The dark side of the force - constraints and complications of cell therapies for stroke

Frontiers in Neurology

Volumn 6, Issue JUN, 2015, Pages

  Boltze, Johannes ^a,b   Arnold, Antje ^c,d   Walczak, Piotr ^c,d   Jolkkonen, Jukka ^e   Cui, Lili ^e   Wagner, Daniel Christoph ^a  

^a FRAUNHOFER INSTITUTE FOR CELL THERAPY AND IMMUNOLOGY   (Germany)

^b UNIVERSITY OF LEIPZIG   (Germany)

^c JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^d JOHNS HOPKINS UNIVERSITY   (United States)

^e UNIVERSITY OF EASTERN FINLAND   (Finland)

Author keywords

Adverse event; Cell therapy; Cell transplantation; Clinical trial; Ischemic stroke; Safety; Side effect, complication; Translational research

Indexed keywords

ARTICLE; AUTOLOGOUS STEM CELL TRANSPLANTATION; BRAIN INJURY; CELL INTERACTION; CEREBROVASCULAR ACCIDENT; CLINICAL EFFECTIVENESS; FEVER; GRAFT REJECTION; GRAFT VERSUS HOST REACTION; HEADACHE; HUMAN; HYDROCEPHALUS; INCIDENCE; LOSS OF APPETITE; LUMBOSACRAL RADICULOPATHY; LUNG EMBOLISM; MESENCHYMAL STEM CELL TRANSPLANTATION; NAUSEA; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); RADICULOPATHY; RISK BENEFIT ANALYSIS; SAFETY; SEIZURE; SKIN PRURITUS; SOMNOLENCE; STEM CELL TRANSPLANTATION; SUBDURAL HEMATOMA; TERATOCARCINOMA; TERATOMA;

EID: 84936937628     PISSN: None     EISSN: 16642295     Source Type: Journal    
DOI: 10.3389/fneur.2015.00155     Document Type: Article

References (196)

1. Abraham, E.J., Kodama, S., Lin, J.C., Ubeda, M., Faustman, D.L., and Habener, J.F. (2004). Human pancreatic islet-derived progenitor cell engraftment in immunocompetent mice. Am J Pathol. 164, 817-830.
2. Ali, J.M., Bolton, E.M., Bradley, J.A., and Pettigrew, G.J. (2013). Allorecognition pathways in transplant rejection and tolerance. Transplantation. 96, 681-688. doi: 10.1097/TP.0b013e31829853ce.
3. Amariglio, N., Hirshberg, A., Scheithauer, B.W., Cohen, Y., Loewenthal, R., Trakhtenbrot, L., et al. (2009). Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS Med. 6, e1000029. doi: 10.1371/journal.pmed.1000029.
4. Andres, R.H., Horie, N., Slikker, W., Keren-Gill, H., Zhan, K., Sun, G., et al. (2011). Human neural stem cells enhance structural plasticity and axonal transport in the ischaemic brain. Brain. 134, 1777-1789. doi: 10.1093/brain/awr094.
5. Anton, K., Banerjee, D., and Glod, J. (2012). Macrophage-associated mesenchymal stem cells assume an activated, migratory, pro-inflammatory phenotype with increased IL-6 and CXCL10 secretion. PLoS One. 7, e35036. doi: 10.1371/journal.pone.0035036.
6. Araki, R., Uda, M., Hoki, Y., Sunayama, M., Nakamura, M., Ando, S., et al. (2013). Negligible immunogenicity of terminally differentiated cells derived from induced pluripotent or embryonic stem cells. Nature. 494, 100-104. doi: 10.1038/nature11807.
7. Arboix, A., García-Eroles, L., Massons, J.B., Oliveres, M., and Comes E. (1997). Predictive factors of early seizures after acute cerebrovascular disease. Stroke. 28, 1590-1594.
8. Arthur, A., Rychkov, G., Shi, S., Koblar, S.A., and Gronthos, S. (2008). Adult human dental pulp stem cells differentiate toward functionally active neurons under appropriate environmental cues. Stem Cells. 26, 1787-1795. doi: 10.1634/stemcells.2007-0979.
9. Bachier, C., Potter, J., Potter, G., Sugay, R., Shaughnessy, P., Chan, K., et al. (2012). High white blood cell concentration in the peripheral blood stem cell product can induce seizures during infusion of autologous peripheral blood stem cells. Biol Blood Marrow Transplant. 18, 1055-1060. doi: 10.1016/j.bbmt.2011.12.500.
10. Bacigaluppi, M., Pluchino, S., Peruzzotti-Jametti, L., Kilic, E., Kilic, U., Salani, G., et al. (2009). Delayed post-ischaemic neuroprotection following systemic neural stem cell transplantation involves multiple mechanisms. Brain. 132, 2239-2251. doi: 10.1093/brain/awp174.
11. Balami, J.S., Sutherland, B.A., and Buchan, A.M. (2013). Complications associated with recombinant tissue plasminogen activator therapy for acute ischaemic stroke. CNS Neurol Disord Drug Targets. 12, 155-169.
12. Balseanu, A.T., Buga, A.M., Catalin, B., Wagner, D.C., Boltze, J., Zagrean, A.M., et al. (2014). Multimodal Approaches for Regenerative Stroke Therapies: Combination of Granulocyte Colony-Stimulating Factor with Bone Marrow Mesenchymal Stem Cells is Not Superior to G-CSF Alone. Front Aging Neurosci. 6, 130. doi: 10.3389/fnagi.2014.00130.
13. Banerjee, S., Bentley, P., Hamady, M., Marley, S., Davis, J., Shlebak, A., Nicholls, J., et al. (2014). Intra-Arterial Immunoselected CD34+ Stem Cells for Acute Ischemic Stroke. Stem Cells Transl Med. 3, 1322-1330. doi: 10.5966/sctm.2013-0178.
14. Bang, O.Y., Lee, J.S., Lee, P.H., and Lee, G. (2005). Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol. 57, 874-882.
15. Barbosa da Fonseca, L.M., Gutfilen, B., Rosado de Castro, P.H., Battistella, V., Goldenberg, R.C., Kasai-Brunswick, T., et al. (2010). Migration and homing of bone854 marrow mononuclear cells in chronic ischemic stroke after intra-arterial injection. Exp Neurol. 221, 122-128. doi: 10.1016/j.expneurol.2009.10.010.
16. Battistella, V., de Freitas, G.R., da Fonseca, L.M., Mercante, D., Gutfilen, B., Goldenberg, R.C., et al. (2011). Safety of autologous bone marrow mononuclear cell transplantation in patients with nonacute ischemic stroke. Regen. Med. 6, 45-52. doi: 10.2217/rme.10.97.
17. Bhasin, A., Srivastava, M.V., Mohanty, S., Bhatia, R., Kumaran, S.S., and Bose, S. (2013). Stem cell therapy: a clinical trial of stroke. Clin Neurol Neurosurg. 115, 1003- 1008. doi: 10.1016/j.clineuro.2012.10.015.
18. Binder, D.K., Rau, G., and Starr, P.A. (2003). Hemorrhagic complications of microelectrode-guided deep brain stimulation. Stereotact Funct Neurosurg. 80, 28-31.
