Summary
Neural stem and progenitor cells have great potential for the treatment of neurological disorders. However, many obstacles remain to translate this field to the patient’s bedside, including rationales for using neural stem cells in individual neurological disorders; the challenges of neural stem cell biology; and the caveats of current strategies of isolation and culturing neural precursors. Addressing these challenges is critical for the translation of neural stem cell biology to the clinic. Recent work using neural stem cells has yielded novel biologic concepts such as the importance of the reciprocal interaction between neural stem cells and the neurodegenerative environment. The prospect of using transplants of neural stem cells and progenitors to treat neurological diseases requires a better understanding of the molecular mechanisms of both neural stem cell behavior in experimental models and the intrinsic repair capacity of the injured brain.
Key Words: Neural stem cells, neural progenitors, neurospheres, self-renewal, multipotency
References
- 1.Gage FH, Kempermann G, Palmer TD, Peterson DA, Ray J. Multipotent progenitor cells in the adult dentate gyrus. J Neurobiol. 1998;36:249–266. doi: 10.1002/(SICI)1097-4695(199808)36:2<249::AID-NEU11>3.0.CO;2-9. [DOI] [PubMed] [Google Scholar]
- 2.Alvarez-Buylla A, Temple S. Stem cells in the developing and adult nervous system. J Neurobiol. 1998;36:105–110. doi: 10.1002/(SICI)1097-4695(199808)36:2<105::AID-NEU1>3.0.CO;2-5. [DOI] [PubMed] [Google Scholar]
- 3.Sheen VL, Ganesh VS, Topcu M, et al. Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex. Nat Genet. 2004;36:69–76. doi: 10.1038/ng1276. [DOI] [PubMed] [Google Scholar]
- 4.Sheen VL, Ferland RJ, Harney M, et al. Impaired proliferation and migration in human Miller-Dieker neural precursors. Ann Neurol. 2006;60:137–144. doi: 10.1002/ana.20843. [DOI] [PubMed] [Google Scholar]
- 5.Li J, Imitola J, Snyder EY, Sidman RL. Neural stem cells rescue nervous purkinje neurons by restoring molecular homeostasis of tissue plasminogen activator and downstream targets. J Neurosci. 2006;26:7839–7848. doi: 10.1523/JNEUROSCI.1624-06.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Fraidenraich D, Stillwell E, Romero E, et al. Rescue of cardiac defects in id knockout embryos by injection of embryonic stem cells. Science. 2004;306:247–252. doi: 10.1126/science.1102612. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Fraidenraich D, Benezra R. Embryonic stem cells prevent developmental cardiac defects in mice. Nat Clin Pract Cardiovasc Med. 2006;3(Suppl 1):S14–17. doi: 10.1038/ncpcardio0402. [DOI] [PubMed] [Google Scholar]
- 8.Pluchino S, Zanotti L, Rossi B, et al. Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism. Nature. 2005;436:266–271. doi: 10.1038/nature03889. [DOI] [PubMed] [Google Scholar]
- 9.Morshead CM, Benveniste P, Iscove NN, van der Kooy D. Hematopoietic competence is a rare property of neural stem cells that may depend on genetic and epigenetic alterations. Nat Med. 2002;8:268–273. doi: 10.1038/nm0302-268. [DOI] [PubMed] [Google Scholar]
- 10.Ziv Y, Ron N, Butovsky O, et al. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci. 2006;9:268–275. doi: 10.1038/nn1629. [DOI] [PubMed] [Google Scholar]
- 11.Magavi SS, Leavitt BR, Macklis JD. Induction of neurogenesis in the neocortex of adult mice [see comments] Nature. 2000;405:951–955. doi: 10.1038/35016083. [DOI] [PubMed] [Google Scholar]
- 12.Flax JD, Aurora S, Yang C, et al. Engraftable human neural stem cells respond to developmental cues, replace neurons, and express foreign genes. Nat Biotechnol. 1998;16:1033–1039. doi: 10.1038/3473. [DOI] [PubMed] [Google Scholar]
- 13.Gokhan S, Song Q, Mehler MF. Generation and regulation of developing immortalized neural cell lines. Methods. 1998;16:345–358. doi: 10.1006/meth.1998.0689. [DOI] [PubMed] [Google Scholar]
- 14.Johansson CB, Momma S, Clarke DL, Risling M, Lendahl U, Frisen J. Identification of a neural stem cell in the adult mammalian central nervous system. Cell. 1999;96:25–34. doi: 10.1016/S0092-8674(00)80956-3. [DOI] [PubMed] [Google Scholar]
- 15.Mezey E, Chandross KJ, Harta G, Maki RA, McKercher SR. Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow [in process citation] Science. 2000;290:1779–1782. doi: 10.1126/science.290.5497.1779. [DOI] [PubMed] [Google Scholar]
- 16.Roy NS, Nakano T, Keyoung HM, et al. Telomerase immortalization of neuronally restricted progenitor cells derived from the human fetal spinal cord. Nat Biotechnol. 2004;22:297–305. doi: 10.1038/nbt944. [DOI] [PubMed] [Google Scholar]
