocardial infarction. Eur J Haematol 2005; 75: 461–67.CrossRefGoogle ScholarPubMed
73Yanqing, Z, Yu-Min, L, Jian, Q, Bao-Guo, X, Chuan-Zhen, L. Fibronectin and neuroprotective effect of granulocyte colony-stimulating factor in focal cerebral ischemia. Brain Res 2006; 1098: 161–69.CrossRefGoogle ScholarPubMed
74Xiao, J, Nan, Z, Motooka, Y, Low, WC. Transplantation of a novel cell line population of umbilical cord blood stem cells ameliorates neurological deficits associated with ischemic brain injury. Stem Cells Dev 2005; 14: 722–33.CrossRefGoogle ScholarPubMed
75Willing, AE, Vendrame, M, Mallery, J, Cassady, CJ, Davis, CD, Sanchez-Ramos, J, Sanberg, PR. Mobilized peripheral blood cells administered intravenously produce functional recovery in stroke. Cell Transplant 2003; 12: 449–54.CrossRefGoogle ScholarPubMed
76Borlongan, CV, Hadman, M, Sanberg, CD, Sanberg, PR. Central nervous system entry of peripherally injected umbilical cord blood cells is not required for neuroprotection in stroke. Stroke 2004; 35: 2385–89.CrossRefGoogle Scholar
77Vendrame, M, Cassady, J, Newcomb, J, Butler, T, Pennypacker, KR, Zigova, T, Sanberg, CD, Sanberg, PR, Willing, AE. Infusion of human umbilical cord blood cells in a rat model of stroke dose-dependently rescues behavioral deficits and reduces infarct volume. Stroke 2004; 35: 2390–95.CrossRefGoogle Scholar
78Willing, AE, Lixian, J, Milliken, M, Poulos, S, Zigova, T, Song, S, Hart, C, Sanchez-Ramos, J, Sanberg, PR. Intravenous versus intrastriatal cord blood administration in a rodent model of stroke. J Neurosci Res 2003; 73: 296–307.CrossRefGoogle Scholar
79Mäkinen, S, Kekarainen, T, Nystedt, J, Liimatainen, T, Huhtala, T, Närvänen, A, Laine, J, Jolkkonen, J. Human umbilical cord blood cells do not improve sensorimotor or cognitive outcome following transient middle cerebral artery occlusion in rats. Brain Res 2006; 1123: 207–15.CrossRefGoogle ScholarPubMed
80Savitz, 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: 101–7.CrossRefGoogle ScholarPubMed
81Kurozumi, K, Nakamura, K, Tamiya, T, Kawano, Y, Kobune, M, Hirai, S, Uchida, H, Sasaki, K, Ito, Y, Kato, K, Honmou, O, Houkin, K, Date, I, Hamada, H. BDNF gene-modified mesenchymal stem cells promote functional recovery and reduce infarct size in the rat middle cerebral artery occlusion model. Mol Ther 2004; 9: 189–97.CrossRefGoogle ScholarPubMed
82Liu, H, Honmou, O, Harada, K, Nakamura, K, Houkin, K, Hamada, H, Kocsis, JD. Neuroprotection by PlGF gene-modified human mesenchymal stem cells after cerebral ischaemia. Brain 2006; 129: 2734–45.CrossRefGoogle ScholarPubMed
83Lee, HJ, Kim, KS, Park, IH, Kim, SU. Human neural stem cells over-expressing VEGF provide neuroprotection, angiogenesis and functional recovery in mouse stroke model. PLoS ONE 2007; 2: e156.CrossRefGoogle ScholarPubMed
84Gray, JA, Grigoryan, G, Virley, D, Patel, S, Sinden, JD, Hodges, H. Conditionally immortalized, multipotential and multifunctional neural stem cell lines as an approach to clinical transplantation. Cell Transplant 2000; 9: 153–68.CrossRefGoogle ScholarPubMed
85Benowitz, LI, Carmichael, ST. Promoting axonal rewiring to improve outcome after stroke. Neurobiol Dis 2010; 37: 259–66.CrossRefGoogle ScholarPubMed
86Murphy, TH, Corbett, D. Plasticity during stroke recovery: from synapse to behaviour. Nat Rev Neurosci 2009; 10: 861–72.CrossRefGoogle ScholarPubMed
87Morshead, CM, Reynolds, BA, Craig, CG, McBurney, MW, Staines, WA, Morassutti, D, Weiss, S, van der Kooy, D. Neural stem cells in the adult mammalian forebrain: a relatively quiescent subpopulation of subependymal cells. Neuron 1994; 13: 1071–82.CrossRefGoogle ScholarPubMed
