Multimodal actions of neural stem cells in a mouse model of als: A meta-analysis

Science Translational Medicine

Volumn 4, Issue 165, 2012, Pages

  Teng, Yang D ^a,b,c   Benn, Susanna C ^c   Kalkanis, Steven N ^a,c   Shefner, Jeremy M ^d   Onario, Renna C ^a,b,c   Cheng, Bin ^e   Lachyankar, Mahesh B ^c   Marconi, Michael ^c   Li, Jianxue ^c   Yu, Dou ^a,b   Han, Inbo ^a,b   Maragakis, Nicholas J ^f   Lládo, Jeronia ^f   Erkmen, Kadir ^a,c   Redmond, D Eugene ^g   Sidman, Richard L ^a,c   Przedborski, Serge ^h   Rothstein, Jeffrey D ^f   Brown, Robert H ^c,i   Snyder, Evan Y ^a,c,j  

^a and Red Sox Foundation and Massachusetts General Hospital Home Base Program   (United States)

^b VETERANS AFFAIRS MEDICAL CENTER   (United States)

^c HARVARD MEDICAL SCHOOL   (United States)

^d SUNY UPSTATE MEDICAL UNIVERSITY   (United States)

^e Columbia University ^*  (United States)

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

^g YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^h NEUROLOGICAL INSTITUTE   (United States)

ⁱ UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL   (United States)

^j BURNHAM INSTITUTE   (United States)

more..

Author keywords

[No Author keywords available]

Indexed keywords

BRAIN DERIVED NEUROTROPHIC FACTOR; COPPER ZINC SUPEROXIDE DISMUTASE; GLIAL CELL LINE DERIVED NEUROTROPHIC FACTOR; NESTIN;

AMYOTROPHIC LATERAL SCLEROSIS; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; ASTROCYTOSIS; CONTROLLED STUDY; FETUS; GENE EXPRESSION; HINDLIMB; HUMAN; HUMAN CELL; LUMBAR SPINAL CORD; MOTONEURON; MOTOR PERFORMANCE; MOUSE; NERVE CELL DIFFERENTIATION; NERVE DEGENERATION; NERVOUS SYSTEM INFLAMMATION; NEURAL STEM CELL TRANSPLANTATION; NEUROMUSCULAR FUNCTION; NEUROPROTECTION; NONHUMAN; PLURIPOTENT STEM CELL; PRIORITY JOURNAL;

EID: 84871497430     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.3004579     Document Type: Article

References (112)