- 17.Schuldiner M, Yanuka O, Itskovitz-Eldor J, Melton DA, Benvenisty N. From the cover: effects of eight growth factors on the differentiation of cells derived from human embryonic stem cells [in process citation] Proc Natl Acad Sci U S A. 2000;97:11307–11312. doi: 10.1073/pnas.97.21.11307. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Tamaki S, Eckert K, He D, et al. Engraftment of sorted/expanded human central nervous system stem cells from fetal brain. J Neurosci Res. 2002;69:976–986. doi: 10.1002/jnr.10412. [DOI] [PubMed] [Google Scholar]
- 19.Gage FH. Mammalian neural stem cells. Science. 2000;287:1433–1438. doi: 10.1126/science.287.5457.1433. [DOI] [PubMed] [Google Scholar]
- 20.Kondo T, Raff M. Oligodendrocyte precursor cells reprogrammed to become multipotential CNS stem cells [see comments] Science. 2000;289:1754–1757. doi: 10.1126/science.289.5485.1754. [DOI] [PubMed] [Google Scholar]
- 21.Marmur R, Mabie PC, Gokhan S, Song Q, Kessler JA, Mehler MF. Isolation and developmental characterization of cerebral cortical multipotent progenitors. Dev Biol. 1998;204:577–591. doi: 10.1006/dbio.1998.9099. [DOI] [PubMed] [Google Scholar]
- 22.Ben-Hur T, Rogister B, Murray K, Rougon G, Dubois-Dalcq M. Growth and fate of PSA-NCAM+ precursors of the postnatal brain. J Neurosci. 1998;18:5777–5788. doi: 10.1523/JNEUROSCI.18-15-05777.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Palmer TD, Markakis EA, Willhoite AR, Safar F, Gage FH. Fibroblast growth factor-2 activates a latent neurogenic program in neural stem cells from diverse regions of the adult CNS. J Neurosci. 1999;19:8487–8497. doi: 10.1523/JNEUROSCI.19-19-08487.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Laywell ED, Rakic P, Kukekov VG, Holland EC, Steindler DA. Identification of a multipotent astrocytic stem cell in the immature and adult mouse brain. Proc Natl Acad Sci U S A. 2000;97:13883–13888. doi: 10.1073/pnas.250471697. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Lie DC, Dziewczapolski G, Willhoite AR, Kaspar BK, Shults CW, Gage FH. The adult substantia nigra contains progenitor cells with neurogenic potential. J Neurosci. 2002;22:6639–6649. doi: 10.1523/JNEUROSCI.22-15-06639.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Villa A, Snyder EY, Vescovi A, Martinez-Serrano A. Establishment and properties of a growth factor-dependent, perpetual neural stem cell line from the human CNS. Exp Neurol. 2000;161:67–84. doi: 10.1006/exnr.1999.7237. [DOI] [PubMed] [Google Scholar]
- 27.Aboody KS, Brown A, Rainov NG, et al. From the cover: neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas [In Process Citation] Roc Natl Acad Sci U S A. 2000;97:12846–12851. doi: 10.1073/pnas.97.23.12846. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Chiasson BJ, Tropepe V, Morshead CM, van der Kooy D. Adult mammalian forebrain ependymal and subependymal cells demonstrate proliferative potential, but only subependymal cells have neural stem cell characteristics. J Neurosci. 1999;19:4462–4471. doi: 10.1523/JNEUROSCI.19-11-04462.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Clarke DL, Johansson CB, Wilbertz J, et al. Generalized potential of adult neural stem cells [see comments] Science. 2000;288:1660–1663. doi: 10.1126/science.288.5471.1660. [DOI] [PubMed] [Google Scholar]
- 30.Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell. 1999;97:703–716. doi: 10.1016/S0092-8674(00)80783-7. [DOI] [PubMed] [Google Scholar]
- 31.McLaren FH, Svendsen CN, Van der Meide P, Joly E. Analysis of neural stem cells by flow cytometry: cellular differentiation modifies patterns of MHC expression [in process citation] J Neuroimmunol. 2001;112:35–46. doi: 10.1016/S0165-5728(00)00410-0. [DOI] [PubMed] [Google Scholar]
- 32.Morshead CM, Reynolds BA, Craig CG, et al. Neural stem cells in the adult mammalian forebrain: a relatively quiescent subpopulation of subependymal cells. Neuron. 1994;13:1071–1082. doi: 10.1016/0896-6273(94)90046-9. [DOI] [PubMed] [Google Scholar]
- 33.Gritti A, Bonfanti L, Doetsch F, et al. Multipotent neural stem cells reside into the rostral extension and olfactory bulb of adult rodents. J Neurosci. 2002;22:437–445. doi: 10.1523/JNEUROSCI.22-02-00437.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Quinones-Hinojosa A, Sanai N, Soriano-Navarro M, et al. Cellular composition and cytoarchitecture of the adult human sub-ventricular zone: a niche of neural stem cells. J Comp Neurol. 2006;494:415–434. doi: 10.1002/cne.20798. [DOI] [PubMed] [Google Scholar]
