Neural stem cells: ready for therapeutic applications?
Abstract
Neural stem cells (NSCs) offer a unique and powerful tool for basic research and regenerative medicine. However, the challenges that scientists face in the comprehension of the biology and physiological function of these cells are still many. Deciphering NSCs fundamental biological aspects represents indeed a crucial step to control NSCs fate and functional integration following transplantation, and is essential for a safe and appropriate use of NSCs in injury/disease conditions. In this review, we focus on the biological properties of NSCs and discuss how these cells may be exploited to provide effective therapies for neurological disorders. We also review and discuss ongoing NSC-based clinical trials for these diseases.
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Lindvall O, Barker RA, Brustle O, Isacson O, Svendsen CN: Clinical translation of stem cells in neurodegenerative disorders. Cell Stem Cell. 2012, 10: 151-155. 10.1016/j.stem.2012.01.009.
PubMedCentralCrossRefPubMedGoogle Scholar
Conti L, Cattaneo E: Neural stem cell systems: physiological players or in vitro entities?. Nat Rev Neurosci. 2010, 11: 176-187.
CrossRefPubMedGoogle Scholar
Fuentealba LC, Obernier K, Alvarez-Buylla A: Adult neural stem cells bridge their niche. Cell Stem Cell. 2012, 10: 698-708. 10.1016/j.stem.2012.05.012.
PubMedCentralCrossRefPubMedGoogle Scholar
Gage FH, Temple S: Neural stem cells: generating and regenerating the brain. Neuron. 2013, 80: 588-601. 10.1016/j.neuron.2013.10.037.
CrossRefPubMedGoogle Scholar
Grabel L: Developmental origin of neural stem cells: the glial cell that could. Stem Cell Rev. 2012, 8: 577-585. 10.1007/s12015-012-9349-8.
CrossRefPubMedGoogle Scholar
Malatesta P, Hartfuss E, Gotz M: Isolation of radial glial cells by fluorescent-activated cell sorting reveals a neuronal lineage. Development. 2000, 127: 5253-5263.
PubMedGoogle Scholar
Pollard SM, Conti L: Investigating radial glia in vitro. Prog Neurobiol. 2007, 83: 53-67. 10.1016/j.pneurobio.2007.02.008.
CrossRefPubMedGoogle Scholar
Miyata T, Kawaguchi A, Saito K, Kawano M, Muto T, Ogawa M: Asymmetric production of surface-dividing and non-surface-dividing cortical progenitor cells. Development. 2004, 131: 3133-3145. 10.1242/dev.01173.
CrossRefPubMedGoogle Scholar
Alvarez-Buylla A, Lim DA: For the long run: maintaining germinal niches in the adult brain. Neuron. 2004, 41: 683-686. 10.1016/S0896-6273(04)00111-4.
CrossRefPubMedGoogle Scholar
Altman J: Are new neurons formed in the brains of adult mammals?. Science. 1962, 135: 1127-1128. 10.1126/science.135.3509.1127.
CrossRefPubMedGoogle Scholar
Reynolds BA, Tetzlaff W, Weiss S: A multipotent EGF-responsive striatal embryonic progenitor cell produces neurons and astrocytes. J Neurosci. 1992, 12: 4565-4574.
PubMedGoogle Scholar
Reynolds BA, Weiss S: Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science. 1992, 255: 1707-1710. 10.1126/science.1553558.
CrossRefPubMedGoogle Scholar
Christie KJ, Turnley AM: Regulation of endogenous neural stem/progenitor cells for neural repair-factors that promote neurogenesis and gliogenesis in the normal and damaged brain. Front Cell Neurosci. 2012, 6: 70.
PubMedCentralCrossRefPubMedGoogle Scholar
Parent JM, Kron MM: Neurogenesis and Epilepsy. Jasper’s Basic Mechanisms of the Epilepsies. Edited by: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV. 2012, Bethesda (MD), USA: Published by Oxford University Press, 4
Google Scholar
Reynolds BA, Rietze RL: Neural stem cells and neurospheres–re-evaluating the relationship. Nat Methods. 2005, 2: 333-336. 10.1038/nmeth758.
CrossRefPubMedGoogle Scholar
Conti L, Pollard SM, Gorba T, Reitano E, Toselli M, Biella G, Sun Y, Sanzone S, Ying QL, Cattaneo E, Smith A: Niche-independent symmetrical self-renewal of a mammalian tissue stem cell. PLoS Biol. 2005, 3: e283-10.1371/journal.pbio.0030283.
