Stem cells have been touted as a potential source of cells for repair in regenerative medicine. When transplanted into the central nervous system, stem cells have been shown to differentiate into neurons and glia. Recent studies, however, have also revealed neuroprotective properties of stem cells. These studies suggest that various types of stem cells are able to protect against the loss of neurons in conditions of ischemic brain injury. In this article, we discuss the use of stem cells for ischemic stroke and the parameters under which neuroprotection can occur in the translation of stem cell therapy to the clinical setting.
References
[1]
Roger, V.; Go, A.; Lloyd-Jones, S.; Benjamin, E.; Berry, J.; Borden, W.; Bravata, D.; Dai, S.; Ford, E.; Fox, C.; et al. Heart disease and stroke statistics—2012 update: A report from the american heart association. Circulation？2012, 125, e2–e220, doi:10.1161/CIR.0b013e31823ac046.
[2]
Donnan, G.A.; Howells, D.W.; Markus, R.; Toni, D.; Davis, S.M. Can the time window for the administration of thrombolytics in stroke be increased? CNS Drugs？2003, 17, 995–1011, doi:10.2165/00023210-200317140-00001. 14594441
[3]
Bose, A.; Henkes, H.; Alfke, K.; Reith, W.; Mayer, T.E.; Berlis, A.; Branca, V.; Po Sit, S. The penumbra system: A mechanical device for the treatment of acute stroke due to thromboembolism. Am. J. Neuroradiol.？2008, 29, 1409–1413, doi:10.3174/ajnr.A1110.
[4]
Kim, D.; Jahan, R.; Starkman, S.; Abolian, A.; Kidwell, C.S.; Vinuela, F.; Duckwiler, G.R.; Ovbiagele, B.; Vespa, P.M.; Selco, S.; et al. Endovascular mechanical clot retrieval in a broad ischemic stroke cohort. Am. J. Neuroradiol.？2006, 27, 2048–2052. 17110664
[5]
Jahan, R. Solitaire flow-restoration device for treatment of acute ischemic stroke: Safety and recanalization efficacy study in a swine vessel occlusion model. Am. J. Neuroradiol.？2010, 31, 1938–1943, doi:10.3174/ajnr.A2169. 20634306
[6]
Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N. Engl. J. Med.？1995, 333, 1581–1587, doi:10.1056/NEJM199512143332401.
[7]
Colucci-D’Amato, L.; Bonavita, V.; Di Porzio, U. The end of the central dogma of neurobiology: Stem cells and neurogenesis in adult CNS. Neurol. Sci.？2006, 27, 266–270, doi:10.1007/s10072-006-0682-z.
[8]
Altman, J.; Das, G. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J. Comp. Neurol.？1965, 124, 319–335, doi:10.1002/cne.901240303.
[9]
Nottebohm, F. From bird song to neurogenesis. Sci. Am.？1989, 260, 74–79, doi:10.1038/scientificamerican0289-74.
[10]
Doetsch, F. A niche for adult neural stem cells. Curr. Opin. Genet. Dev.？2003, 13, 543–550, doi:10.1016/j.gde.2003.08.012.
[11]
Parent, J.M. Injury-induced neurogenesis in the adult mammalian brain. Neuroscientist？2003, 4, 261–272, doi:10.1177/1073858403252680.
[12]
Weiss, S.; Reynolds, B.; Vescovi, A.; Morshead, C.; Craig, C.; van der Kooy, D. Is there a neural stem cell in the mammalian forebrain? Trends Neurosci. Trends Neurosci.？1996, 19, 387–393, doi:10.1016/S0166-2236(96)10035-7.
[13]
Liu, J.; Solway, K.; Messing, R.O.; Sharp, F.R. Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. J. Neurosci.？1998, 18, 7768–7778. 9742147
[14]
Arvidsson, A.; Collin, T.; Kirik, D.; Kokaia, Z.; Lindvall, O. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat. Med.？2002, 8, 963–970, doi:10.1038/nm747.