- 35.Sanai N, Tramontin AD, Quinones-Hinojosa A, et al. Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature. 2004;427:740–744. doi: 10.1038/nature02301. [DOI] [PubMed] [Google Scholar]
- 36.Lois C, Alvarez-Buylla A. Proliferating subventricular zone cells in the adult mammalian forebrain can differentiate into neurons and glia. Proc Natl Acad Sci U S A. 1993;90:2074–2077. doi: 10.1073/pnas.90.5.2074. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Doetsch F, Petreanu L, Caille I, Garcia-Verdugo JM, Alvarez-Buylla A. EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron. 2002;36:1021–1034. doi: 10.1016/S0896-6273(02)01133-9. [DOI] [PubMed] [Google Scholar]
- 38.Imura T, Komblum HI, Sofroniew MV. The predominant neural stem cell isolated from postnatal and adult forebrain but not early embryonic forebrain expresses GFAP. J Neurosci. 2003;23:2824–2832. doi: 10.1523/JNEUROSCI.23-07-02824.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.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. [DOI] [PubMed] [Google Scholar]
- 40.Snyder EY, Vescovi AL. The possibilities/perplexities of stem cells [news] Nat Biotechnol. 2000;18:827–828. doi: 10.1038/78428. [DOI] [PubMed] [Google Scholar]
- 41.Bjomson CR, Rietze RL, Reynolds BA, Magli MC, Vescovi AL. Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo [see comments] Science. 1999;283:534–537. doi: 10.1126/science.283.5401.534. [DOI] [PubMed] [Google Scholar]
- 42.Terada N, Hamazaki T, Oka M, et al. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature. 2002;416:542–545. doi: 10.1038/nature730. [DOI] [PubMed] [Google Scholar]
- 43.Ying QL, Nichols J, Evans EP, Smith AG. Changing potency by spontaneous fusion. Nature. 2002;416:545–548. doi: 10.1038/nature729. [DOI] [PubMed] [Google Scholar]
- 44.Weimann JM, Charlton CA, Brazelton TR, Hackman RC, Blau HM. Contribution of transplanted bone marrow cells to Purkinje neurons in human adult brains. Proc Natl Acad Sci U S A. 2003;100:2088–2093. doi: 10.1073/pnas.0337659100. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Wagers AJ, Sherwood RI, Christensen JL, Weissman IL. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science. 2002;297:2256–2259. doi: 10.1126/science.1074807. [DOI] [PubMed] [Google Scholar]
- 46.Tourbah A, Linnington C, Bachelin C, Avellana-Adalid V, Wekerle H, Baron-Van Evercooren A. Inflammation promotes survival and migration of the CG4 oligodendrocyte progenitors transplanted in the spinal cord of both inflammatory and demy-elinated EAE rats. J Neurosci Res. 1997;50:853–861. doi: 10.1002/(SICI)1097-4547(19971201)50:5<853::AID-JNR21>3.0.CO;2-0. [DOI] [PubMed] [Google Scholar]
- 47.Nait-Oumesmar B, Decker L, Lachapelle F, Avellana-Adalid V, Bachelin C, Van Evercooren AB. Progenitor cells of the adult mouse subventricular zone proliferate, migrate and differentiate into oligodendrocytes after demyelination. Eur J Neurosci. 1999;11:4357–4366. doi: 10.1046/j.1460-9568.1999.00873.x. [DOI] [PubMed] [Google Scholar]
- 48.Conover JC, Doetsch F, Garcia-Verdugo JM, Gale NW, Yancopoulos GD, Alvarez-Buylla A. Disruption of Eph/ephrin signaling affects migration and proliferation in the adult subventricular zone [in process citation] Nat Neurosci. 2000;3:1091–1097. doi: 10.1038/80606. [DOI] [PubMed] [Google Scholar]
- 49.Forsberg-Nilsson K, Behar TN, Afrakhte M, Barker JL, McKay RD. Platelet-derived growth factor induces chemotaxis of neuro-epithelial stem cells. J Neurosci Res. 1998;53:521–530. doi: 10.1002/(SICI)1097-4547(19980901)53:5<521::AID-JNR2>3.0.CO;2-B. [DOI] [PubMed] [Google Scholar]
- 50.Imitola J, Raddassi K, Park KI, et al. Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor lalpha/CXC chemokine receptor 4 pathway. Proc Natl Acad Sci U S A. 2004;101:18117–18122. doi: 10.1073/pnas.0408258102. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51.Pluchino S, Quattrini A, Brambilla E, et al. Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature. 2003;422:688–694. doi: 10.1038/nature01552. [DOI] [PubMed] [Google Scholar]
- 52.Liu Y, Himes BT, Solowska J, et al. Intraspinal delivery of neurotrophin-3 using neural stem cells genetically modified by recombinant retrovirus. Exp Neurol. 1999;158:9–26. doi: 10.1006/exnr.1999.7079. [DOI] [PubMed] [Google Scholar]
- 53.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. doi: 10.1038/35075141. [DOI] [PubMed] [Google Scholar]