19. Bladin, C.F., Alexandrov, A.V., Bellavance, A., Bornstein, N., Chambers, B., Coté, R., et al. (2000). Seizures after stroke: a prospective multicenter study. Arch Neurol. 57, 1617-1622.
20. Blum, B., and Benvenisty, N. (2008). The tumorigenicity of human embryonic stem cells. Adv Cancer Res. 100, 133-58. doi: 10.1016/S0065-230X(08)00005-5.
21. Boltze, J., Förschler, A., Nitzsche, B., Waldmin, D., Hoffmann, A., Boltze, C.M., et al. (2008). Permanent middle cerebral artery occlusion in sheep: a novel large animal model of focal cerebral ischemia. J Cereb Blood Flow Metab. 28, 1951-1964. doi: 10.1038/jcbfm.2008.89.
22. Boltze, J., Reich, D.M., Hau, S., Reymann, K.G., Strassburger, M., Lobsien, D., et al. (2012a). Assessment of neuroprotective effects of human umbilical cord blood mononuclear cell subpopulations in vitro and in vivo. Cell Transplant. 21, 723-737. doi: 10.3727/096368911X586783.
23. Boltze, J., Schmidt, U.R., Reich, D.M., Kranz, A., Reymann, K.G., Strassburger, M., et al. (2012b). Determination of the therapeutic time window for human umbilical cord blood mononuclear cell transplantation following experimental stroke in rats. Cell Transplant. 21, 1199-1211. doi: 10.3727/096368911X589609.
24. Borlongan, C.V., Hadman, M., Sanberg, C.D., and Sanberg, P.R. (2004). Central nervous system entry of peripherally injected umbilical cord blood cells is not required for neuroprotection in stroke. Stroke. 35, 2385-2389.
25. Breunig, J.J., Haydar, T.F., Rakic, P. (2011). Neural stem cells: Historical perspective and future prospects. Neuron. 70, 614-625. doi: 10.1016/j.neuron.2011.05.005.
26. Buga, A.M., Di Napoli, M., and Popa-Wagner, A. (2013). Preclinical models of stroke in aged animals with or without comorbidities: role of neuroinflammation. Biogerontology. 14(6), 651-662. doi: 10.1007/s10522-013-9465-0.
27. Buga, A.M., Scheibe, J., Möller, K., Ciobanu, O., Pösel, C., Boltze, J. et al. (2015). Granulocyte colony-stimulating factor and bone marrow mononuclear cells for stroke treatment in the aged brain. Curr Neurovasc Res. 12, 155-162.
28. Bühnemann, C., Scholz, A., Bernreuther, C., Malik, C.Y., Braun, H., Schachner, M., et al. (2006). Neuronal differentiation of transplanted embryonic stem cell-derived precursors in stroke lesions of adult rats. Brain. 129, 3238-3248.
29. Bystron, I., Blakemore, C., Rakic, P. (2008). Development of the human cerebral cortex: Boulder committee revisited. Nat Rev Neurosci. 9, 110-122. doi: 10.1038/nrn2252.
30. Chang, D.J., Oh, S.H., Lee, N., Choi, C., Jeon, I., Kim, H.S., et al. (2013). Contralaterally transplanted human embryonic stem cell-derived neural precursor cells (ENStem-A) migrate and improve brain functions in stroke-damaged rats. Exp Mol Med. 45, e53. doi: 10.1038/emm.2013.93.
31. Chen, X., Gan, Y., Li, W., Su, J., Zhang, Y., Huang, Y., et al. (2014). The interaction between mesenchymal stem cells and steroids during inflammation. Cell Death Dis. 5, e1009. doi: 10.1038/cddis.2013.537.
32. Chen, D.C., Lin, S.Z., Fan, J.R., Lin, C.H., Lee, W., Lin, C.C., et al. (2014). Intracerebral implantation of autologous peripheral blood stem cells in stroke patients: a randomized phase II study. Cell Transplant. 23, 1599-1612. doi: 10.3727/096368914X678562.
33. Chen, Z., Phillips, L.K., Gould, E., Campisi, J., Lee, S.W., Ormerod, B.K., et al. (2011). MHC mismatch inhibits neurogenesis and neuron maturation in stem cell allografts. PLoS One. 6, e14787. doi: 10.1371/journal.pone.0014787.
34. Chen, J., Sanberg, P.R., Li, Y., Wang, L., Lu, M., Willing, A. E., et al. (2001). Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats. Stroke. 32, 2682-2688.
35. Chen, L., Xi, H., Huang, H., Zhang, F., Liu, Y., Chen, D., et al. (2013). Multiple cell transplantation based on an intraparenchymal approach for patients with chronic phase stroke. Cell Transplant. 22, S83-S91. doi: 10.3727/096368913X672154.
36. Chen, J., Ye, X., Yan, T., Zhang, C., Yang, X.P., Cui, X., et al. (2011). Adverse effects of bone marrow stromal cell treatment of stroke in diabetic rats. Stroke. 42, 3551-3558. doi: 10.1161/STROKEAHA.111.627174.
37. Chen, J., Zhang, Z.G., Li, Y., Wang, L., Xu, Y.X., Gautam, S.C., et al. (2003). Intravenous administration of human bone marrow stromal cells induces angiogenesis in the ischemic boundary zone after stroke in rats. Circ Res. 92, 692-699.
38. Chen-Plotkin, A.S., Vossel, K.A., Samuels, M.A., and Chen, M.H. (2007). Encephalopathy, stroke, and myocardial infarction with DMSO use in stem cell transplantation. Neurology. 68, 859-861.
39. Chiarelli, F., Pomilio, M., Mohn, A., Tumini, S., Verrotti, A., Mezzetti, A., et al. 2002). Serum angiogenin concentrations in young patients with diabetes mellitus. Eur J Clin Invest. 32, 110-114.
40. Clarkson, A.N., Huang, B.S., Macisaac, S.E., Mody, I., and Carmichael, S.T. (2010). Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke. Nature. 468, 305-309. doi: 10.1038/nature09511.
41. Clarkson, A.N., Overman, J.J., Zhong, S., Mueller, R., Lynch, G., and Carmichael, S.T. (2011). AMPA receptor-induced local brain-derived neurotrophic factor signaling mediates motor recovery after stroke. J Neurosci. 31, 3766-3775. doi: 10.1523/JNEUROSCI.5780-10.2011.
42. Cook, D.J., and Tymianski, M. (2012). Nonhuman primate models of stroke for translational neuroprotection research. Neurotherapeutics 9, 371-379. doi: 10.1007/s13311-012-0115-z.
43. Cooley, L.D., Sears, D.A., Udden, M.M., Harrison, W.R., and Baker, K.R. (2000). Donor cell leukemia: report of a case occurring 11 years after allogeneic bone marrow transplantation and review of the literature. Am J Hematol. 2000 63, 46-53.
44. Covacu, R., Arvidsson, L., Andersson, A., Khademi, M., Erlandsson-Harris, H., Harris, R.A., et al. (2009). TLR activation induces TNF-alpha production from adult neural stem/progenitor cells. J Immunol. 182, 6889-6895. doi: 10.4049/jimmunol.0802907.
45. Cui, X., Chopp, M., Zacharek, A., Dai, J., Zhang, C., Yan, T., et al. (2012). Combination treatment of stroke with sub-therapeutic doses of Simvastatin and human umbilical cord blood cells enhances vascular remodeling and improves functional outcome. Neuroscience. 227, 223-231. doi: 10.1016/j.neuroscience.2012.09.066.