1. L. P. Rowland, N. A. Schneider, Amyotrophic lateral sclerosis. N. Engl. J. Med. 344, 1688-1700 (2001).
2. H. Ilieva, M. Polymenidou, D. W. Cleveland, Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J. Cell Biol. 187, 761-772 (2009).
3. J. D. Rothstein, Current hypotheses for the underlying biology of amyotrophic lateral sclerosis. Ann. Neurol. 65 (Suppl. 1), S3-S9 (2009).
4. M. E. Gurney, H. Pu, A. Y. Chiu, M. C. Dal Canto, C. Y. Polchow, D. D. Alexander, J. Caliendo, A. Hentati, Y. W. Kwon, H. X. Deng, W. Chen, P. Zhai, R. L. Sufit, T. Siddique, Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264, 1772-1775 (1994).
5. M. Li, V. O. Ona, C. Guégan, M. Chen, V. Jackson-Lewis, L. J. Andrews, A. J. Olszewski, P. E. Stieg, J. P. Lee, S. Przedborski, R. M. Friedlander, Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model. Science 288, 335-339 (2000).
6. D. A. Bosco, G. Morfini, N. M. Karabacak, Y. Song, F. Gros-Louis, P. Pasinelli, H. Goolsby, B. A. Fontaine, N. Lemay, D. McKenna-Yasek, M. P. Frosch, J. N. Agar, J. P. Julien, S. T. Brady, R. H. Brown Jr., Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS. Nat. Neurosci. 13, 1396-1403 (2010).
7. D. R. Rosen, T. Siddique, D. Patterson, D. A. Figlewicz, P. Sapp, A. Hentati, D. Donaldson, J. Goto, J. P. O'Regan, H. X. Deng, Z. Rahmani, A. Krizus, D. McKenna-Yasek, A. Cayabyab, S. M. Gaston, R. Berger, R. E. Tanzi, J. J. Halperin, B. Herzfeldt, R. Van den Bergh, W. Y. Hung, T. Bird, G. Deng, D. W. Mulder, C. Smyth, N. G. Laing, E. Soriano, M. A. Pericak-Vance, J.Haines, G. A. Rouleau, J. S. Gusella, H. R. Horvitz, R. H. Brown Jr., Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362, 59-62 (1993).
8. P. C. Wong, C. A. Pardo, D. R. Borchelt, M. K. Lee, N. G. Copeland, N. A. Jenkins, S. S. Sisodia, D. W. Cleveland, D. L. Price, An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron 14, 1105-1116 (1995).
9. P. Pasinelli, M. K. Houseweart, R. H. Brown Jr., D. W. Cleveland, Caspase-1 and -3 are sequentially activated in motor neuron death in Cu,Zn superoxide dismutase-mediated familial amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. U.S.A. 97, 13901-13906 (2000).
10. M. Li, V.O.Ona, C. Guégan, M. Chen, V. Jackson-Lewis, L. J. Andrews, A. J. Olszewski, P. E. Stieg, J. P. Lee, S. Przedborski, R. M. Friedlander, Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model. Science 288, 335-339 (2000).
11. C. Guégan, S. Przedborski, Programmed cell death in amyotrophic lateral sclerosis. J. Clin. Invest. 111, 153-161 (2003).
12. M. M. Lino, C. Schneider, P. Caroni, Accumulation of SOD1 mutants in postnatal motoneurons does not cause motoneuron pathology or motoneuron disease. J. Neurosci. 22, 4825-4832 (2002).
13. A. Pramatarova, J. Laganière, J. Roussel, K. Brisebois, G. A. Rouleau, Neuron-specific expression of mutant superoxide dismutase 1 in transgenic mice does not lead to motor impairment. J. Neurosci. 21, 3369-3374 (2001).
14. Y. H. Gong, A. S. Parsadanian, A. Andreeva, W. D. Snider, J. L. Elliott, Restricted expression of G86R Cu/Zn superoxide dismutase in astrocytes results in astrocytosis but does not cause motoneuron degeneration. J. Neurosci. 20, 660-665 (2000).
15. M. Nagai, D. B. Re, T. Nagata, A. Chalazonitis, T. M. Jessell, H. Wichterle, S. Przedborski, Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat. Neurosci. 10, 615-622 (2007).