- 54.Nunes MC, Roy NS, Keyoung HM, et al. Identification and isolation of multipotential neural progenitor cells from the sub-cortical white matter of the adult human brain. Nat Med. 2003;9:439–447. doi: 10.1038/nm837. [DOI] [PubMed] [Google Scholar]
- 55.Windrem MS, Nunes MC, Rashbaum WK, et al. Fetal and adult human oligodendrocyte progenitor cell isolates myelinate the congenitally dysmyelinated brain. Nat Med. 2004;10:93–97. doi: 10.1038/nm974. [DOI] [PubMed] [Google Scholar]
- 56.Wu P, Tarasenko YI, Gu Y, Huang LY, Coggeshall RE, Yu Y. Region-specific generation of cholinergic neurons from fetal human neural stem cells grafted in adult rat. Nat Neurosci. 2002;5:1271–1278. doi: 10.1038/nn974. [DOI] [PubMed] [Google Scholar]
- 57.Flicker RA, Carpenter MK, Winkler C, Greco C, Gates MA, Bjorklund A. Site-specific migration and neuronal differentiation of human neural progenitor cells after transplantation in the adult rat brain. J Neurosci. 1999;19:5990–6005. doi: 10.1523/JNEUROSCI.19-14-05990.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 58.Brustle O, Choudhary K, Karram K, et al. Chimeric brains generated by intraventricular transplantation of fetal human brain cells into embryonic rats. Nat Biotechnol. 1998;16:1040–1044. doi: 10.1038/3481. [DOI] [PubMed] [Google Scholar]
- 59.Bjorklund A, Lindvall O. Cell replacement therapies for central nervous system disorders. Nat Neurosci. 2000;3:537–544. doi: 10.1038/75705. [DOI] [PubMed] [Google Scholar]
- 60.Imitola J, Snyder EY, Khoury SJ. Genetic programs and responses of neural stem/progenitor cells during demyelination: potential insights into repair mechanisms in multiple sclerosis. Physiol Genomics. 2003;14:171–197. doi: 10.1152/physiolgenomics.00021.2002. [DOI] [PubMed] [Google Scholar]
- 61.Snyder EY, Yoon C, Flax JD, Macklis JD. Multipotent neural precursors can differentiate toward replacement of neurons undergoing targeted apoptotic degeneration in adult mouse neocortex. Proc Natl Acad Sci U S A. 1997;94:11663–11668. doi: 10.1073/pnas.94.21.11663. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62.Park KI, Liu S, Flax JD, Nissim S, Stieg PE, Snyder EY. Transplantation of neural progenitor and stem cells: developmental insights may suggest new therapies for spinal cord and other CNS dysfunction. J Neurotrauma. 1999;16:675–687. doi: 10.1089/neu.1999.16.675. [DOI] [PubMed] [Google Scholar]
- 63.Riess P, Zhang C, Saatman KE, et al. Transplanted neural stem cells survive, differentiate, and improve neurological motor function after experimental traumatic brain injury. Neurosurgery. 2002;51:1043–1052. doi: 10.1097/00006123-200210000-00035. [DOI] [PubMed] [Google Scholar]
- 64.Park KI, Teng YD, Snyder EY. The injured brain interacts reciprocally with neural stem cells supported by scaffolds to reconstitute lost tissue. Nat Biotechnol. 2002;20:1111–1117. doi: 10.1038/nbt751. [DOI] [PubMed] [Google Scholar]
- 65.Ohab JJ, Fleming S, Blesch A, Carmichael ST. A neurovascular niche for neurogenesis after stroke. J Neurosci. 2006;26:13007–13016. doi: 10.1523/JNEUROSCI.4323-06.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 66.Auerbach JM, Eiden MV, McKay RD. Transplanted CNS stem cells form functional synapses in vivo. Eur J Neurosci. 2000;12:1696–1704. doi: 10.1046/j.1460-9568.2000.00067.x. [DOI] [PubMed] [Google Scholar]
- 67.Lundberg C, Englund U, Trono D, Bjorklund A, Wictorin K. Differentiation of the RN33B cell line into forebrain projection neurons after transplantation into the neonatal rat brain. Exp Neurol. 2002;175:370–387. doi: 10.1006/exnr.2002.7888. [DOI] [PubMed] [Google Scholar]
- 68.Vroemen M, Aigner L, Winkler J, Weidner N. Adult neural progenitor cell grafts survive after acute spinal cord injury and integrate along axonal pathways. Eur J Neurosci. 2003;18:743–751. doi: 10.1046/j.1460-9568.2003.02804.x. [DOI] [PubMed] [Google Scholar]
- 69.Yamamoto S, Nagao M, Sugimori M, et al. Transcription factor expression and Notch-dependent regulation of neural progenitors in the adult rat spinal cord. J Neurosci. 2001;21:9814–9823. doi: 10.1523/JNEUROSCI.21-24-09814.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 70.Ourednik J, Ourednik V, Lynch WP, Schachner M, Snyder EY. Neural stem cells display an inherent mechanism for rescuing dysfunctional neurons. Nat Biotechnol. 2002;20:1103–1110. doi: 10.1038/nbt750. [DOI] [PubMed] [Google Scholar]
- 71.Hagan M, Wennersten A, Meijer X, Holmin S, Wahlberg L, Mathiesen T. Neuroprotection by human neural progenitor cells after experimental contusion in rats. Neurosci Lett. 2003;351:149–152. doi: 10.1016/j.neulet.2003.07.021. [DOI] [PubMed] [Google Scholar]