46. Cui, L., Kerkelä, E., Bakreen, A., Nitzsche, F., Andrzejewska, A., Nowakowski, A., et (2015). The cerebral embolism evoked by intra-arterial delivery of allogeneic bone marrow mesenchymal stem cells in rats is related to cell dose and infusion velocity. Stem Cell Res Ther. 6, 11. doi:10.1186/scrt544.
47. Danielyan, L., Beer-Hammer, S., Stolzing, A., Schäfer, R., Siegel, G., Fabian, C., et (2014). Intranasal delivery of bone marrow-derived mesenchymal stem cells, macrophages, and microglia to the brain in mouse models of Alzheimer's and Parkinson's disease. Cell Transplant. 23, S123-139. doi: 10.3727/096368914X684970.
48. Delarosa, O., Dalemans, W., and Lombardo, E. (2012). Toll-like receptors as modulators of mesenchymal stem cells. Front Immunol. 3, 182. doi: 10.3389/fimmu.2012.00182.
49. Devine, S.M., Cobbs, C., Jennings, M., Bartholomew, A., and Hoffman, R. (2003). Mesenchymal stem cells distribute to a wide range of tissues following systemic infusion into nonhuman primates. Blood. 101, 2999-3001.
50. Dihné, M., Bernreuther, C., Hagel, C., Wesche, K.O., and Schachner, M. (2006). Embryonic stem cell-derived neuronally committed precursor cells with reduced teratoma formation after transplantation into the lesioned adult mouse brain. Stem Cells. 24, 1458-1466.
51. Dirnagl, U., Hakim, A., Macleod, M., Fisher, M., Howells, D., Alan, S.M., et al. 2013). A concerted appeal for international cooperation in preclinical stroke research. Stroke. 44, 1754-1760. doi: 10.1161/STROKEAHA.113.000734.
52. Doeppner, T.R., Ewert, T.A., Tönges, L., Herz, J., Zechariah, A., ElAli, A., et al. 2012). Transduction of neural precursor cells with TAT-heat shock protein 70 chaperone: therapeutic potential against ischemic stroke after intrastriatal and systemic transplantation. Stem Cells. 30, 1297-1310. doi: 10.1002/stem.1098.
53. Donega, V., Nijboer, C.H., van Tilborg, G., Dijkhuizen, R.M., Kavelaars, A., and Heijnen, C.J. (2014). Intranasally administered mesenchymal stem cells promote a regenerative niche for repair of neonatal ischemic brain injury. Exp Neurol. 261, 53- 64. doi: 10.1016/j.expneurol.2014.06.009.
54. Donovan, S.L., and Dyer, M.A. (2005). Regulation of proliferation during central nervous system development. Semin Cell Dev Biol. 16, 407-421.
55. Duijvestein, M., Vos, A.C., Roelofs, H., Wildenberg, M.E., Wendrich, B.B., Verspaget, H.W., et al. (2010). Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn's disease: results of a phase I study. Gut. 59, 1662-1669. doi: 10.1136/gut.2010.215152.
56. Erdö, F., Bührle, C., Blunk, J., Hoehn, M., Xia, Y., Fleischmann, B., et al. (2003). Host-dependent tumorigenesis of embryonic stem cell transplantation in experimental stroke. J Cereb Blood Flow Metab. 23, 780-785.
57. Felfly, H., Muotri, A., Yao, H., and Haddad, G.G. (2010). Hematopoietic stem cell transplantation protects mice from lethal stroke. Exp Neurol. 225, 284-293. doi: 10.1016/j.expneurol.2010.06.001.
58. Freyman, T., Polin, G., Osman, H., Crary, J., Lu, M., Cheng, L., et al. (2006). A quantitative, randomized study evaluating three methods of mesenchymal stem cell delivery following myocardial infarction. Eur Heart J. 27, 1114-1122.
59. Fischer, U.M., Harting, M.T., Jimenez, F., Monzon-Posadas, W.O., Xue, H., Savitz, S.I., et al. (2009). Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem Cells Dev. 18, 683-692. doi: 10.1089/scd.2008.0253.
60. Fraser, C.J., Hirsch, B.A., Dayton, V., Creer, M.H., Neglia, J.P., Wagner, J.E., et al. (2005). First report of donor cell-derived acute leukemia as a complication of umbilical cord blood transplantation. Blood. 106, 4377-4380.
61. Freed, C.R., Greene, P.E., Breeze, R.E., Tsai, W.Y., DuMouchel, W., Kao, R., et al. (2001). Transplantation of embryonic dopamine neurons for severe Parkinson's disease. N Engl J Med. 344, 710-719.
62. Friedrich, M.A., Martins, M.P., Araújo, M.D., Klamt, C., Vedolin, L., Garicochea, B., et al. (2012). Intra-arterial infusion of autologous bone marrow mononuclear cells in patients with moderate to severe middle cerebral artery acute ischemic stroke. Cell Transplant. 21 Suppl 1, S13-S21. doi: 10.3727/096368912X612512.
63. Gao, J., Dennis, J.E., Muzic, R.F., Lundberg, M., and Caplan, A.I. (2001). The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion. Cells Tissues Organs. 169, 12-20.
64. Ge, J., Guo, L., Wang, S., Zhang, Y., Cai, T., Zhao, R.C., et al. (2014). The size of mesenchymal stem cells is a significant cause of vascular obstructions and stroke. Stem Cell Rev. 10, 295-303. doi: 10.1007/s12015-013-9492-x.
65. Gilad, R. (2012). Management of seizures following a stroke: what are the options? Drugs Aging. 29, 533-538. doi: 10.2165/11631540-000000000-00000.
66. Goker, H., Haznedaroglu, I.C., and Chao, N.J. (2001). Acute graft-vs-host disease: pathobiology and management. Exp Hematol. 29, 259-277.
67. Green, D.R., Ferguson, T., Zitvogel, L., and Kroemer, G. (2009). Immunogenic and tolerogenic cell death. Nat Rev Immunol. 9, 353-363. doi: 10.1038/nri2545.
68. Guck, J., Schinkinger, S., Lincoln, B., Wottawah, F., Ebert, S., Romeyke, M., et al. 2005). Optical deformability as an inherent cell marker for testing malignant transformation and metastatic competence. Biophys J. 88, 3689-3698.
69. Hacke, W., Kaste, M., Bluhmki, E., Brozman, M., Dávalos, A., Guidetti, D., et al. (2008). Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 359, 1317-1329. doi: 10.1056/NEJMoa0804656.
70. Hauser, R.A., Furtado, S., Cimino, C.R., Delgado, H., Eichler, S., Schwartz, S., et al. (2002). Bilateral human fetal striatal transplantation in Huntington's disease. Neurology. 58, 687-695.
71. Hayashi, J., Takagi, Y., Fukuda, H., Imazato, T., Nishimura, M., Fujimoto, M., et al. (2006). Primate embryonic stem cell-derived neuronal progenitors transplanted into ischemic brain. J Cereb Blood Flow Metab. 26, 906-914.
72. Hermann, D.M., and Chopp, M. (2012). Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation. Lancet Neurol. 11, 369-380. doi: 10.1016/S1474-4422(12)70039-X.