PubMedCentralCrossRefPubMedGoogle Scholar
Koch P, Opitz T, Steinbeck JA, Ladewig J, Brustle O: A rosette-type, self-renewing human ES cell-derived neural stem cell with potential for in vitro instruction and synaptic integration. Proc Natl Acad Sci U S A. 2009, 106 (9): 3225-3230. 10.1073/pnas.0808387106.
PubMedCentralCrossRefPubMedGoogle Scholar
Palmer TD, Schwartz PH, Taupin P, Kaspar B, Stein SA, Gage FH: Cell culture. Progenitor cells from human brain after death. Nature. 2001, 411: 42-43. 10.1038/35075141.
CrossRefPubMedGoogle Scholar
Rossi F, Cattaneo E: Opinion: neural stem cell therapy for neurological diseases: dreams and reality. Nat Rev Neurosci. 2002, 3: 401-409. 10.1038/nrn809.
CrossRefPubMedGoogle Scholar
Maisel M, Herr A, Milosevic J, Hermann A, Habisch HJ, Schwarz S, Kirsch M, Antoniadis G, Brenner R, Hallmeyer-Elgner S, Lerche H, Schwarz J, Storch A: Transcription profiling of adult and fetal human neuroprogenitors identifies divergent paths to maintain the neuroprogenitor cell state. Stem Cells. 2007, 25: 1231-1240. 10.1634/stemcells.2006-0617.
CrossRefPubMedGoogle Scholar
Marei HE, Ahmed AE, Michetti F, Pescatori M, Pallini R, Casalbore P, Cenciarelli C, Elhadidy M: Gene expression profile of adult human olfactory bulb and embryonic neural stem cell suggests distinct signaling pathways and epigenetic control. PLoS One. 2012, 7: e33542-10.1371/journal.pone.0033542.
PubMedCentralCrossRefPubMedGoogle Scholar
Fan Y, Marcy G, Lee ES, Rozen S, Mattar CN, Waddington SN, Goh EL, Choolani M, Chan JK: Regionally-specified second trimester fetal neural stem cells reveals differential neurogenic programming. PLoS One. 2014, 9: e105985-10.1371/journal.pone.0105985.
PubMedCentralCrossRefPubMedGoogle Scholar
Evans MJ, Kaufman MH: Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981, 292: 154-156. 10.1038/292154a0.
CrossRefPubMedGoogle Scholar
Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM: Embryonic stem cell lines derived from human blastocysts. Science. 1998, 282: 1145-1147.
CrossRefPubMedGoogle Scholar
Yamanaka S: Induced pluripotent stem cells: past, present, and future. Cell Stem Cell. 2012, 10: 678-684. 10.1016/j.stem.2012.05.005.
CrossRefPubMedGoogle Scholar
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. 10.1016/j.cell.2007.11.019.
CrossRefPubMedGoogle Scholar
Takahashi K, Yamanaka S: Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006, 126: 663-676. 10.1016/j.cell.2006.07.024.
CrossRefPubMedGoogle Scholar
Okabe S, Forsberg-Nilsson K, Spiro AC, Segal M, McKay RD: Development of neuronal precursor cells and functional postmitotic neurons from embryonic stem cells in vitro. Mech Dev. 1996, 59: 89-102. 10.1016/0925-4773(96)00572-2.
CrossRefPubMedGoogle Scholar
Zhang SC, Wernig M, Duncan ID, Brustle O, Thomson JA: In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nat Biotechnol. 2001, 19: 1129-1133. 10.1038/nbt1201-1129.
CrossRefPubMedGoogle Scholar
Chambers SM, Fasano CA, Papapetrou EP, Tomishima M, Sadelain M, Studer L: Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol. 2009, 27: 275-280. 10.1038/nbt.1529.
PubMedCentralCrossRefPubMedGoogle Scholar
Ying QL, Stavridis M, Griffiths D, Li M, Smith A: Conversion of embryonic stem cells into neuroectodermal precursors in adherent monoculture. Nat Biotechnol. 2003, 21: 183-186. 10.1038/nbt780.
CrossRefPubMedGoogle Scholar
Emborg ME, Liu Y, Xi J, Zhang X, Yin Y, Lu J, Joers V, Swanson C, Holden JE, Zhang SC: Induced pluripotent stem cell-derived neural cells survive and mature in the nonhuman primate brain. Cell Rep. 2013, 3: 646-650. 10.1016/j.celrep.2013.02.016.