88Zhang, RL, Zhang, ZG, Zhang, L, Chopp, M. Proliferation and differentiation of progenitor cells in the cortex and the subventricular zone in the adult rat after focal cerebral ischemia. Neuroscience 2001; 105: 33–41.CrossRefGoogle ScholarPubMed
89Arvidsson, A, Collin, T, Kirik, D, Kokaia, Z, Lindvall, O. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 2002; 8: 963–70.CrossRefGoogle ScholarPubMed
90Darsalia, V, Heldmann, U, Lindvall, O, Kokaia, Z. Stroke-induced neurogenesis in aged brain. Stroke 2005; 36: 1790–95.CrossRefGoogle ScholarPubMed
91Thored, P, Arvidsson, A, Cacci, E, Ahlenius, H, Kallur, T, Darsalia, V, Ekdahl, CT, Kokaia, Z, Lindvall, O. Persistent production of neurons from adult brain stem cells during recovery after stroke. Stem Cells 2006; 24: 739–47.CrossRefGoogle ScholarPubMed
92Minger, SL, Ekonomou, A, Carta, EM, Chinoy, A, Perry, RH, Ballard, CG. Endogenous neurogenesis in the human brain following cerebral infarction. Regen Med 2007; 2: 69–74.CrossRefGoogle ScholarPubMed
93Daadi, MM, Li, Z, Arac, A, Grueter, BA, Sofilos, M, Malenka, RC, Wu, JC, Steinberg, GK. Molecular and magnetic resonance imaging of human embryonic stem cell-derived neural stem cell grafts in ischemic rat brain. Mol Ther 2009; 17: 1282–91.CrossRefGoogle ScholarPubMed
94Stroemer, 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 dose-dependent fashion. Neurorehabil Neural Repair 2009; 23: 895–909.CrossRefGoogle Scholar
95Liauw, J, Hoang, S, Choi, M, Eroglu, C, Choi, M, Sun, GH, Percy, M, Wildman-Tobriner, B, Bliss, T, Guzman, RG, Barres, BA, Steinberg, GK. Thrombospondins 1 and 2 are necessary for synaptic plasticity and functional recovery after stroke. J Cereb Blood Flow Metab 2008; 28: 1722–32.CrossRefGoogle ScholarPubMed
96Ting, AE, Mays, RW, Frey, MR, Hof, WV, Medicetty, S, Deans, R. Therapeutic pathways of adult stem cell repair. Crit Rev Oncol Hematol 2008; 65: 81–93.CrossRefGoogle ScholarPubMed
97Bible, E, Chau, DY, Alexander, MR, Price, J, Shakesheff, KM, Modo, M. The support of neural stem cells transplanted into stroke-induced brain cavities by PLGA particles. Biomaterials 2009; 30: 2985–94CrossRefGoogle Scholar
98Honmou, O, Houkin, K, Matsunaga, T, Niitsu, Y, Ishiai, S, Waxman, SG, Kocsis, JD. Intravenous transplantation of autologous mesenchymal stem cells derived from bone marrow into stroke patients. Stroke 2008; 39: 543.Google Scholar
99Shyu, WC, Lin, SZ, Lee, CC, Liu, DD, Li, H. Granulocyte colony-stimulating factor for acute ischemic stroke: a randomized controlled trial. CMAJ 2006; 174: 927–33.CrossRefGoogle ScholarPubMed
100Sprigg, N, Bath, PM, Zhao, L, Willmot, MR, Gray, LJ, Walker, MF, Dennis, MS, Russell, N. 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 2006; 37: 2979–83.CrossRefGoogle ScholarPubMed
101Kondziolka, D, Wechsler, L, Goldstein, S, Meltzer, C, Thulborn, KR, Gebel, J, Jannetta, P, DeCesare, S, Elder, EM, McGrogan, M, Reitman, MA, Bynum, L. Transplantation of cultured human neuronal cells for patients with stroke. Neurology 2000; 55: 565–69.CrossRefGoogle ScholarPubMed
102Kondziolka, D, Steinberg, GK, Wechsler, L, Meltzer, CC, Elder, E, Gebel, J, Decesare, S, Jovin, T, Zafonte, R, Lebowitz, J, Flickinger, JC, Tong, D, Marks, MP, Jamieson, C, Luu, D, Bell-Stephens, T, Teraoka, J. Neurotransplantation for patients with subcortical motor stroke: a phase 2 randomized trial. J Neurosurg 2005; 103: 38–45.CrossRefGoogle ScholarPubMed
103Nelson, PT, Kondziolka, D, Wechsler, L, Goldstein, S, Gebel, J, DeCesare, S, Elder, EM, Zhang, PJ, Jacobs, A, McGrogan, M, Lee, VM, Trojanowski, JQ. Clonal human (hNT) neuron grafts for stroke therapy: neuropathology in a patient 27 months after implantation. Am J Pathol 2002; 160: 1201–6.CrossRefGoogle Scholar