73. Hess, D.C., Sila, C.A., Furlan, A.J., Wechsler, L.R., Switzer, J.A., and Mays, R.W. (2014). A double-blind placebo-controlled clinical evaluation of MultiStem for the treatment of ischemic stroke. Int J Stroke. 9, 381-386. doi: 10.1111/ijs.12065
74. Hoehn, M., Küstermann, E., Blunk, J., Wiedermann, D., Trapp, T., Wecker, S., et al. (2002). 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 U S A. 99, 16267-16272.
75. Honmou, O., Houkin, K., Matsunaga, T., Niitsu, Y., Ishiai, S., Onodera, R., et al. (2011). Intravenous administration of auto serum-expanded autologous mesenchymal stem cells in stroke. Brain. 134, 1790-1807. doi: 10.1093/brain/awr063.
76. Hori, J., Ng, T.F., Shatos, M., Klassen, H., Streilein, J.W., and Young, M.J. (2003). Neural progenitor cells lack immunogenicity and resist destruction as allografts. Stem Cells. 21, 405-416.
77. Hurst, R.W., Bosch, E.P., Morris, J.M., Dyck, P.J., and Reeves, R.K. (2013). Inflammatory hypertrophic cauda equina following intrathecal neural stem cell injection. Muscle Nerve. 48, 831-825. doi: 10.1002/mus.23920.
78. Hwa Cho, H., Bae, Y.C., and Jung, J.S. (2006). Role of toll-like receptors on human adipose-derived stromal cells. Stem Cells. 24, 2744-2752.
79. Issa, R., Al Qteishat, A., Mitsios, N., Saka, M., Krupinski, J., Tarkowski, E., et al. (2005). Expression of basic fibroblast growth factor mRNA and protein in the human brain following ischaemic stroke. Angiogenesis. 8, 53-62.
80. Jablonska, A., Janowski, M., and Lukomska, B. (2013). Different methods of immunosuppresion do not prolong the survival of human cord blood-derived neural stem cells transplanted into focal brain-injured immunocompetent rats. Acta Neurobiol Exp (Wars). 73, 88-101.
81. Janowski, M., Lyczek, A., Engels, C., Xu, J., Lukomska, B., Bulte, J. W., et al. (2013). Cell size and velocity of injection are major determinants of the safety of intracarotid stem cell transplantation. J Cereb Blood Flow Metab. 33, 921-927. doi: 10.1038/jcbfm.2013.32.
82. Janowski, M., Wagner, D.C., and Boltze, J. (2015). Stem cell-based tissue replacement after stroke: factual necessity or notorious fiction? Stroke. (accepted)
83. Jawad, S., Al-Yassin, A., Herridge, D., Lai, W.K., Rozario, N., and Hendy, J. (2012). Safeguarding patients against stem cell tourism. Br J Gen Pract. 62, 269-270. doi: 10.3399/bjgp12X641591.
84. Jensen, M.B., Yan, H., Krishnaney-Davison, R., Al Sawaf, A., and Zhang, S.C. (2013). Survival and differentiation of transplanted neural stem cells derived from human induced pluripotent stem cells in a rat stroke model. J Stroke Cerebrovasc Dis. 22, 304-308. doi: 10.1016/j.jstrokecerebrovasdis.2011.09.008.
85. Jeong, H., Yim, H.W., Cho, Y.S., Kim, Y.I., Jeong, S.N., Kim, H.B., et al. (2014). Efficacy and safety of stem cell therapies for patients with stroke: a systematic review and single arm meta-analysis. Int J Stem Cells. 7, 63-69. doi: 10.15283/ijsc.2014.7.2.63.
86. Jiang, Y., Zhu, W., Zhu, J., Wu, L., Xu, G., and Liu, X. (2013). Feasibility of delivering mesenchymal stem cells via catheter to the proximal end of the lesion artery in patients with stroke in the territory of the middle cerebral artery. Cell Transplant. 22, 2291-2298. doi: 10.3727/096368912X658818.
87. Jin, K., Sun, Y., Xie, L., Mao, X.O., Childs, J., Peel, A., et al. (2005). Comparison of ischemia-directed migration of neural precursor cells after intrastriatal, intraventricular, or intravenous transplantation in the rat. Neurobiol Dis. 18, 366-374.
88. Jozwiak, S., Habich, A., Kotulska, K., Sarnowska, A., Kropiwnicki, T., Janowski, M., et al. (2010). Intracerebroventricular Transplantation of Cord Blood-Derived Neural Progenitors in a Child with Severe Global Brain Ischemic Injury. Cell Medicine. 1, 71-80. doi: 10.3727/215517910X536618.
89. Jung, J.W., Kwon, M., Choi, J.C., Shin, J.W., Park, I.W., Choi, B.W., et al. (2013). Familial occurrence of pulmonary embolism after intravenous, adipose tissue-derived stem cell therapy. Yonsei Med J. 54, 1293-1296. doi: 10.3349/ymj.2013.54.5.1293.
90. Kaneko, S., and Yamanaka, S. (2013). To be immunogenic, or not to be: that's the iPSC question. Cell Stem Cell. 12, 385-386. doi: 10.1016/j.stem.2013.03.008.
91. Kang, W.J., Kang, H.J., Kim, H.S., Chung, J.K., Lee MC, Lee, D.S. (2006). Tissue distribution of 18F-FDG-labeled peripheral hematopoietic stem cells after intracoronary administration in patients with myocardial infarction. J Nucl Med. 47, 1295-301.
92. Karhunen, H., Bezvenyuk, Z., Nissinen, J., Sivenius, J., Jolkkonen, J., and Pitkänen, A. (2007). Epileptogenesis after cortical photothrombotic brain lesion in rats. Neuroscience. 148, 314-324.
93. Karlupia, N., Manley, N.C., Prasad, K., Schäfer, R., and Steinberg, G.K. (2014). Intraarterial transplantation of human umbilical cord blood mononuclear cells is more efficacious and safer compared with umbilical cord mesenchymal stromal cells in a rodent stroke model. Stem Cell Res Ther. 5, 45. doi: 10.1186/scrt434.
94. Karussis, D., Karageorgiou, C., Vaknin-Dembinsky, A., Gowda-Kurkalli, B., Gomori, J.M., Kassis, I., et al. (2010). Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol. 67, 1187-1194. doi: 10.1001/archneurol.2010.248.
95. Kawai, H., Yamashita, T., Ohta, Y., Deguchi, K., Nagotani, S., Zhang, X., et al. (2010). Tridermal tumorigenesis of induced pluripotent stem cells transplanted in ischemic brain. J Cereb Blood Flow Metab. 30, 1487-1493. doi: 10.1038/jcbfm.2010.32.
96. Kim, J.M., Lee, S.T., Chu, K., Jung, K.H., Song, E.C., Kim, S.J., et al. (2007). Systemic transplantation of human adipose stem cells attenuated cerebral inflammation and degeneration in a hemorrhagic stroke model. Brain Res. 1183, 43- 50.
97. Kim, D.Y., Park, S.H., Lee, S.U., Choi, D.H., Park, H.W., Paek, S. H., et al. (2007). Effect of human embryonic stem cell-derived neuronal precursor cell transplantation into the cerebral infarct model of rat with exercise. Neurosci Res. 58, 164-175.