PubMedCentralCrossRefPubMedGoogle Scholar
Kriks S, Shim JW, Piao J, Ganat YM, Wakeman DR, Xie Z, Carrillo-Reid L, Auyeung G, Antonacci C, Buch A, Yang L, Beal MF, Surmeier DJ, Kordower JH, Tabar V, Studer L: Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease. Nature. 2011, 480: 547-551.
PubMedCentralPubMedGoogle Scholar
Thier M, Wörsdörfer P, Lakes YB, Gorris R, Herms S, Opitz T, Seiferling D, Quandel T, Hoffmann P, Nöthen MM, Brüstle O, Edenhofer F: Direct conversion of fibroblasts into stably expandable neural stem cells. Cell Stem Cell. 2012, 10 (4): 473-479. 10.1016/j.stem.2012.03.003.
CrossRefPubMedGoogle Scholar
Lindvall O, Kokaia Z: Stem cells in human neurodegenerative disorders–time for clinical translation?. J Clin Invest. 2010, 120: 29-40. 10.1172/JCI40543.
PubMedCentralCrossRefPubMedGoogle Scholar
Giusto E, Donega M, Cossetti C, Pluchino S: Neuro-immune interactions of neural stem cell transplants: from animal disease models to human trials. Exp Neurol. 2013, 260C: 19-32.
Google Scholar
Martino G, Pluchino S, Bonfanti L, Schwartz M: Brain regeneration in physiology and pathology: the immune signature driving therapeutic plasticity of neural stem cells. Physiol Rev. 2011, 91: 1281-1304. 10.1152/physrev.00032.2010.
PubMedCentralCrossRefPubMedGoogle Scholar
Tamaki S, Eckert K, He D, Sutton R, Doshe M, Jain G, Tushinski R, Reitsma M, Harris B, Tsukamoto A, Gage F, Weissman I, Uchida N: Engraftment of sorted/expanded human central nervous system stem cells from fetal brain. J Neurosci Res. 2002, 69: 976-986. 10.1002/jnr.10412.
CrossRefPubMedGoogle Scholar
Uchida N, Buck DW, He D, Reitsma MJ, Masek M, Phan TV, Tsukamoto AS, Gage FH, Weissman IL: Direct isolation of human central nervous system stem cells. Proc Natl Acad Sci U S A. 2000, 97: 14720-14725. 10.1073/pnas.97.26.14720.
PubMedCentralCrossRefPubMedGoogle Scholar
Selden NR, Al-Uzri A, Huhn SL, Koch TK, Sikora DM, Nguyen-Driver MD, Guillaume DJ, Koh JL, Gultekin SH, Anderson JC, Vogel H, Sutcliffe TL, Jacobs Y, Steiner RD: Central nervous system stem cell transplantation for children with neuronal ceroid lipofuscinosis. J Neurosurg Pediatr. 2013, 11: 643-652. 10.3171/2013.3.PEDS12397.
CrossRefPubMedGoogle Scholar
Garbern JY: Pelizaeus-Merzbacher disease: genetic and cellular pathogenesis. Cell Mol Life Sci. 2007, 64: 50-65. 10.1007/s00018-006-6182-8.
CrossRefPubMedGoogle Scholar
Uchida N, Chen K, Dohse M, Hansen KD, Dean J, Buser JR, Riddle A, Beardsley DJ, Wan Y, Gong X, Nguyen T, Cummings BJ, Anderson AJ, Tamaki SJ, Tsukamoto A, Weissman IL, Matsumoto SG, Sherman LS, Kroenke CD, Back SA: Human neural stem cells induce functional myelination in mice with severe dysmyelination. Sci Transl Med. 2012, 4: 155ra136.
CrossRefPubMedGoogle Scholar
Gupta N, Henry RG, Strober J, Kang SM, Lim DA, Bucci M, Caverzasi E, Gaetano L, Mandelli ML, Ryan T, Perry R, Farrell J, Jeremy RJ, Ulman M, Huhn SL, Barkovich AJ, Rowitch DH: Neural stem cell engraftment and myelination in the human brain. Sci Transl Med. 2012, 4: 155ra137.
PubMedCentralCrossRefPubMedGoogle Scholar
Tsukamoto A, Uchida N, Capela A, Gorba T, Huhn S: Clinical translation of human neural stem cells. Stem Cell Res Ther. 2013, 4: 102-10.1186/scrt313.