[15]
Parent, J.M.; Vexler, Z.S.; Gong, C.; Derugin, N.; Ferriero, D.M. Rat forebrain neurogenesis and striatal neuron replacement after focal stroke. Ann. Neurol.？2002, 52, 802–813, doi:10.1002/ana.10393.
[16]
Borlongan, C.V.; Hess, D.C. New hope for stroke patients: Mobilization of endogenous stem cells. CMAJ？2006, 174, 954–955, doi:10.1503/cmaj.060199. 16517763
[17]
Cui, X.; Chopp, M.; Shehadah, A.; Zacharek, A.; Kuzmin-Nichols, N.; Sanberg, D.; Dai, J.; Zhang, C.; Ueno, Y.; Roberts, C.; et al. Therapeutic benefit of treatment of stroke with simvastin and human umbilical cord blood cells: Neurogenesis, synaptic plasticity, and axon growth. Cell Transplant.？2012, 21, 845–856, doi:10.3727/096368911X627417.
[18]
Rowe, D.; Leonardo, C.; Recio, J.; Collier, L.; Willing, A.; Pennypacker, K. Human umbilical cord blood cells protect oligodendrocytes from brain ischemia through Akt signal transduction. J. Biol. Chem.？2012, 287, 4177–4187, doi:10.1074/jbc.M111.296434. 22158864
[19]
Xiao, J.; Nan, Z.; Motooka, Y.; Low, W.C. 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, 722–733, doi:10.1089/scd.2005.14.722.
[20]
Lee, J.; Hong, J.; Moon, G.; Lee, P.; Ahn, Y.; Bang, O. A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patient with ischemic stroke. Stem Cells？2010, 28, 1099–1106, doi:10.1002/stem.430.
[21]
Bang, O.; Lee, J.; Lee, P.; Lee, G. Autologous mesenchymal stem cell transplantation in stroke patients. Ann. Neurol.？2005, 57, 874–882, doi:10.1002/ana.20501.
[22]
Li, L.; Jiang, Q.; Ding, G.; Zhang, L.; Zhang, Z.; Li, Q.; Panda, S.; Lu, M.; Ewing, J.; Chopp, M. Effects of administration route on migration and distribution of neural progenitor cells transplanted into rats with focal cerebral ischemia, an mri study. J. Cereb. Blood Flow Metab.？2010, 30, 653–662, doi:10.1038/jcbfm.2009.238.
[23]
Walczak, P.; Zhang, J.; Gilad, A.; Kedzioreck, D.; Ruiz-Cabello, J.; Young, R.; Pittenger, M.; van Zijl, P.; Huang, J.; Bulte, J. Dual modality monitoring of targeted intraarterial delivery of mesenchymal stem cells after transient ischemia. Stroke？2008, 39, 1569–1574, doi:10.1161/STROKEAHA.107.502047.
[24]
Kondziolka, D.; Steinberg, G.; Wechsler, L.; Meltzer, C.C.; Elder, E.; Gebel, J.; Decesare, S.; Jovin, T.; Zafonte, R.; Lebowitz, J.; et al. Neurotransplantation for patients with subcortical motor stroke: A phase 2 randomized trial. J. Neurosurg.？2005, 103, 38–45, doi:10.3171/jns.2005.103.1.0038.
[25]
Savitz, S.; Dinsmore, J.; Wu, J.; Henderson, G.; Stieg, P.; Caplan, L. Neurotransplantation of fetal porcine cells in patients with basal ganglia infarcts: A preliminary safety and feasability study. Cerebrovasc. Dis.？2005, 20, 101–107. 16327259
[26]
Hayase, M.; Kitada, M.; Wakao, S.; Itozaku, Y.; Nozaki, K.; Hashimoto, N.; Takagi, Y.; Dezawa, M. Committed neural progenitor cells derived from genetically modified bone marrow stromal cells ameliorate deficits in a rat model of stroke. J. Cereb. Blood Flow Metab.？2009, 29, 1409–1420, doi:10.1038/jcbfm.2009.62.