98. Kleinschnitz, C., Kraft, P., Dreykluft, A., Hagedorn, I., Göbel, K., Schuhmann, M.K., et al. (2013). Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature. Blood. 121, 679-91. doi: 10.1182/blood-2012-04-426734.
99. Kondziolka, D., Steinberg, G.K., Wechsler, L., Meltzer, C.C., Elder, E., Gebel, J., et al. (2005). Neurotransplantation for patients with subcortical motor stroke: a phase 2 randomized trial. J Neurosurg. 103, 38-45.
100. Kondziolka, D., Wechsler, L., Goldstein, S., Meltzer, C., Thulborn, K.R., Gebel, J., et al. (2000). Transplantation of cultured human neuronal cells for patients with stroke. Neurology. 55, 565-569.
101. Kota, D.J., DiCarlo, B., Hetz, R.A., Smith, P., Cox, C.S. Jr., and Olson, S.D. (2014). Differential MSC activation leads to distinct mononuclear leukocyte binding mechanisms. Sci Rep. 4, 4565. doi: 10.1038/srep04565.
102. Kranz, A., Wagner, D.C., Kamprad, M., Scholz, M., Schmidt, U.R., Nitzsche, F., et al. (2010). Transplantation of placenta-derived mesenchymal stromal cells upon experimental stroke in rats. Brain Res. 1315, 128-136. doi: 10.1016/j.brainres.2009.12.001.
103. Lappalainen, R.S., Narkilahti, S., Huhtala, T., Liimatainen, T., Suuronen, T., Närvänen, A., et al. (2008). The SPECT imaging shows the accumulation of neural progenitor cells into internal organs after systemic administration in middle cerebral artery occlusion rats. Neurosci Lett. 440, 246-250. doi: 10.1016/j.neulet.2008.05.090.
104. Le Blanc, K., Frassoni, F., Ball, L., Locatelli, F., Roelofs, H., Lewis, I., et al. (2008). Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus host disease: a phase II study. Lancet. 371, 1579-1586. doi: 10.1016/S0140- 6736(08)60690-X.
105. Le Blanc, K., Rasmusson, I., Sundberg, B., Götherström, C., Hassan, M., Uzunel, M., et al. (2004). Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet. 363, 1439-1441
106. Lee, E.S., Im, H.J., Kim, H.S., Youn, H., Lee, H.J., Kim, S.U., et al. (2014). In Vivo Brain Delivery of v-myc Overproduced Human Neural Stem Cells via the Intranasal Pathway: Tumor Characteristics in the Lung of a Nude Mouse. Mol Imaging. 13, 1- 10.
107. Lee, J.S., Hong, J.M., Moon, G.J., Lee, P.H., Ahn, Y.H., Bang, O.Y., et al. (2010). A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells. 28, 1099-1106. doi: 10.1002/stem.430.
108. Lee, P.H., Kim, J.W., Bang, O.Y., Ahn, Y.H., Joo, I.S., and Huh, K. (2008). Autologous mesenchymal stem cell therapy delays the progression of neurological deficits in patients with multiple system atrophy. Clin Pharmacol Ther. 83, 723-730.
109. Lee, R.H., Seo, M.J., Pulin, A.A., Gregory, C.A., Ylostalo, J., and Prockop, D.J. 2009). The CD34-like protein PODXL and alpha6-integrin (CD49f) identify early progenitor MSCs with increased clonogenicity and migration to infarcted heart in mice. Blood. 113, 816-826. doi: 10.1182/blood-2007-12-128702.
110. Lee, S.T., Chu, K., Jung, K.H., Kim, S.J., Kim, D.H., Kang, K.M., et al., (2008). Anti inflammatory mechanism of intravascular neural stem cell transplantation in haemorrhagic stroke. Brain. 131, 616-29.
111. Li, Z.M., Zhang, Z.T., Guo, C.J., Geng, F.Y., Qiang, F., Wang, L.X. (2013). Autologous bone marrow mononuclear cell implantation for intracerebral hemorrhage-a prospective clinical observation. Clin Neurol Neurosurg. 115, 72-76. doi: 10.1016/j.clineuro.2012.04.030.
112. Lim, J.Y., Jeong, C.H., Jun, J.A., Kim, S.M., Ryu, C.H., Hou, Y., et al. (2011). Therapeutic effects of human umbilical cord blood-derived mesenchymal stem cells after intrathecal administration by lumbar puncture in a rat model of cerebral ischemia. Stem Cell Res Ther. 2, 38. doi: 10.1186/scrt79.
113. Lincoln, B., Wottawah, F., Schinkinger, S., Ebert, S., and Guck, J. (2007). High throughput rheological measurements with an optical stretcher. Methods Cell Biol. 83, 397-423.
114. Lindvall, O., Kokaia, Z., Bengzon, J., Elmér, E., and Kokaia, M. (1994). Neurotrophins and brain insults. Trends Neurosci. 17, 490-496.
115. Lochhead, J.J., and Thorne, R.G. (2012). Intranasal delivery of biologics to the central nervous system. Adv Drug Deliv Rev. 64, 614-628. doi: 10.1016/j.addr.2011.11.002.
116. Loubinoux, I., Demain, B., Davoust, C., Plas, B., and Vaysse, L. (2014). Stem cells and motor recovery after stroke. Ann Phys Rehabil Med. 57, 499-508. doi: 10.1016/j.rehab.2014.08.008.
117. Ma, M., Ding, S., Lundqvist, A., San, H., Fang, F., Konoplyannikov, M., et al. (2010). Major histocompatibility complex-I expression on embryonic stem cell-derived vascular progenitor cells is critical for syngeneic transplant survival. Stem Cells. 28, 1465-1475. doi: 10.1002/stem.475.
118. Ma, S., Xie, N., Li, W., Yuan, B., Shi, Y., and Wang, Y. (2014). Immunobiology of mesenchymal stem cells. Cell Death Differ. 21, 216-225. doi: 10.1038/cdd.2013.158
119. Mammolenti, M., Gajavelli, S., Tsoulfas, P., and Levy, R. (2004). Absence of major histocompatibility complex class I on neural stem cells does not permit natural killer cell killing and prevents recognition by alloreactive cytotoxic T lymphocytes in vitro. Stem Cells. 22, 1101-1110
120. Master, Z., Zarzeczny, A., Rachul, C., and Caulfield, T. (2013). What's missing? Discussing stem cell translational research in educational information on stem cell tourism". J Law Med Ethics. 41, 254-268. doi: 10.1111/jlme.12017.
121. Meisel, C., Schwab, J.M., Prass, K., Meisel, A., and Dirnagl, U. (2005). Central nervous system injury-induced immune deficiency syndrome. Nat Rev Neurosci. 10), 775-786.
122. Miura, Y., Kami, M., Tsubokura, M., Takei, N., and Komatsu, T. (2008). Mesenchymal stem cells for acute graft-versus-host disease. Lancet. 372, 715-716. doi: 10.1016/S0140-6736(08)61299-4.
123. Miyake, Y., Asano, K., Kaise, H., Uemura, M., Nakayama, M., and Tanaka, M. 2007). Critical role of macrophages in the marginal zone in the suppression of immune responses to apoptotic cell-associated antigens. J Clin Invest. 117, 2268- 2278.