16. F. P. Di Giorgio, M. A. Carrasco, M. C. Siao, T. Maniatis, K. Eggan, Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nat. Neurosci. 10, 608-614 (2007).
17. A. G. Reaume, J. L. Elliott, E. K. Hoffman, N. W. Kowall, R. J. Ferrante, D. F. Siwek, H. M. Wilcox, D. G. Flood, M. F. Beal, R. H. Brown Jr., R. W. Scott, W. D. Snider, Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. Nat. Genet. 13, 43-47 (1996).
18. D. S. Howland, J. Liu, Y. She, B. Goad, N. J. Maragakis, B. Kim, J. Erickson, J. Kulik, L. DeVito, G. Psaltis, L. J. DeGennaro, D. W. Cleveland, J. D. Rothstein, Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proc. Natl. Acad. Sci. U.S.A. 99, 1604-1609 (2002).
19. A. M. Clement, M. D. Nguyen, E. A. Roberts, M. L. Garcia, S. Boillée, M. Rule, A. P. McMahon, W. Doucette, D. Siwek, R. J. Ferrante, R. H. Brown Jr., J. P. Julien, L. S. Goldstein, D. W. Cleveland, Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 302, 113-117 (2003).
20. K. Yamanaka, S. J. Chun, S. Boillee, N. Fujimori-Tonou, H. Yamashita, D. H. Gutmann, R. Takahashi, H. Misawa, D. W. Cleveland, Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat. Neurosci. 11, 251-253 (2008).
21. K. Yamanaka, S. Boillee, E. A. Roberts, M. L. Garcia, M. McAlonis-Downes, O. R. Mikse, D. W. Cleveland, L. S. Goldstein, Mutant SOD1 in cell types other than motor neurons and oligodendrocytes accelerates onset of disease in ALS mice. Proc. Natl. Acad. Sci. U.S.A. 105, 7594-7599 (2008).
22. J. S. Beckman, M. Carson, C. D. Smith, W. H. Koppenol, ALS, SOD and peroxynitrite. Nature 364, 584 (1993).
23. D. Trotti, M. Aoki, P. Pasinelli, U. V. Berger, N. C. Danbolt, R. H. Brown Jr., M. A. Hediger, Amyotrophic lateral sclerosis-linked glutamate transporter mutant has impaired glutamate clearance capacity. J. Biol. Chem. 276, 576-582 (2001).
24. J. A. Johnston, M. J. Dalton, M. E. Gurney, R. R. Kopito, Formation of high molecular weight complexes of mutant Cu,Zn-superoxide dismutase in a mouse model for familial amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. U.S.A. 97, 12571-12576 (2000).
25. J. P. Julien, Amyotrophic lateral sclerosis. unfolding the toxicity of the misfolded. Cell 104, 581-591 (2001).
26. L. I. Bruijn,M. W. Becher, M. K. Lee, K. L. Anderson, N. A. Jenkins, N. G. Copeland, S. S. Sisodia, J. D. Rothstein, D. R. Borchelt, D. L. Price, D. W. Cleveland, ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 18, 327-338 (1997).
27. C. M. Karch, M. Prudencio, D. D. Winkler, P. J. Hart, D. R. Borchelt, Role of mutant SOD1 disulfide oxidation and aggregation in the pathogenesis of familial ALS. Proc. Natl. Acad. Sci. U.S.A. 106, 7774-7779 (2009).
28. J. D. Atkin, M. A. Farg, B. J. Turner, D. Tomas, J. A. Lysaght, J. Nunan, A. Rembach, P. Nagley, P. M. Beart, S. S. Cheema, M. K. Horne, Induction of the unfolded protein response in familial amyotrophic lateral sclerosis and association of protein-disulfide isomerase with superoxide dismutase 1. J. Biol. Chem. 281, 30152-30165 (2006).
29. C. Cheroni, M. Marino, M. Tortarolo, P. Veglianese, S. De Biasi, E. Fontana, L. V. Zuccarello, C. J. Maynard, N. P. Dantuma, C. Bendotti, Functional alterations of the ubiquitin-proteasome system in motor neurons of a mouse model of familial amyotrophic lateral sclerosis. Hum. Mol. Genet. 18, 82-96 (2009).
30. S. C. Ling, C. P.Albuquerque, J. S. Han, C. Lagier-Tourenne, S. Tokunaga,H. Zhou, D. W. Cleveland, ALS-associated mutations in TDP-43 increase its stability and promote TDP-43 complexes with FUS/TLS. Proc. Natl. Acad. Sci. U.S.A. 107, 13318-13323 (2010).