- 72.Haughey NJ, Nath A, Chan SL, Borchard AC, Rao MS, Mattson MP. Disruption of neurogenesis by amyloid beta-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer’s disease. J Neurochem. 2002;83:1509–1524. doi: 10.1046/j.1471-4159.2002.01267.x. [DOI] [PubMed] [Google Scholar]
- 73.Mehta V, Hong M, Spears J, Mendez I. Enhancement of graft survival and sensorimotor behavioral recovery in rats undergoing transplantation with dopaminergic cells exposed to glial cell line-derived neurotrophic factor. J Neurosurg. 1998;88:1088–1095. doi: 10.3171/jns.1998.88.6.1088. [DOI] [PubMed] [Google Scholar]
- 74.Lindvall O. Neural transplantation in Parkinson’s disease. Novartis Found Symp. 2000;231:110–123. doi: 10.1002/0470870834.ch7. [DOI] [PubMed] [Google Scholar]
- 75.Piccini P, Lindvall O, Bjorklund A, et al. Delayed recovery of movement-related cortical function in Parkinson’s disease after striatal dopaminergic grafts. Ann Neurol. 2000;48:689–695. doi: 10.1002/1531-8249(200011)48:5<689::AID-ANA1>3.0.CO;2-N. [DOI] [PubMed] [Google Scholar]
- 76.Anton R, Kordower JH, Maidment NT, et al. Neural-targeted gene therapy for rodent and primate hemiparkinsonism. Exp Neurol. 1994;127:207–218. doi: 10.1006/exnr.1994.1097. [DOI] [PubMed] [Google Scholar]
- 77.Lundberg C, Field PM, Ajayi YO, Raisman G, Bjorklund A. Conditionally immortalized neural progenitor cell lines integrate and differentiate after grafting to the adult rat striatum. A combined autoradiographic and electron microscopic study. Brain Res. 1996;737:295–300. doi: 10.1016/0006-8993(96)00923-7. [DOI] [PubMed] [Google Scholar]
- 78.Svendsen CN, Caldwell MA, Shen J, et al. Long-term survival of human central nervous system progenitor cells transplanted into a rat model of Parkinson’s disease. Exp Neurol. 1997;148:135–146. doi: 10.1006/exnr.1997.6634. [DOI] [PubMed] [Google Scholar]
- 79.Bjugstad KB, Redmond DE, Teng YD, et al. Neural stem cells implanted into MPTP-treated monkeys increase the size of endogenous tyrosine hydroxylase-positive cells found in the striatum: a return to control measures. Cell Transplant. 2005;14:183–192. doi: 10.3727/000000005783983098. [DOI] [PubMed] [Google Scholar]
- 80.Redmond DE, Bjugstad KB, Teng YD, et al. From the cover: behavioral improvement in a primate Parkinson’s model is associated with multiple homeostatic effects of human neural stem cells. Proc Natl Acad Sci U S A. 2007;104:12175–12180. doi: 10.1073/pnas.0704091104. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 81.Kim JH, Auerbach JM, Rodriguez-Gomez JA, et al. Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson’s disease. Nature. 2002;418:50–56. doi: 10.1038/nature00900. [DOI] [PubMed] [Google Scholar]
- 82.Kim DW, Chung S, Hwang M, et al. Stromal cell-derived inducing activity, Nurr1, and signaling molecules synergistically induce dopaminergic neurons from mouse embryonic stem cells. Stem Cells. 2006;24:557–567. doi: 10.1634/stemcells.2005-0233. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 83.Roy NS, Cleren C, Singh SK, Yang L, Beal MF, Goldman SA. Functional engraftment of human ES cell-derived dopaminergic neurons enriched by coculture with telomerase-immortalized midbrain astrocytes. Nat Med. 2006;12:1259–1268. doi: 10.1038/nm1495. [DOI] [PubMed] [Google Scholar]
- 84.Komek B, Storch MK, Weissert R, et al. Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am J Pathol. 2000;157:267–276. doi: 10.1016/S0002-9440(10)64537-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 85.Imitola J, Chitnis T, Khoury SJ. Insights into the molecular pathogenesis of progression in multiple sclerosis: potential implications for future therapies. Arch Neurol. 2006;63:25–33. doi: 10.1001/archneur.63.1.25. [DOI] [PubMed] [Google Scholar]
- 86.Einstein O, Fainstein N, Vaknin I, et al. Neural precursors attenuate autoimmune encephalomyelitis by peripheral immunosuppression. Ann Neurol. 2007;61:209–218. doi: 10.1002/ana.21033. [DOI] [PubMed] [Google Scholar]
- 87.Yandava BD, Billinghurst LL, Snyder EY. “Global” cell replacement is feasible via neural stem cell transplantation: evidence from the dysmyelinated shiverer mouse brain. Proc Natl Acad Sci U S A. 1999;96:7029–7034. doi: 10.1073/pnas.96.12.7029. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 88.Hammang JP, Archer DR, Duncan ID. Myelination following transplantation of EGF-responsive neural stem cells into a myelin-deficient environment. Exp Neurol. 1997;147:84–95. doi: 10.1006/exnr.1997.6592. [DOI] [PubMed] [Google Scholar]