124. Moll, G., Alm, J.J., Davies, L.C., von Bahr, L., Heldring, N., Stenbeck-Funke, L., et (2014). Do cryopreserved mesenchymal stromal cells display impaired immunomodulatory and therapeutic properties? Stem Cells. 32, 2430-2442. doi: 10.1002/stem.1729.
125. Moll, G., Rasmusson-Duprez, I., von Bahr, L., Connolly-Andersen, A.M., Elgue, G., Funke, L., et al. (2012). Are therapeutic human mesenchymal stromal cells compatible with human blood? Stem Cells. 30, 1565-1574. doi: 10.1002/stem.1111.
126. Moniche, F., Gonzalez, A., Gonzalez-Marcos, J.R., Carmona, M., Piñero, P., Espigado, I., et al. (2012). Intra-arterial bone marrow mononuclear cells in ischemic stroke: a pilot clinical trial. Stroke. 43, 2242-2244. doi: 10.1161/STROKEAHA.112.659409.
127. Mora-Lee, S., Sirerol-Piquer, M.S., Gutiérrez-Pérez, M., Gomez-Pinedo, U., Roobrouck, V.D., López, T., et al. (2012). Therapeutic effects of hMAPC and hMSC transplantation after stroke in mice. PLoS One. 7, e43683. doi: 10.1371/journal.pone.0043683.
128. Mozaffarian, D., Benjamin, E.J., Go, A.S., Arnett, D.K., Blaha, M.J., Cushman, M., et al. (2015). Heart disease and stroke statistics--2015 update: a report from the American Heart Association. Circulation. 131, e29-322. doi: 10.1161/CIR.0000000000000152.
129. Nystedt, J., Anderson, H., Tikkanen, J., Pietilä, M., Hirvonen, T., Takalo, R., et al. 2013). Cell surface structures influence lung clearance rate of systemically infused mesenchymal stromal cells. Stem Cells. 31, 317-26. doi: 10.1002/stem.1271.
130. Osman, A.M., Porritt, M.J., Nilsson, M., and Kuhn H.G. (2011). Long-term stimulation of neural progenitor cell migration after cortical ischemia in mice. Stroke. 42, 3559-3565. doi: 10.1161/STROKEAHA.111.627802.
131. Pan, Q., Fouraschen, S.M., de Ruiter, P.E., Dinjens, W.N., Kwekkeboom, J., Tilanus, H.W., et al. (2014). Detection of spontaneous tumorigenic transformation during culture expansion of human mesenchymal stromal cells. Exp Biol Med (Maywood). 239, 105-115. doi: 10.1177/1535370213506802.
132. Pellegrini, L., Bennis, Y., Guillet, B., Velly, L., Garrigue, P., Sabatier, F., et al. 2013). Therapeutic benefit of a combined strategy using erythropoietin and endothelial progenitor cells after transient focal cerebral ischemia in rats. Neurol Res. 35, 937-947. doi: 10.1179/1743132813Y.0000000235.
133. Phillips, L.K., Gould, E.A., Babu, H., Krams, S.M., Palmer, T.D., and Martinez, O.M. 2013). Natural killer cell-activating receptor NKG2D mediates innate immune targeting of allogeneic neural progenitor cell grafts. Stem Cells. 31, 1829-1839. doi: 10.1002/stem.1422.
134. Poncelet, A.J., Vercruysse, J., Saliez, A., and Gianello, P. (2007). Although pig allogeneic mesenchymal stem cells are not immunogenic in vitro, intracardiac injection elicits an immune response in vivo. Transplantation. 83, 783-790.
135. Popa-Wagner, A., Buga, A.M., Doeppner, T.R., and Hermann, D.M. (2014). Stem cell therapies in preclinical models of stroke associated with aging. Front Cell Neurosci. 8, 347. doi: 10.3389/fncel.2014.00347.
136. Pösel, C., Scheibe, J., Kranz, A., Bothe, V., Quente, E., Fröhlich, W., et al. (2014). Bone marrow cell transplantation time-dependently abolishes efficacy of granulocyte colony-stimulating factor after stroke in hypertensive rats. Stroke. 45, 2431-2437. doi: 10.1161/STROKEAHA.113.004460.
137. Potts, M.B., Silvestrini, M.T., and Lim, D.A. (2013). Devices for cell transplantation into the central nervous system: Design considerations and emerging technologies. Surg Neurol Int. 4, S22-S30. doi: 10.4103/2152-7806.109190.
138. Prasad, K., Mohanty, S., Bhatia, R., Srivastava, M.V., Garg, A., Srivastava, A., et al. (2012). Autologous intravenous bone marrow mononuclear cell therapy for patients with subacute ischaemic stroke: a pilot study. Indian J Med Res. 136, 221-228.
139. Prasad, K., Sharma, A., Garg, A., Mohanty, S., Bhatnagar, S., Johri, S., et al. (2014). Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke: a multicentric, randomized trial. Stroke. 45, 3618-3624. doi: 10.1161/STROKEAHA.114.007028.
140. Qian, H., Tryggvason, K., Jacobsen, S.E., and Ekblom, M. (2006). Contribution of alpha6 integrins to hematopoietic stem and progenitor cell homing to bone marrow and collaboration with alpha4 integrins. Blood. 107, 3503-3510.
141. Rewell, S.S., Fernandez, J.A., Cox, S.F., Spratt, N.J., Hogan, L., Aleksoska, E., et al. (2010). Inducing stroke in aged, hypertensive, diabetic rats. J Cereb Blood Flow Metab. 30, 729-733. doi: 10.1038/jcbfm.2009.273.
142. Rickhag, M., Teilum, M., and Wieloch, T. (2007). Rapid and long-term induction of effector immediate early genes (BDNF, Neuritin and Arc) in peri-infarct cortex and dentate gyrus after ischemic injury in rat brain. Brain Res. 1151, 203-210.
143. Rolls, A., Shechter, R., London, A., Ziv, Y., Ronen, A., Levy, R., et al. (2007). Toll1405 like receptors modulate adult hippocampal neurogenesis. Nat Cell Biol. 9, 1081-1088.
144. Romieu-Mourez, R., François, M. Boivin, M.N., Bouchentouf, M., Spaner, D.E., and Galipeau, J. (2009). Cytokine modulation of TLR expression and activation in mesenchymal stromal cells leads to a proinflammatory phenotype. J Immunol. 182, 7963-7973. doi: 10.4049/jimmunol.0803864.
145. Rosado-de-Castro, P.H., Pimentel-Coelho, P.M., da Fonseca, L.M., de Freitas, G.R., and Mendez-Otero, R. (2013a). The rise of cell therapy trials for stroke: review of published and registered studies. Stem Cells Dev. 22, 2095-2111. doi: 10.1089/scd.2013.0089.
146. Rosado-de-Castro, P.H., Schmidt, F.R., Battistella, V., Lopes de Souza, S.A., Gutfilen, B., Goldenberg, R.C. et al. (2013b). Biodistribution of bone marrow mononuclear cells after intra-arterial or intravenous transplantation in subacute stroke patients. Regen Med. 8, 145-155. doi: 10.2217/rme.13.2.