31. T. Yamazaki, S. Chen, Y. Yu, B. Yan, T. C. Haertlein, M. A. Carrasco, J. C. Tapia, B. Zhai, R. Das, M. Lalancette-Hebert, A. Sharma, S. Chandran, G. Sullivan, A. L. Nishimura, C. E. Shaw, S. P. Gygi, N. A. Shneider, T. Maniatis, R. Reed, FUS-SMN protein interactions link the motor neuron diseases ALS and SMA. Cell Rep. 2, 799-806 (2012).
32. A. A. Filipchuk, J. Durand, Postnatal dendritic development in lumbar motoneurons in mutant superoxide dismutase 1 mouse model of amyotrophic lateral sclerosis. Neuroscience 209, 144-154 (2012).
33. G93A in astrocytes induces functional deficits in motoneuron mitochondria. J. Neurochem. 107, 1271-1283 (2008).
34. A. Israelson, N. Arbel, S. Da Cruz, H. Ilieva, K. Yamanaka, V. Shoshan-Barmatz, D. W. Cleveland, Misfolded mutant SOD1 directly inhibits VDAC1 conductance in a mouse model of inherited ALS. Neuron 67, 575-587 (2010).
35. D. Papadimitriou, V. Le Verche, A. Jacquier, B. Ikiz, S. Przedborski, D. B. Re, Inflammation in ALS and SMA: Sorting out the good from the evil. Neurobiol. Dis. 37, 493-502 (2010).
36. E. D. Hall, J. A. Oostveen, M. E. Gurney, Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS. Glia 23, 249-256 (1998).
37. S. Boillée, K. Yamanaka, C. S. Lobsiger, N. G. Copeland, N. A. Jenkins, G. Kassiotis, G. Kollias, D. W. Cleveland, Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312, 1389-1392 (2006).
38. F. Meissner, K. Molawi, A. Zychlinsky, Mutant superoxide dismutase 1-induced IL-1b accelerates ALS pathogenesis. Proc. Natl. Acad. Sci. U.S.A. 107, 13046-13050 (2010).
39. D. R. Beers, J. S.Henkel, Q. Xiao,W. Zhao, J.Wang, A. A. Yen, L. Siklos, S. R. McKercher, S. H. Appel, Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. U.S.A. 103, 16021-16026 (2006).
40. D. R. Beers, J. S. Henkel, W. Zhao, J. Wang, S. H. Appel, CD4+ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS. Proc. Natl. Acad. Sci. U.S.A. 105, 15558-15563 (2008).
41. T. Kawamata, H. Akiyama, T. Yamada, P. L. McGeer, Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue. Am. J. Pathol. 140, 691 -707 (1992).
42. R. G. Miller, J. D. Mitchell, M. Lyon, D. H. Moore, Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst. Rev. 3, CD001447 (2012).
43. M. K. Olsen, S. L. Roberds, B. R. Ellerbrock, T. J. Fleck, D. K. McKinley, M. E. Gurney, Disease mechanisms revealed by transcription profiling in SOD1-G93A transgenic mouse spinal cord. Ann. Neurol. 50, 730-740 (2001).
44. S. Przedborski, H. Mitsumoto, L. P. Rowland, Recent advances in amyotrophic lateral sclerosis research. Curr. Neurol. Neurosci. Rep. 3, 70-77 (2003).
45. B. K. Kaspar, J. Lladó, N. Sherkat, J. D. Rothstein, F. H. Gage, Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model. Science 301, 839-842 (2003).
46. J. C. Dodge, A. M. Haidet, W. Yang, M. A. Passini, M. Hester, J. Clarke, E. M. Roskelley, C. M. Treleaven, L. Rizo, H. Martin, S. H. Kim, R. Kaspar, T. V. Taksir, D. A. Griffiths, S. H. Cheng, L. S. Shihabuddin, B. K. Kaspar, Delivery of AAV-IGF-1 to the CNS extends survival in ALS mice through modification of aberrant glial cell activity. Mol. Ther. 16, 1056-1064 (2008).