PubMedCentralCrossRefPubMedGoogle Scholar
Guo X, Johe K, Molnar P, Davis H, Hickman J: Characterization of a human fetal spinal cord stem cell line, NSI-566RSC, and its induction to functional motoneurons. J Tissue Eng Regen Med. 2010, 4: 181-193. 10.1002/term.223.
PubMedCentralCrossRefPubMedGoogle Scholar
Glass JD, Boulis NM, Johe K, Rutkove SB, Federici T, Polak M, Kelly C, Feldman EL: Lumbar intraspinal injection of neural stem cells in patients with amyotrophic lateral sclerosis: results of a phase I trial in 12 patients. Stem Cells. 2012, 30: 1144-1151. 10.1002/stem.1079.
CrossRefPubMedGoogle Scholar
Pollock 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: 143-155. 10.1016/j.expneurol.2005.12.011.
CrossRefPubMedGoogle Scholar
Lebkowski J: GRNOPC1: the world’s first embryonic stem cell-derived therapy. Interview with Jane Lebkowski. Regen Med. 2011, 6: 11-13. 10.2217/rme.11.77.
CrossRefPubMedGoogle Scholar
Okamura RM, Lebkowski J, Au M, Priest CA, Denham J, Majumdar AS: Immunological properties of human embryonic stem cell-derived oligodendrocyte progenitor cells. J Neuroimmunol. 2007, 192: 134-144. 10.1016/j.jneuroim.2007.09.030.
CrossRefPubMedGoogle Scholar
Zhang YW, Denham J, Thies RS: Oligodendrocyte progenitor cells derived from human embryonic stem cells express neurotrophic factors. Stem Cell Dev. 2006, 15: 943-952. 10.1089/scd.2006.15.943.
CrossRefGoogle Scholar
Majores M, Schoch S, Lie A, Becker AJ: Molecular neuropathology of temporal lobe epilepsy: complementary approaches in animal models and human disease tissue. Epilepsia. 2007, 48 (Suppl 2): 4-12.
CrossRefPubMedGoogle Scholar
Shetty AK: Neural Stem Cell Therapy for Temporal Lobe Epilepsy. Jasper’s Basic Mechanisms of the Epilepsies. Edited by: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV. 2012, Bethesda (MD), USA: Published by Oxford University Press, 4
Google Scholar
Costa-Ferro ZS, de Borba CF, de Freitas Souza BS, Leal MM, da Silva AA, de Bellis Kuhn TI, Forte A, Sekiya EJ, Soares MB, Dos Santos RR: Antiepileptic and neuroprotective effects of human umbilical cord blood mononuclear cells in a pilocarpine-induced epilepsy model. Cytotechnology. 2014, 66: 193-199. 10.1007/s10616-013-9557-3.
PubMedCentralCrossRefPubMedGoogle Scholar
Long Q, Qiu B, Wang K, Yang J, Jia C, Xin W, Wang P, Han R, Fei Z, Liu W: Genetically engineered bone marrow mesenchymal stem cells improve functional outcome in a rat model of epilepsy. Brain Res. 2013, 1532: 1-13.
CrossRefPubMedGoogle Scholar
Stone EM: Progress toward effective treatments for human photoreceptor degenerations. Curr Opin Genet Dev. 2009, 19: 283-289. 10.1016/j.gde.2009.03.006.
PubMedCentralCrossRefPubMedGoogle Scholar
Lakowski J, Han YT, Pearson RA, Gonzalez-Cordero A, West EL, Gualdoni S, Barber AC, Hubank M, Ali RR, Sowden JC: Effective transplantation of photoreceptor precursor cells selected via cell surface antigen expression. Stem Cells. 2011, 29: 1391-1404.
PubMedCentralPubMedGoogle Scholar
MacLaren RE, Pearson RA, MacNeil A, Douglas RH, Salt TE, Akimoto M, Swaroop A, Sowden JC, Ali RR: Retinal repair by transplantation of photoreceptor precursors. Nature. 2006, 444: 203-207. 10.1038/nature05161.
CrossRefPubMedGoogle Scholar
Pearson RA, Barber AC, Rizzi M, Hippert C, Xue T, West EL, Duran Y, Smith AJ, Chuang JZ, Azam SA, Xue T, West EL, Duran Y, Smith AJ, Chuang JZ, Azam SA, Luhmann UF, Benucci A, Sung CH, Bainbridge JW, Carandini M, Yau KW, Sowden JC, Ali RR: Restoration of vision after transplantation of photoreceptors. Nature. 2012, 485: 99-103. 10.1038/nature10997.