147. Sanai, N., Nguyen, T., Ihrie, R.A., Mirzadeh, Z., Tsai, H.H., Wong, M., et al. (2011). Corridors of migrating neurons in the human brain and their decline during infancy. Nature. 478, 382-286. doi: 10.1038/nature10487.
148. Savitz, S.I., Chopp, M., Deans, R., Carmichael, T., Phinney, D., Wechsler, L., et al. (2011a). Stem Cell Therapy as an Emerging Paradigm for Stroke (STEPS) II. Stroke. 42, 825-829. doi: 10.1161/STROKEAHA.110.601914.
149. Savitz, S.I., Cramer, S.C., Wechsler, L., and STEPS 3 Consortium. (2014). Stem cells as an emerging paradigm in stroke 3: enhancing the development of clinical trials. Stroke. 45, 634-639. doi: 10.1161/STROKEAHA.113.003379.
150. Savitz, S.I., Dinsmore, J., Wu, J., Henderson, G.V., Stieg, P., et al. (2005). Neurotransplantation of fetal porcine cells in patients with basal ganglia infarcts: A preliminary safety and feasibility study. Cerebrovasc Dis. 20, 101-107.
151. Savitz, S.I., Misra, V., Kasam, M., Juneja, H., Cox, C.S. Jr., Alderman, S., et al. (2011b). Intravenous autologous bone marrow mononuclear cells for ischemic stroke. Ann Neurol. 70, 59-69. doi: 10.1002/ana.22458.
152. Scheibe, F., Ladhoff, J., Huck, J., Grohmann, M., Blazej, K., Oersal, A., et al. (2012). Immune effects of mesenchymal stromal cells in experimental stroke. J Cereb Blood Flow Metab. 32, 1578-1588. doi: 10.1038/jcbfm.2012.55.
153. Schmidt, K., Schulz, A.S., Debatin, K.M., Friedrich, W., and Classen, C.F. (2008). CNS complications in children receiving chemotherapy or hematopoietic stem cell transplantation: retrospective analysis and clinical study of survivors. Pediatr Blood Cancer. 50, 331-336.
154. Schrepfer, S., Deuse, T., Reichenspurner, H., Fischbein, M.P., Robbins, R.C., and Pelletier, M.P. (2007). Stem cell transplantation: the lung barrier. Transplant Proc. 39, 573-576.
155. Schu, S., Nosov, M., O'Flynn, L., Shaw, G., Treacy, O., Barry, F., et al. (2012). Immunogenicity of allogeneic mesenchymal stem cells. J Cell Mol Med. 16, 2094- 2103. doi: 10.1111/j.1582-4934.2011.01509.x.
156. Schwarting, S., Litwak, S., Hao, W., Bähr, M., Weise, J., and Neumann, H. (2008). Hematopoietic stem cells reduce postischemic inflammation and ameliorate ischemic brain injury. Stroke. 2008 39, 2867-2875. doi: 10.1161/STROKEAHA.108.513978.
157. Seminatore, C., Polentes, J., Ellman, D., Kozubenko, N., Itier, V., Tine, S., et al. (2010). The postischemic environment differentially impacts teratoma or tumor formation after transplantation of human embryonic stem cell-derived neural progenitors. Stroke. 41, 153-159. doi: 10.1161/STROKEAHA.109.563015.
158. Sharma, A., Sane, H., Gokulchandran, N., Khopkar, D., Paranjape, A, Sundaram, J., al. (2014). Autologous bone marrow mononuclear cells intrathecal transplantation chronic stroke. Stroke Res Treat. 2014, 234095. doi: 10.1155/2014/234095.
159. Shichita, T., Ito, M., and Yoshimura, A. (2014). Post-ischemic inflammation regulates neural damage and protection. Front Cell Neurosci. 8, 319. doi: 10.3389/fncel.2014.00319.
160. Shyu, W.C., Lin, S.Z., Chiang, M.F., Su, C.Y., and Li, H. (2006). Intracerebral peripheral blood stem cell (CD34+) implantation induces neuroplasticity by enhancing beta1 integrin-mediated angiogenesis in chronic stroke rats. J Neurosci. 26, 3444-3453.
161. Sostak, P., Reich, P., Padovan, C.S., Gerbitz, A., Holler, E., and Straube, A. (2004). Cerebral endothelial expression of adhesion molecules in mice with chronic graft versus-host disease. Stroke. 35, 1158-1163.
162. Spaggiari, G.M., Capobianco, A., Becchetti, S., Mingari, M.C., and Moretta, L. 2006). Mesenchymal stem cell-natural killer cell interactions: evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK cell proliferation. Blood. 107, 1484-1490.
163. Stem Cell Therapies as an Emerging Paradigm in Stroke 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. doi: 10.1161/STROKEAHA.108.526863.
164. Steward, O., Sharp, K.G., Yee, K.M., Hatch, M.N., and Bonner, J.F. (2014). Characterization of ectopic colonies that form in widespread areas of the nervous system with neural stem cell transplants into the site of a severe spinal cord injury. J Neurosci. 34, 14013-14021. doi: 10.1523/JNEUROSCI.3066-14.2014.
165. Stripecke, R., Carmen Villacres, M., Skelton, D., Satake, N., Halene, S., and Kohn, D. (1999). Immune response to green fluorescent protein: implications for gene therapy. Gene Ther. 6, 1305-1312.
166. Stroemer, P., Patel, S., Hope, A., Oliveira, C., Pollock, K., and Sinden, J. (2009). The neural stem cell line CTX0E03 promotes behavioral recovery and endogenous neurogenesis after experimental stroke in a dose-dependent fashion. Neurorehabil Neural Repair. 23, 895-909. doi: 10.1177/1545968309335978.
167. Suárez-Monteagudo, C., Hernández-Ramírez, P., Alvarez-González, L., García-Maeso, I., de la Cuétara-Bernal, K., Castillo-Díaz, L., et al. (2009). Autologous bone marrow stem cell neurotransplantation in stroke patients. An open study. Restor Neurol Neurosci. 27, 151-161. doi: 10.3233/RNN-2009-0483.
168. Tabar, V., Panagiotakos, G., Greenberg, E.D., Chan, B.K., Sadelain, M., Gutin, P.H., et al. (2005). Migration and differentiation of neural precursors derived from human embryonic stem cells in the rat brain. Nat Biotechnol. 23, 601-606.
169. Taguchi, A., Soma, T., Tanaka, H., Kanda, T., Nishimura, H., Yoshikawa, H., et al. 2004). Administration of CD34+ cells after stroke enhances neurogenesis via angiogenesis in a mouse model. J Clin Invest. 114, 330-338.
170. Tang, Q., Chen, Q., Lai, X., Liu, S., Chen, Y., Zheng, Z., et al. (2013). Malignant transformation potentials of human umbilical cord mesenchymal stem cells both spontaneously and via 3-methycholanthrene induction. PLoS One. 8, e81844. doi: 10.1371/journal.pone.0081844.
171. Tatarishvili, J., Oki, K., Monni, E., Koch, P., Memanishvili, T., Buga, A.M., et al. 2014). Human induced pluripotent stem cells improve recovery in stroke-injured aged rats. Restor Neurol Neurosci. 32, 547-558. doi: 10.3233/RNN-140404.