104Thomas, RJ, Hope, AD, Hourd, P, Baradez, M, Miljan, EA, Sinden, JD, Williams, DJ. Automated, serum-free production of CTX0E03: a therapeutic clinical grade human neural stem cell line. Biotechnol Lett 2009; 31: 1167–72.CrossRefGoogle ScholarPubMed
105Stevanato, L, Corteling, RL, Stroemer, P, Hope, A, Heward, J, Miljan, EA, Sinden, JD. c-MycERTAM transgene silencing in a genetically modified human neural stem cell line implanted into MCAo rodent brain. BMC Neurosci 2009; 10: 86.CrossRefGoogle Scholar
106Hattiangady, B, Shuai, B, Cai, J, Coksaygan, T, Rao, MS, Shetty, AK. Increased dentate neurogenesis after grafting of glial restricted progenitors or neural stem cells in the aging hippocampus. Stem Cells 2007; 25: 2104–17.CrossRefGoogle ScholarPubMed
107Park, DH, Eve, DJ, Sanberg, PR, Musso, J III, Bachstetter, AD, Wolfson, A et al. Increased neuronal proliferation in the dentate gyrus of aged rats following neural stem cell implantation. Stem Cells Dev 2010; 19: 175–80.CrossRefGoogle ScholarPubMed
108Lee, HJ, Kim, KS, Kim, EJ, Choi, HB, Lee, KH, Park, IH, Ko, Y, Jeong, SW, Kim, SU. Brain transplantation of immortalized human neural stem cells promotes functional recovery in mouse intracerebral hemorrhage stroke model. Stem Cells 2007; 25: 1204–12.CrossRefGoogle ScholarPubMed
109Seyfried, D, Ding, J, Han, Y, Li, Y, Chen, J, Chopp, M. Effects of intravenous administration of human bone marrow stromal cells after intracerebral hemorrhage in rats. J Neurosurg 2006; 104: 313–18.CrossRefGoogle ScholarPubMed
110Bliss, TM, Kelly, S, Shah, AK, Foo, WC, Kohli, P, Stokes, C, Sun, GH, Ma, M, Masel, J, Kleppner, SR, Schallert, T, Palmer, T, Steinberg, GK. Transplantation of hNT neurons into the ischemic cortex: cell survival and effect on sensorimotor behavior. J Neurosci Res 2006; 83: 1004–14.CrossRefGoogle ScholarPubMed
111Feeney, DM, Hovda, DA. Reinstatement of binocular depth perception by amphetamine and visual experience after visual cortex ablation. Brain Res 1985; 342: 352–56.CrossRefGoogle ScholarPubMed
112Feeney, DM, Gonzalez, A, Law, WA. Amphetamine, haloperidol, and experience interact to affect rate of recovery after motor cortex injury. Science 1982; 217: 855–57.CrossRefGoogle ScholarPubMed
113Garcia-Alias, G, Barkhuysen, S, Buckle, M, Fawcett, JW. Chondroitinase ABC treatment opens a window of opportunity for task-specific rehabilitation. Nat Neurosci 2009; 12: 1145–51.CrossRefGoogle ScholarPubMed
114Hicks, AU, Hewlett, K, Windle, V, Chernenko, G, Ploughman, M, Jolkkonen, J, Weiss, S, Corbett, D. Enriched environment enhances transplanted subventricular zone stem cell migration and functional recovery after stroke. Neuroscience 2007; 146: 31–40.CrossRefGoogle ScholarPubMed
115Hicks, AU, MacLellan, CL, Chernenko, GA, Corbett, D. Long-term assessment of enriched housing and subventricular zone derived cell transplantation after focal ischemia in rats. Brain Res 2008; 1231: 103–12.CrossRefGoogle ScholarPubMed
116Stem Cell Therapies as an Emerging Paradigm in Stroke 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 2009; 40: 510–15.CrossRefGoogle Scholar
117Borlongan, CV, Chopp, M, Steinberg, GK, Bliss, TM, Li, Y, Lu, M, Hess, DC, Kondziolka, D. Potential of stem/progenitor cells in treating stroke: the missing steps in translating cell therapy from laboratory to clinic. Regen Med 2008; 3: 249–50.CrossRefGoogle ScholarPubMed
118Dobkin, BH, Curt, A, Guest, J. Cellular transplants in China: observational study from the largest human experiment in chronic spinal cord injury. Neurorehabil Neural Repair 2006; 20: 5–13.CrossRefGoogle Scholar