[27]
Roybon, L.; Zhi, M.; Asztely, F.; Fosum, A.; Jacobsen, S.; Brundin, P.; Li, J. Failure of transdifferentiation of adult hematopoietic stem cells into neurons. Stem Cells？2006, 24, 1594–1604, doi:10.1634/stemcells.2005-0548.
Liu, N.; Chen, R.; Du, H.; Wang, J.; Zhang, Y.; Wen, J. Expression of IL-10 and TNF-α in rats with cerebral infarction after transplantation with mesenchymal stem cells. Cell. Mol. Immunol.？2009, 6, 207–213, doi:10.1038/cmi.2009.28. 19567204
[30]
Walker, P.; Harting, M.; Jimenez, F.; Shah, S.; Pati, S.; Dash, P.; Cox, C. Direct intrathecal implantation of mesenchymal stromal cells leads to enhanced neuroprotection via NFκB-mediated increase in interleukin-6 production. Stem Cells Dev.？2010, 19, 867–876, doi:10.1089/scd.2009.0188.
[31]
Fischer, U.; Harting, M.; Jimenez, F.; Monzon-Posadas, W.; Xue, H.; Savitz, S.; Laine, G.; Cox, C. Pulmonary passage is a major obstacle for intravenous stem cell delivery: The pulmonary first-pass effect. Stem Cells Dev.？2009, 18, 683–691, doi:10.1089/scd.2008.0253.
[32]
Nemeth, K.; Leelahavinichkul, A.; Yuen, P.; Mayer, B.; Parmelee, A.; Doi, K.; Robey, P.; Leelahavinchkul, K.; Koller, B.; Brown, J.; et al. Bone marrow stromal cells attenuate sepsis via prostoglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat. Med.？2009, 15, 42–49, doi:10.1038/nm.1905.
[33]
Lee, S.; Chu, K.; Jung, K.; Kim, S.; Kim, D.; Kang, K.; Hong, N.; Kim, J.; Ban, J.; Park, H.; et al. Anti-inflammatory mechanism of intravascular neural stem cell transplantation in haemorrhagic stroke. Brain？2008, 131, 616–629, doi:10.1093/brain/awm306.
[34]
Neuhoff, S.; Moers, J.; Rieks, M.; Grunwald, T.; Jensen, A.; Dermietzel, R.; Meier, C. Proliferation, differentiation, and cytokine secretion of human umbilical cord blood-derived mononuclear cells in vitro. Exp. Hematol.？2007, 35, 1119–1131, doi:10.1016/j.exphem.2007.03.019.
[35]
Seminatore, C.; Polentes, J.; Ellman, D.; Kozubenko, N.; Itier, V.; Tine, S.; Tritschler, L.; Brenot, M.; Guidou, E.; Blondeau, J.; et al. The postischemic environment differentially impacts teratoma or tumor formation after transplantation of human embryonic stem cell-derived neural progenitors. Stroke？2010, 41, 153–159, doi:10.1161/STROKEAHA.109.563015.
[36]
Buhnemann, C.; Scholz, A.; Bernreuther, C.; Malik, C.; Braun, H.; Schachner, M.; Reymann, K.; Dihne, M. Neuronal differentiation of transplanted embryonic stem cell-derived precursors in stroke lesions of adult rats. Brain？2006, 129, 3238–3248, doi:10.1093/brain/awl261.
[37]
Takagi, Y.; Takahashi, J.; Saiki, H.; Morizane, A.; Hayashi, T.; Kishi, Y.; Fukada, H.; Okamoto, Y.; Koyanagi, M.; Ideguchi, M.; et al. Dopaminergic neurons generated from monkey embryonic stem cells function in a parkinson primate model. J. Clin. Invest.？2005, 115, 102–109, doi:10.1172/JCI21137. 15630449
[38]
Ideguchi, M.; Palmer, T.; Recht, L.; Weimann, J. Murine embryonic stem cell-derived pyramidal neurons integrate into the cerebral cortex and appropriately project axons to subcortical targets. J. Neurosci.？2010, 30, 894–904, doi:10.1523/JNEUROSCI.4318-09.2010.