47. K. Poesen, D. Lambrechts, P. Van Damme, J. Dhondt, F. Bender, N. Frank, E. Bogaert, B. Claes, L. Heylen, A. Verheyen, K. Raes, M. Tjwa, U. Eriksson, M. Shibuya, R. Nuydens, L. Van Den Bosch, T. Meert, R. D'Hooge, M. Sendtner, W. Robberecht, P. J. Carmeliet, Novel role for vascular endothelial growth factor (VEGF) receptor-1 and its ligand VEGF-B in motor neuron degeneration. J. Neurosci. 28, 10451-10459 (2008).
48. J. D. Rothstein, S. Patel, M. R. Regan, C. Haenggeli, Y. H. Huang, D. E. Bergles, L. Jin, M. Dykes Hoberg, S. Vidensky, D. S. Chung, S. V. Toan, L. I. Bruijn, Z. Z. Su, P. Gupta, P. B. Fisher, β-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433, 73-77 (2005).
49. A. H. Williams, G. Valdez, V. Moresi, X. Qi, J. McAnally, J. L. Elliott, R. Bassel-Duby, J. R. Sanes, E. N. Olson, MicroRNA-206 delays ALS progression and promotes regeneration of neuromuscular synapses in mice. Science 326, 1549-1554 (2009).
50. A. C. Lepore, B. Rauck, C. Dejea, A. C. Pardo, M. S. Rao, J. D. Rothstein, N. J. Maragakis, Focal transplantation-based astrocyte replacement is neuroprotective in a model of motor neuron disease. Nat. Neurosci. 11, 1294-1301 (2008).
51. S. Ohnishi, H. Ito, Y. Suzuki, Y. Adachi, R. Wate, J. Zhang, S. Nakano, H. Kusaka, S. Ikehara, Intra-bone marrow-bone marrow transplantation slows disease progression and prolongs survival in G93A mutant SOD1 transgenic mice, an animal model mouse for amyotrophic lateral sclerosis. Brain Res. 1296, 216-224 (2009).
52. S. Garbuzova-Davis, A. E. Willing, M. Milliken, S. Saporta, T. Zigova, D. W. Cahill, P. R. Sanberg, Positive effect of transplantation of hNT neurons (NTera 2/D1 cell-line) in a model of familial amyotrophic lateral sclerosis. Exp. Neurol. 174, 169-180 (2002).
53. Y. D. Teng, E. B. Lavik, X. Qu, K. I. Park, J. Ourednik, D. Zurakowski, R. Langer, E. Y. Snyder, Functional recovery following traumatic spinal cord injury mediated by a unique polymer scaffold seeded with neural stem cells. Proc. Natl. Acad. Sci. U.S.A. 99, 3024-3029 (2002).
54. J. P. Lee, M. Jeyakumar, R. Gonzalez, H. Takahashi, P. J. Lee, R. C. Baek, D. Clark, H. Rose, G. Fu, J. Clarke, S. McKercher, J. Meerloo, F. J. Muller, K. I. Park, T. D. Butters, R. A. Dwek, P. Schwartz, G. Tong, D. Wenger, S. A. Lipton, T. N. Seyfried, F. M. Platt, E. Y. Snyder, Stem cells act through multiple mechanisms to benefit mice with neurodegenerative metabolic disease. Nat. Med. 13, 439-447 (2007).
55. J. Ourednik, V. Ourednik, W. P. Lynch, M. Schachner, E. Y. Snyder, Neural stem cells display an inherent mechanism for rescuing dysfunctional neurons. Nat. Biotechnol. 20, 1103-1110 (2002).
56. D. E. Redmond Jr., K. B. Bjugstad, Y. D. Teng, V. Ourednik, J. Ourednik, D. R. Wakeman, X. H. Parsons, R. Gonzalez, B. C. Blanchard, S. U. Kim, Z. Gu, S. A. Lipton, E. A. Markakis, R. H. Roth, J. D. Elsworth, J. R. Sladek Jr., R. L. Sidman, E. Y. Snyder, 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. 104, 12175-12180 (2007).
57. J. Jäderstad, L. M. Jäderstad, J. Li, S. Chintawar, C. Salto, M. Pandolfo, V. Ourednik, Y. D. Teng, R. L. Sidman, E. Arenas, E. Y. Snyder, E. Herlenius, Communication via gap junctions underlies early functional and beneficial interactions between grafted neural stem cells and the host. Proc. Natl. Acad. Sci. U.S.A. 107, 5184-5189 (2010).
58. J. Li, J. Imitola, E. Y. Snyder, R. L. Sidman, Neural stem cells rescue nervous Purkinje neurons by restoring molecular homeostasis of tissue plasminogen activator and downstreamtargets. J. Neurosci. 26, 7839-7848 (2006).