- 89.Milward EA, Lundberg CG, Ge B, Lipsitz D, Zhao M, Duncan ID. Isolation and transplantation of multipotential populations of epidermal growth factor-responsive, neural progenitor cells from the canine brain. J Neurosci Res. 1997;50:862–871. doi: 10.1002/(SICI)1097-4547(19971201)50:5<862::AID-JNR22>3.0.CO;2-1. [DOI] [PubMed] [Google Scholar]
- 90.Liu S, Qu Y, Stewart TJ, et al. Embryonic stem cells differentiate into oligodendrocytes and myelinate in culture and after spinal cord transplantation. Proc Natl Acad Sci U S A. 2000;97:6126–6131. doi: 10.1073/pnas.97.11.6126. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 91.Brustle O, Jones KN, Learish RD, et al. Embryonic stem cell-derived glial precursors: a source of myelinating transplants [see comments] Science. 1999;285:754–756. doi: 10.1126/science.285.5428.754. [DOI] [PubMed] [Google Scholar]
- 92.Archer DR, Cuddon PA, Lipsitz D, Duncan LD. Myelination of the canine central nervous system by glial cell transplantation: a model for repair of human myelin disease. Nat Med. 1997;3:54–93. doi: 10.1038/nm0197-54. [DOI] [PubMed] [Google Scholar]
- 93.Espinosa de los Monteros A, Zhao P, Huang C, et al. Transplantation of CG4 oligodendrocyte progenitor cells in the myelin-deficient rat brain results in myelination of axons and enhanced oligodendroglial markers. J Neurosci Res. 1997;50:872–887. doi: 10.1002/(SICI)1097-4547(19971201)50:5<872::AID-JNR23>3.0.CO;2-1. [DOI] [PubMed] [Google Scholar]
- 94.Zhang SC, Ge B, Duncan ID. Adult brain retains the potential to generate oligodendroglial progenitors with extensive myelination capacity. Proc Natl Acad Sci U S A. 1999;96:4089–4094. doi: 10.1073/pnas.96.7.4089. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 95.Imaizumi T, Lankford KL, Burton WV, Fodor WL, Kocsis JD. Xenotransplantation of transgenic pig olfactory ensheathing cells promotes axonal regeneration in rat spinal cord. Nat Biotechnol. 2000;18:949–953. doi: 10.1038/79432. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 96.Kato T, Honmou O, Uede T, Hashi K, Kocsis JD. Transplantation of human olfactory ensheathing cells elicits remyelination of demyelinated rat spinal cord. Glia. 2000;30:209–218. doi: 10.1002/(SICI)1098-1136(200005)30:3<209::AID-GLIA1>3.0.CO;2-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 97.Bamett SC, Alexander CL, Iwashita Y, et al. Identification of a human olfactory ensheathing cell that can effect transplant-mediated remyelination of demyelinated CNS axons. Brain. 2000;123:1581–1588. doi: 10.1093/brain/123.8.1581. [DOI] [PubMed] [Google Scholar]
- 98.Kohama I, Lankford KL, Preiningerova J, White FA, Vollmer TL, Kocsis JD. Transplantation of cryopreserved adult human Schwann cells enhances axonal conduction in demyelinated spinal cord. J Neurosci. 2001;21:944–950. doi: 10.1523/JNEUROSCI.21-03-00944.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 99.Franklin RJ, Blakemore WF. Transplanting oligodendrocyte progenitors into the adult CNS. J Anat. 1997;190:23–33. doi: 10.1046/j.1469-7580.1997.19010023.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 100.Rosario CM, Yandava BD, Kosaras B, Zurakowski D, Sidman RL, Snyder EY. Differentiation of engrafted multipotent neural progenitors towards replacement of missing granule neurons in meander tail cerebellum may help determine the locus of mutant gene action. Development. 1997;124:4213–4224. doi: 10.1242/dev.124.21.4213. [DOI] [PubMed] [Google Scholar]
- 101.Snyder EY, Taylor RM, Wolfe JH. Neural progenitor cell engraftment corrects lysosomal storage throughout the MPS VII mouse brain. Nature. 1995;374:367–370. doi: 10.1038/374367a0. [DOI] [PubMed] [Google Scholar]
- 102.Meng XL, Shen JS, Ohashi T, Maeda H, Kim SU, Eto Y. Brain transplantation of genetically engineered human neural stem cells globally corrects brain lesions in the mucopolysaccharidosis type VII mouse. J Neurosci Res. 2003;74:266–277. doi: 10.1002/jnr.10764. [DOI] [PubMed] [Google Scholar]
- 103.Lacorazza HD, Flax JD, Snyder EY, Jendoubi M. Expression of human beta-hexosaminidase alpha-subunit gene (the gene defect of Tay-Sachs disease) in mouse brains upon engraftment of transduced progenitor cells. Nat Med. 1996;2:424–429. doi: 10.1038/nm0496-424. [DOI] [PubMed] [Google Scholar]
- 104.Torchiana E, Lulli L, Cattaneo E, et al. Retroviral-mediated transfer of the galactocerebrosidase gene in neural progenitor cells. Neuroreport. 1998;9:3823–3827. doi: 10.1097/00001756-199812010-00011. [DOI] [PubMed] [Google Scholar]