PubMedCentralCrossRefPubMedGoogle Scholar
Hambright D, Park KY, Brooks M, McKay R, Swaroop A, Nasonkin IO: Long-term survival and differentiation of retinal neurons derived from human embryonic stem cell lines in un-immunosuppressed mouse retina. Mol Vis. 2012, 18: 920-936.
PubMedCentralPubMedGoogle Scholar
Tucker BA, Park IH, Qi SD, Klassen HJ, Jiang C, Yao J, Redenti S, Daley GQ, Young MJ: Transplantation of adult mouse iPS cell-derived photoreceptor precursors restores retinal structure and function in degenerative mice. PLoS One. 2011, 6: e18992-10.1371/journal.pone.0018992.
PubMedCentralCrossRefPubMedGoogle Scholar
West EL, Gonzalez-Cordero A, Hippert C, Osakada F, Martinez-Barbera JP, Pearson RA, Sowden JC, Takahashi M, Ali RR: Defining the integration capacity of embryonic stem cell-derived photoreceptor precursors. Stem Cells. 2012, 30: 1424-1435. 10.1002/stem.1123.
PubMedCentralCrossRefPubMedGoogle Scholar
Sadan O, Melamed E, Offen D: Bone-marrow-derived mesenchymal stem cell therapy for neurodegenerative diseases. Expert Opin Biol Ther. 2009, 9: 1487-1497. 10.1517/14712590903321439.
CrossRefPubMedGoogle Scholar
Wislet-Gendebien S, Laudet E, Neirinckx V, Rogister B: Adult bone marrow: which stem cells for cellular therapy protocols in neurodegenerative disorders?. J Biomed Biotechnol. 2012, 2012: 601560.
PubMedCentralCrossRefPubMedGoogle Scholar
Sanchez-Ramos JR: Neural cells derived from adult bone marrow and umbilical cord blood. J Neurosci Res. 2002, 69: 880-893. 10.1002/jnr.10337.
CrossRefPubMedGoogle Scholar
Wislet-Gendebien S, Wautier F, Leprince P, Rogister B: Astrocytic and neuronal fate of mesenchymal stem cells expressing nestin. Brain Res Bull. 2005, 68: 95-102. 10.1016/j.brainresbull.2005.08.016.
CrossRefPubMedGoogle Scholar
Venkataramana NK, Kumar SK, Balaraju S, Radhakrishnan RC, Bansal A, Dixit A, Rao DK, Das M, Jan M, Gupta PK, Totey SM: Open-labeled study of unilateral autologous bone-marrow-derived mesenchymal stem cell transplantation in Parkinson’s disease. Transl Res. 2010, 155: 62-70. 10.1016/j.trsl.2009.07.006.
CrossRefPubMedGoogle Scholar
Biffi A, Montini E, Lorioli L, Cesani M, Fumagalli F, Plati T, Baldoli C, Martino S, Calabria A, Canale S, Benedicenti F, Vallanti G, Biasco L, Leo S, Kabbara N, Zanetti G, Rizzo WB, Mehta NA, Cicalese MP, Casiraghi M, Boelens JJ, Del Carro U, Dow DJ, Schmidt M, Assanelli A, Neduva V, Di Serio C, Stupka E, Gardner J, von Kalle C: Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science. 2013, 341: 1233158-10.1126/science.1233158.
CrossRefPubMedGoogle Scholar
Cartier N, Hacein-Bey-Abina S, Bartholomae CC, Veres G, Schmidt M, Kutschera I, Vidaud M, Abel U, Dal-Cortivo L, Caccavelli L, Mahlaoui N, Kiermer V, Mittelstaedt D, Bellesme C, Lahlou N, Lefrère F, Blanche S, Audit M, Payen E, Leboulch P, l’Homme B, Bougnères P, Von Kalle C, Fischer A, Cavazzana-Calvo M, Aubourg P: Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science. 2009, 326: 818-823. 10.1126/science.1171242.
CrossRefPubMedGoogle Scholar
Cattaneo E, Bonfanti L: Therapeutic potential of neural stem cells: greater in people’s perception than in their brains?. Front Neurosci. 2014, 8: 79.
PubMedCentralCrossRefPubMedGoogle Scholar

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