59. K. I. Park, M. A. Hack, J. Ourednik, B. Yandava, J. D. Flax, P. E. Stieg, S. Gullans, F. E. Jensen, R. L. Sidman, V. Ourednik, E. Y. Snyder, Acute injury directs the migration, proliferation, and differentiation of solid organ stem cells: Evidence from the effect of hypoxia-ischemia in the CNS on clonal "reporter" neural stem cells. Exp. Neurol. 199, 156-178 (2006).
60. E. Y. Snyder, C. Yoon, J. D. Flax, J. D. Macklis, Multipotent neural precursors can differentiate toward replacement of neurons undergoing targeted apoptotic degeneration in adult mouse neocortex. Proc. Natl. Acad. Sci. U.S.A. 94, 11663-11668 (1997).
61. S. S. Magavi, B. R. Leavitt, J. D. Macklis, Induction of neurogenesis in the neocortex of adult mice. Nature 405, 951-955 (2000).
62. S. R. Cho, A. Benraiss, E. Chmielnicki, A. Samdani, A. Economides, S. A. Goldman, Induction of neostriatal neurogenesis slows disease progression in a transgenic murine model of Huntington disease. J. Clin. Invest. 117, 2889- 2902 (2007).
63. Y. D. Teng, D. Yu, A. E. Ropper, J. Li, S. Kabatas, D. R. Wakeman, J. Wang, M. P. Sullivan, D. E. Redmond Jr., R. Langer, E. Y. Snyder, R. L. Sidman, Functionalmultipotency of stem cells: A conceptual review of neurotrophic factor-based evidence and its role in translational research. Curr. Neuropharmacol. 9, 574-585 (2011).
64. K. I. Park, Y. D. Teng, E. Y. Snyder, The injured brain interacts reciprocally with neural stem cells supported by scaffolds to reconstitute lost tissue. Nat. Biotechnol. 20, 1111 -1117 (2002).
65. M. Jeyakumar, J. P. Lee, N. R. Sibson, J. P. Lowe, D. J. Stuckey, K. Tester, G. Fu, R. Newlin, D. A. Smith, E. Y. Snyder, F. M. Platt, Neural stem cell transplantation benefits a monogenic neurometabolic disorder during the symptomatic phase of disease. Stem Cells 27, 2362-2370 (2009).
66. D. M. Basso, M. S. Beattie, J. C. Bresnahan, A sensitive and reliable locomotor rating scale for open field testing in rats. J. Neurotrauma 12, 1-21 (1995).
67. C. M. Rosario, B. D. Yandava, B. Kosaras, D. Zurakowski, R. L. Sidman, E. Y. Snyder, 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 124, 4213-4224 (1997).
68. J. Imitola, K. Raddassi, K. I. Park, F. J. Mueller, M. Nieto, Y. D. Teng, D. Frenkel, J. Li, R. L. Sidman, C. A. Walsh, E. Y. Snyder, S. J. Khoury, Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1α/CXC chemokine receptor 4 pathway. Proc. Natl. Acad. Sci. U.S.A. 101, 18117-18122 (2004).
69. P. Lu, L. L. Jones, E. Y. Snyder, M. H. Tuszynski, Neural stem cells constitutively secrete neurotrophic factors and promote extensive host axonal growth after spinal cord injury. Exp. Neurol. 181, 115-129 (2003).
70. J. Yan, A. M. Welsh, S. H. Bora, E. Y. Snyder, V. E. Koliatsos, Differentiation and tropic/trophic effects of exogenous neural precursors in the adult spinal cord. J. Comp. Neurol. 480, 101-114 (2004).
71. K. S. Kim, H. J. Lee, H. S. Jeong, J. Li, Y. D. Teng, R. L. Sidman, E. Y. Snyder, S. U. Kim, Self-renewal induced efficiently, safely, and effective therapeutically with one regulatable gene in a human somatic progenitor cell. Proc. Natl. Acad. Sci. U.S.A. 108, 4876-4881 (2011).
72. J. D. Flax, S. Aurora, C. Yang, C. Simonin, A. M. Wills, L. L. Billinghurst, M. Jendoubi, R. L. Sidman, J. H. Wolfe, S. U. Kim, E. Y. Snyder, Engraftable human neural stem cells respond to developmental cues, replace neurons, and express foreign genes. Nat. Biotechnol. 16, 1033-1039 (1998).