[39]
Takahashi, K.; Tanabe, K.; Ohnuki, M.; Narita, M.; Ichisaka, T.; Tomoda, K.; Yamanaka, S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell？2007, 131, 861–872, doi:10.1016/j.cell.2007.11.019.
[40]
Yu, J.; Vodyanik, M.; Smuga-Otto, K.; Antosiewicz-Bourget, J.; Frane, J.; Tian, S.; Nie, J.; Jonsdottir, G.; Ruotti, V.; Stewart, R.; et al. Induced pluripotent stem cell lines derived from human somatic cells. Science？2007, 318, 1917–1920, doi:10.1126/science.1151526.
[41]
Pera, M. Stem cells: The dark side of induced pluripotency. Nature？2011, 471, 46–47, doi:10.1038/471046a.
[42]
Kawai, H.; Yamashita, T.; Ohta, Y.; Deguchi, K.; Nagotani, S.; Zhang, X.; Ikeda, Y.; Matsuura, T.; Abe, K. Tridermal tumorigenesis of induced pluripotent stem cells transplanted in ischemic brain. J. Cereb. Blood Flow Metab.？2010, 30, 1487–1493, doi:10.1038/jcbfm.2010.32.
[43]
Li, B.; Piao, C.-S.; Liu, X.-Y.; Guo, W.-P.; Xue, Y.-Q.; Duan, W.-M.; Gonzalez-Toledo, M.; Zhao, L.-R. Brain self-protection: The role of endogenous neural progenitor cells in adult brain after cerebral cortical ischemia. Brain Res.？2010, 1327, 91–102, doi:10.1016/j.brainres.2010.02.030.
[44]
Wu, W.; Chen, X.; Hu, C.; Li, J.; Yu, Z.; Cai, W. Transplantation of neural stem cells expressing hypoxia-inducible factor-1alpha (HIF-1α) improves behavioral recovery in a rat stroke model. J. Clin. Neurosci.？2010, 17, 92–95, doi:10.1016/j.jocn.2009.03.039.
Menon, L.; Picinich, S.; Koneru, R.; Gao, H.; Lin, S.; Koneru, M.; Mayer-Kuckuk, P.; Glod, J.; Banerjee, D. Differentiation gene expression associated with migration of mesenchymal stem cells to conditioned medium from tumor cells or bone marrow cells. Stem Cells？2007, 25, 520–528, doi:10.1634/stemcells.2006-0257.
[47]
Coyne, T.; Marcus, A.; Woodbury, D.; Black, I. Marrow stromal cells transplanted to the adult brain are rejected by an inflammatory response and transfer donor labels to host neurons and glia. Stem Cells？2006, 24, 2483–2492, doi:10.1634/stemcells.2006-0174.
[48]
Willing, A.; Vendrame, M.; Mallery, J.; Cassady, C.; Davis, C.; Sanchez-Ramos, J.; Sanberg, P. Mobilized peripheral blood cells administeres intravenously produce functional recovery in stroke. Cell Transplant.？2003, 12, 449–454. 12911133
[49]
Serafini, M.; Dylla, S.; Oki, M.; Heremans, Y.; Tolar, J.; Jiang, Y.; Buckley, S.; Pelacho, B.; Burns, T.; Frommer, S.; et al. Hematopoietic reconstitution by multipotent adult progenitor cells: Precursors to long-term hematopoietic stem cells. J. Exp. Med.？2007, 204, 129–139, doi:10.1084/jem.20061115. 17227908
[50]
Zhao, L.; Duan, W.; Reyes, M.; Keene, C.; Verfaille, C.; Low, W. 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, doi:10.1006/exnr.2001.7853.
[51]
Burns, T.; Ortiz-Gonzalez, X.; Gutierrez-Perez, M.; Keene, C.; Sharda, R.; Demorest, Z.; Jiang, Y.; Nelson-Holte, M.; Soriano, M.; Nakagawa, Y.; et al. Thymidine analogs are transferred from prelabeled donor to host cells in the central nervous system after transplantation: A word of caution. Stem Cells？2006, 24, 1121–1127, doi:10.1634/stemcells.2005-0463.