- 105.Lee JP, Jeyakumar M, Gonzalez R, et al. Stem cells act through multiple mechanisms to benefit mice with neurodegenerative metabolic disease. Nat Med. 2007;13:439–447. doi: 10.1038/nm1548. [DOI] [PubMed] [Google Scholar]
- 106.Ehtesham M, Kabos P, Gutierrez MA, et al. Induction of glio-blastoma apoptosis using neural stem cell-mediated delivery of tumor necrosis factor-related apoptosis-inducing ligand. Cancer Res. 2002;62:7170–7174. [PubMed] [Google Scholar]
- 107.Ehtesham M, Kabos P, Kabosova A, Neuman T, Black KL, Yu JS. The use of interleukin 12-secreting neural stem cells for the treatment of intracranial glioma. Cancer Res. 2002;62:5657–5663. [PubMed] [Google Scholar]
- 108.Benedetti S, Pirola B, Polio B, et al. Gene therapy of experimental brain tumors using neural progenitor cells. Nat Med. 2000;6:447–450. doi: 10.1038/74710. [DOI] [PubMed] [Google Scholar]
- 109.Jackson EL, Garcia-Verdugo JM, Gil-Perotin S, et al. PDGFR alpha-positive B cells are neural stem cells in the adult SVZ that form glioma-like growths in response to increased PDGF signaling. Neuron. 2006;51:187–199. doi: 10.1016/j.neuron.2006.06.012. [DOI] [PubMed] [Google Scholar]
- 110.Quinones-Hinojosa A, Chaichana K. The human subventricular zone: a source of new cells and a potential source of brain tumors. Exp Neurol. 2007;205:313–324. doi: 10.1016/j.expneurol.2007.03.016. [DOI] [PubMed] [Google Scholar]
- 111.Monje ML, Mizumatsu S, Fike JR, Palmer TD. Irradiation induces neural precursor-cell dysfunction. Nat Med. 2002;8:955–962. doi: 10.1038/nm749. [DOI] [PubMed] [Google Scholar]
- 112.Monje ML, Toda H, Palmer TD. Inflammatory blockade restores adult hippocampal neurogenesis. Science. 2003;302:1760–1765. doi: 10.1126/science.1088417. [DOI] [PubMed] [Google Scholar]
- 113.Imitola J, Comabella M, Chandraker AK, et al. Neural stem/ progenitor cells express costimulatory molecules that are differentially regulated by inflammatory and apoptotic stimuli. Am J Pathol. 2004;164:1615–1625. doi: 10.1016/S0002-9440(10)63720-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 114.Gensert JM, Goldman JE. Endogenous progenitors remyelinate demyelinated axons in the adult CNS. Neuron. 1997;19:197–203. doi: 10.1016/S0896-6273(00)80359-1. [DOI] [PubMed] [Google Scholar]
- 115.Wolswijk G. Chronic stage multiple sclerosis lesions contain a relatively quiescent population of oligodendrocyte precursor cells. J Neurosci. 1998;18:601–609. doi: 10.1523/JNEUROSCI.18-02-00601.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 116.Rogister B, Ben-Hur T, Dubois-Dalcq M. From neural stem cells to myelinating oligodendrocytes. Mol Cell Neurosci. 1999;14:287–300. doi: 10.1006/mcne.1999.0790. [DOI] [PubMed] [Google Scholar]
- 117.Lu P, Jones LL, Snyder EY, Tuszynski MH. Neural stem cells constitutively secrete neurotrophic factors and promote extensive host axonal growth after spinal cord injury. Exp Neurol. 2003;181:115–129. doi: 10.1016/S0014-4886(03)00037-2. [DOI] [PubMed] [Google Scholar]
- 118.Ourednik V, Ourednik J, Flax JD, et al. Segregation of human neural stem cells in the developing primate forebrain. Science. 2001;293:1820–1824. doi: 10.1126/science.1060580. [DOI] [PubMed] [Google Scholar]
- 119.Snyder EY, Deitcher DL, Walsh C, Amold-Aldea S, Hartwieg EA, Cepko CL. Multipotent neural cell lines can engraft and participate in development of mouse cerebellum. Cell. 1992;68:33–51. doi: 10.1016/0092-8674(92)90204-P. [DOI] [PubMed] [Google Scholar]
- 120.Tang Y, Shah K, Messerli SM, Snyder E, Breakefield X, Weissleder R. In vivo tracking of neural progenitor cell migration to glioblastomas. Hum Gene Ther. 2003;14:1247–1254. doi: 10.1089/104303403767740786. [DOI] [PubMed] [Google Scholar]
- 121.Yang M, Stull ND, Berk MA, Snyder EY, Iacovitti L. Neural stem cells spontaneously express dopaminergic traits after transplantation into the intact or 6-hydroxydopamine-lesioned rat. Exp Neurol. 2002;177:50–60. doi: 10.1006/exnr.2002.7989. [DOI] [PubMed] [Google Scholar]
- 122.Rothstein JD, Snyder EY. Reality and immortality—neural stem cells for therapies. Nat Biotechnol. 2004;22:283–285. doi: 10.1038/nbt0304-283. [DOI] [PubMed] [Google Scholar]
- 123.De Filippis L, Lamorte G, Snyder EY, Malgaroli A, Vescovi AL. A novel, immortal and multipotent human neural stem cell line generating functional neurons and oligodendrocytes. Stem Cells 2007 Jun 7;[Epub ahead of print]. [DOI] [PubMed]
- 124.Reynolds BA, Rietze RL. Neural stem cells and neurospheres—re-evaluating the relationship. Nat Methods. 2005;2:333–336. doi: 10.1038/nmeth758. [DOI] [PubMed] [Google Scholar]