172. Tatsumi, K., Ohashi, K., Matsubara, Y., Kohori, A., Ohno, T., Kakidachi, H., et al. 2013). Tissue factor triggers procoagulation in transplanted mesenchymal stem cells leading to thromboembolism. Biochem Biophys Res Commun. 431, 203-209. doi: 10.1016/j.bbrc.2012.12.134.
173. Teo, G.S., Yang, Z., Carman, C.V., Karp, J.M., Lin, C.P. (2015). Intravital imaging of mesenchymal stem cell trafficking and association with platelets and neutrophils. Stem Cells. 33, 265-77. doi: 10.1002/stem.1848.
174. Terpolilli, N.A., Kim, S.W., Thal, S.C., Kataoka, H., Zeisig, V., Nitzsche, B., et al. 2012). Inhalation of nitric oxide prevents ischemic brain damage in experimental stroke by selective dilatation of collateral arterioles. Circ Res. 110, 727-738. doi: 10.1161/CIRCRESAHA.111.253419.
175. Toma, C., Wagner, W.R., Bowry, S., Schwartz, A., and Villanueva, F. (2009). Fate of culture-expanded mesenchymal stem cells in the microvasculature: in vivo observations of cell kinetics. Circ Res. 104, 398-402. doi: 10.1161/CIRCRESAHA.108.187724.
176. van Velthoven, C.T., Sheldon, R.A., Kavelaars, A., Derugin, N., Vexler, Z.S., Willemen, H.L., et al. (2013). Mesenchymal stem cell transplantation attenuates brain injury after neonatal stroke. Stroke. 44, 1426-1432. doi: 10.1161/STROKEAHA.111.000326.
177. Vierbuchen, T., Ostermeier, A., Pang, Z.P., Kokubu, Y., Südhof, T.C., and Wernig, M. (2010). Direct conversion of fibroblasts to functional neurons by defined factors. Nature. 463, 1035-1041. doi: 10.1038/nature08797.
178. Vivier, E., Raulet, D.H., Moretta, A., Caligiuri, M.A., Zitvogel, L., Lanier, L.L., et al. 2011). Innate or adaptive immunity? The example of natural killer cells. Science. 331, 44-49. doi: 10.1126/science.1198687.
179. Voll, R.E., Herrmann, M., Roth, E.A., Stach, C., Kalden, J.R., and Girkontaite, I. 1997). Immunosuppressive effects of apoptotic cells. Nature. 390, 350-351.
180. Vulliet, P.R., Greeley, M., Halloran, S.M., MacDonald, K.A., and Kittleson, M.D. (2004). Intra-coronary arterial injection of mesenchymal stromal cells and microinfarction in dogs. Lancet. 363, 783-784.
181. Wagner, D.C., Bojko, M., Peters, M., Lorenz, M., Voigt, C., Kaminski, A., et al. (2012). Impact of age on the efficacy of bone marrow mononuclear cell transplantation in experimental stroke. Exp Transl Stroke Med. 4, 17. doi: 10.1186/2040-7378-4-17.
182. Wang, L., Ji, H., Li, M., Zhou, J., Bai, W., Zhong, Z., et al. (2013). Intrathecal Administration of Autologous CD34 Positive Cells in Patients with Past Cerebral Infarction: A Safety Study. ISRN Neurol. 2013, 128591. doi: 10.1155/2013/128591.
183. Wang, Y.M., Jin, K.L., Mao, X.O., Xie, L., Banwait, S., Marti, H.H., et al. (2007). VEGF-overexpressing transgenic mice show enhanced post-ischemic neurogenesis and neuromigration. J Neurosci Res. 85, 740-747.
184. Wang, Y., Zhang, Z., Chi, Y., Zhang, Q., Xu, F., Yang, Z., et al. (2013). Long-term cultured mesenchymal stem cells frequently develop genomic mutations but do not undergo malignant transformation. Cell Death Dis. 4, e950. doi: 10.1038/cddis.2013.480.
185. Weinger, J.G., Weist, B.M., Plaisted, W.C., Klaus, S.M., Walsh, C.M., and Lane, T.E. (2012). MHC mismatch results in neural progenitor cell rejection following spinal cord transplantation in a model of viral-induced demyelination. Stem Cells. 30, 2584-2595. doi: 10.1002/stem.1234.
186. Wells, A.J., Vink, R., Blumbergs, P.C., Brophy, B.P., Helps, S.C., Knox, S.J., et al. (2012). A surgical model of permanent and transient middle cerebral artery stroke in the sheep. PLoS One. 7, e42157. doi: 10.1371/journal.pone.0042157.
187. Willing, A.E., Vendrame, M., Mallery, J., Cassady, C.J., Davis, C.D., Sanchez-Ramos, J., et al. (2003). Mobilized peripheral blood cells administered intravenously produce functional recovery in stroke. Cell Transplant. 12, 449-454.
188. Woodward, L.J., Edgin, J.O., Thompson, D., and Inder, T.E. (2005). Object working memory deficits predicted by early brain injury and development in the preterm infant. Brain. 128, 2578-2587.
189. Yavagal, D.R., Lin, B., Raval, A.P., Garza, P.S., Dong, C., Zhao, W., et al. (2014). Efficacy and dose-dependent safety of intra-arterial delivery of mesenchymal stem cells in a rodent stroke model. PLoS One. 9, e93735. doi: 10.1371/journal.pone.0093735.
190. Ye, Y., Xu, H., Zhang, X., Li, Z., Jia, Y., He, X., et al. (2014). Association between toll-like receptor 4 expression and neural stem cell proliferation in the hippocampus following traumatic brain injury in mice. Int J Mol Sci. 15, 12651-12664. doi: 10.3390/ijms150712651.
191. Yoo, S.W., Chang, D.Y., Lee, H.S., Kim, G.H., Park, J.S., Ryu, B. Y., et al. (2013). Immune suppression following mesenchymal stem cell transplantation in the ischemic brain is mediated by TGF-ß. Neurobiol Dis. 58, 249-257. doi: 10.1016/j.nbd.2013.06.001.
192. Yu, G., Borlongan, C.V., Stahl, C.E., Hess, D.C., Ou, Y., Kaneko, Y., et al. (2009). Systemic delivery of umbilical cord blood cells for stroke therapy: a review. Restor Neurol Neurosci. 27, 41-54. doi: 10.3233/RNN-2009-0460.
193. Yuan, T., Liao, W., Feng, N.H., Lou, Y.L., Niu, X., Zhang, A.J., et al. (2013). Human induced pluripotent stem cell-derived neural stem cells survive, migrate, differentiate, and improve neurologic function in a rat model of middle cerebral artery occlusion. Stem Cell Res Ther. 4, 73. doi: 10.1186/scrt224.
194. Zakrzewski, J.L., van den Brink, M.R., and Hubbell, J.A. (2014). Overcoming immunological barriers in regenerative medicine. Nat Biotechnol. 32, 786-794. doi: 10.1038/nbt.2960.
195. Zhao, C.S., Hartikainen, S., Schallert, T., Sivenius, J., and Jolkkonen, J. (2008). CNS active drugs in aging population at high risk of cerebrovascular events: evidence from preclinical and clinical studies. Neurosci Biobehav Rev. 32, 56-71.
196. Zhao, T., Zhang, Z.N., Rong, Z., and Xu Y. (2011). Immunogenicity of induced pluripotent stem cells. Nature. 474, 212-215. doi: 10.1038/nature10135.