[52]
Damjanov, I. Teratocarcinoma stem cells. Cancer Surveys？1990, 9, 303–319. 2083411
[53]
Meissner, A.; Wernig, M.; Jaenisch, R. Direct reprogramming of genetically unmodified fibroblasts into pluripotent stem cells. Nat. Biotechnol.？2007, 25, 1177–1181, doi:10.1038/nbt1335.
[54]
Muller, F.; Snyder, E.; Loring, J. Gene therapy: Can neural stem cells deliver? Nat. Rev. Neurosci.？2006, 7, 75–84, doi:10.1038/nrn1829.
[55]
Liu, H.; Honmou, O.; Harada, K.; Nakamura, K.; Houkin, K.; Hamada, H.; Kocsis, J. Neuroprotection by PIGF gene-modified human mesenchymal stem cells after cerebral ischemia. Brain？2006, 129, 2734–2745, doi:10.1093/brain/awl207.
[56]
Onda, T.; Honmou, O.; Harada, K.; Houkin, K.; Hamada, H.; Kocsis, J. Therapeutic benefits by human mesenchymal stem cells (hMSCs) and Ang-1 gene-modified hMSCs after cerebral ischemia. J. Cereb. Blood Flow Metab.？2008, 28, 329–340, doi:10.1038/sj.jcbfm.9600527. 17637706
[57]
Cho, Y.J.; Song, H.S.; Bhang, S.; Lee, S.; Kang, B.G.; Lee, J.C.; An, J.; Cha, C.I.; Nam, D.H.; Kim, B.S.; et al. Therapeutic effects of human adipose stem cell-conditioned medium on stroke. J. Neurosci. Res.？2012, 90, 1794–1802, doi:10.1002/jnr.23063. 22535477
[58]
Kim, J.Y.; Kim, D.H.; Kim, J.H.; Lee, D.; Jeon, H.B.; Kwon, S.J.; Kim, S.M.; Yoo, Y.J.; Lee, E.H.; Choi, S.J.; et al. Soluble intracellular adhesion molecule-1 secreted by human umbilical cord blood-derived mesenchymal stem cell reduces amyloid-b plaques. Cell Death Differ.？2012, 19, 680–691, doi:10.1038/cdd.2011.140.
[59]
Kim, J.Y.; Kim, D.H.; Kim, J.H.; Yang, Y.S.; Oh, W.; Lee, E.H.; Chang, J.W. Umbilical cord blood mesenchymal stem cells protect amyloid-b42 neurotoxicity via paracrine. World J. Stem Cells？2012, 4, 110–116, doi:10.4252/wjsc.v4.i11.110. 23293711
[60]
Van Koppen, A.; Joles, J.A.; van Balkom, B.W.M.; Lim, S.K.; de Kleijn, D.; Giles, R.H.; Verhaar, M.C. Human embryonic mesenchymal stem cell-derived conditioned medium rescues kidney function in rats with established chronic kidney disease. PLoS One？2012, 7, e38746, doi:10.1371/journal.pone.0038746. 22723882
[61]
Ionescu, L.; Byrne, R.N.; van Haaften, T.; Vadivel, A.; Alphonse, R.S.; Rey-Parra, G.J.; Weissman, G.; Hall, A.; Eaton, F.; Thebaud, B. Stem cell conditioned medium improves acute lung injury in mice: In vivo evidence for stem cell paracrine action. Am. J. Physiol. Lung Cell. Mol. Physiol.？2012, 303, L967–L977, doi:10.1152/ajplung.00144.2011. 23023971
[62]
Moniche, F.; Gonzalez, A.; Gonzalez-Marcos, J.R.; Carmona, M.; Pinero, P.; Espigado, I.; Garcia-Solis, D.; Cayuela, A.; Montaner, J.; Boada, C.; et al. Intra-arterial bone marrow mononuclear cells in ischemic stroke: A pilot clinical trial. Stroke？2012, 43, 2242–2244, doi:10.1161/STROKEAHA.112.659409. 22764211