- 125.Singec I, Knoth R, Meyer RP, et al. Defining the actual sensitivity and specificity of the neurosphere assay in stem cell biology. Nat Methods. 2006;3:801–806. doi: 10.1038/nmeth926. [DOI] [PubMed] [Google Scholar]
- 126.Fults D, Pedone C, Dai C, Holland EC. MYC expression promotes the proliferation of neural progenitor cells in culture and in vivo. Neoplasia. 2002;4:32–39. doi: 10.1038/sj.neo.7900200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 127.Sanai N, Alvarez-Buylla A, Berger MS. Neural stem cells and the origin of gliomas. N Engl J Med. 2005;353:811–822. doi: 10.1056/NEJMra043666. [DOI] [PubMed] [Google Scholar]
- 128.Foroni C, Galli R, Cipelletti B, et al. Resilience to transformation and inherent genetic and functional stability of adult neural stem cells ex vivo. Cancer Res. 2007;67:3725–3733. doi: 10.1158/0008-5472.CAN-06-4577. [DOI] [PubMed] [Google Scholar]
- 129.Uhrbom L, Dai C, Celestino JC, Rosenblum MK, Fuller GN, Holland EC. Ink4a-Arf loss cooperates with KRas activation in astrocytes and neural progenitors to generate glioblastomas of various morphologies depending on activated Akt. Cancer Res. 2002;62:5551–5558. [PubMed] [Google Scholar]
- 130.Gabay L, Lowell S, Rubin LL, Anderson DJ. Deregulation of dorsoventral patterning by FGF confers trilineage differentiation capacity on CNS stem cells in vitro. Neuron. 2003;40:485–499. doi: 10.1016/S0896-6273(03)00637-8. [DOI] [PubMed] [Google Scholar]
- 131.Thored P, Arvidsson A, Cacci E, et al. Persistent production of neurons from adult brain stem cells during recovery after stroke. Stem Cells. 2006;24:739–747. doi: 10.1634/stemcells.2005-0281. [DOI] [PubMed] [Google Scholar]
- 132.Picard-Riera N, Decker L, Delarasse C, et al. Experimental autoimmune encephalomyelitis mobilizes neural progenitors from the subventricular zone to undergo oligodendrogenesis in adult mice. Proc Natl Acad Sci U S A. 2002;99:13211–13216. doi: 10.1073/pnas.192314199. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 133.Zappia E, Casazza S, Pedemonte E, et al. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood. 2005;106:1755–1761. doi: 10.1182/blood-2005-04-1496. [DOI] [PubMed] [Google Scholar]
- 134.Muraoka K, Shingo T, Yasuhara T, et al. The high integration and differentiation potential of autologous neural stem cell transplantation compared with allogeneic transplantation in adult rat hippocampus. Exp Neurol. 2006;199:311–327. doi: 10.1016/j.expneurol.2005.12.004. [DOI] [PubMed] [Google Scholar]
- 135.Song H, Stevens CF, Gage FH. Astroglia induce neurogenesis from adult neural stem cells. Nature. 2002;417:39–44. doi: 10.1038/417039a. [DOI] [PubMed] [Google Scholar]
- 136.Faijerson J, Tinsley RB, Aprico K, et al. Reactive astrogliosis induces astrocytic differentiation of adult neural stem/progenitor cells in vitro. J Neurosci Res. 2006;84:1415–1424. doi: 10.1002/jnr.21044. [DOI] [PubMed] [Google Scholar]
- 137.Aarum J, Sandberg K, Haeberlein SL, Persson MA. Migration and differentiation of neural precursor cells can be directed by microglia. Proc Natl Acad Sci U S A. 2003;100:15983–15988. doi: 10.1073/pnas.2237050100. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 138.Zhang SC, Goetz BD, Duncan ID. Suppression of activated microglia promotes survival and function of transplanted oligoden-droglial progenitors. Glia. 2003;41:191–198. doi: 10.1002/glia.10172. [DOI] [PubMed] [Google Scholar]
- 139.Butovsky O, Landa G, Kunis G, et al. Induction and blockage of oligodendrogenesis by differently activated microglia in an animal model of multiple sclerosis. J Clin Invest. 2006;116:905–915. doi: 10.1172/JCI26836. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 140.Miller JT, Bartley JH, Wimbome HJ, et al. The neuroblast and angioblast chemotaxic factor SDF-1 (CXCL12) expression is briefly up regulated by reactive astrocytes in brain following neonatal hypoxic-ischemic injury. BMC Neurosci. 2005;6:63–63. doi: 10.1186/1471-2202-6-63. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 141.Corti S, Locatelli F, Papadimitriou D, et al. Multipotentiality, homing properties, and pyramidal neurogenesis of CNS-derived LeX(ssea-1)+/CXCR4+ stem cells. Faseb J. 2005;19:1860–1862. doi: 10.1096/fj.05-4170fje. [DOI] [PubMed] [Google Scholar]
- 142.Robin AM, Zhang ZG, Wang L, et al. Stromal cell-derived factor 1alpha mediates neural progenitor cell motility after focal cerebral ischemia. J Cereb Blood Flow Metab. 2006;26:125–134. doi: 10.1038/sj.jcbfm.9600172. [DOI] [PubMed] [Google Scholar]