73. A. Blesch, M. H. Tuszynski, GDNF gene delivery to injured adult CNS motor neurons promotes axonal growth, expression of the trophic neuropeptide CGRP, and cellular protection. J. Comp. Neurol. 436, 399-410 (2001).
74. P. Akerud, J. M. Canals, E. Y. Snyder, E. Arenas, Neuroprotection through delivery of glial cell line-derived neurotrophic factor by neural stem cells in a mouse model of Parkinson's disease. J. Neurosci. 21, 8108 -8118 (2001).
75. Y. D. Teng, I. Mocchetti, A. M. Taveira-DaSilva, R. A. Gillis, J. R. Wrathall, Basic fibroblast growth factor increases long-term survival of spinal motor neurons and improves respiratory function after experimental spinal cord injury. J. Neurosci. 19, 7037- 7047 (1999).
76. J. Lladó, C. Haenggeli, N. J. Maragakis, E. Y. Snyder, J. D. Rothstein, Neural stem cells protect against glutamate-induced excitotoxicity and promote survival of injured motor neurons through the secretion of neurotrophic factors. Mol. Cell. Neurosci. 27, 322-331 (2004).
77. J. Lladó, C. Haenggeli, A. Pardo, V. Wong, L. Benson, C. Coccia, J. D. Rothstein, J. M. Shefner, N. J. Maragakis, Degeneration of respiratory motor neurons in the SOD1 G93A transgenic rat model of ALS. Neurobiol. Dis. 21, 110-118 (2006).
78. J. M. Shefner, Motor unit number estimation in human neurological diseases and animal models. Clin. Neurophysiol. 112, 955-964 (2001).
79. M. E. Alexianu, M. Kozovska, S. H. Appel, Immune reactivity in a mouse model of familial ALS correlates with disease progression. Neurology 57, 1282-1289 (2001).
80. L. Wang, D. H. Gutmann, R. P. Roos, Astrocyte loss of mutant SOD1 delays ALS disease onset and progression in G85R transgenic mice. Hum. Mol. Genet. 20, 286-293 (2011).
81. L. S. Shihabuddin, P. J. Horner, J. Ray, F. H. Gage, Adult spinal cord stem cells generate neurons after transplantation in the adult dentate gyrus. J. Neurosci. 20, 8727-8735 (2000).
82. W. Krityakiarana, A. Espinosa-Jeffrey, C. A. Ghiani, P. M. Zhao, N. Topaldjikian, F. Gomez-Pinilla, M. Yamaguchi, N. Kotchabhakdi, J. de Vellis, Voluntary exercise increases oligodendrogenesis in spinal cord. Int. J. Neurosci. 120, 280-290 (2010).
83. G93A ALS mouse. Exp. Neurol. 227, 287- 295 (2011).
84. A. Wilkins, H. Majed, R. Layfield, A. Compston, S. Chandran, Oligodendrocytes promote neuronal survival and axonal length by distinct intracellular mechanisms: A novel role for oligodendrocyte-derived glial cell line-derived neurotrophic factor. J. Neurosci. 23, 4967-4974 (2003).
85. Y. Lee, B. M. Morrison, Y. Li, S. Lengacher, M. H. Farah, P. N. Hoffman, Y. Liu, A. Tsingalia, L. Jin, P. W. Zhang, L. Pellerin, P. J. Magistretti, J. D. Rothstein, Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature 487, 443-448 (2012).
86. J. D. Rothstein, L. Jin, M. Dykes-Hoberg, R. W. Kuncl, Chronic inhibition of glutamate uptake produces a model of slow neurotoxicity. Proc. Natl. Acad. Sci. U.S.A. 90, 6591-6595 (1993).
87. M. A. Parker, J. K. Anderson, D. A. Corliss, V. E. Abraria, R. L. Sidman, K. I. Park, Y. D. Teng, D. A. Cotanche, E. Y. Snyder, Expression profile of an operationally-defined neural stem cell clone. Exp. Neurol. 194, 320-332 (2005).
88. L. Wang, J. Shi, F. W. van Ginkel, L. Lan, G. Niemeyer, D. R. Martin, E. Y. Snyder, N. R. Cox, Neural stem/progenitor cells modulate immune responses by suppressing T lymphocytes with nitric oxide and prostaglandin E2. Exp. Neurol. 216, 177-183 (2009).
89. R. M. Taylor, J. P. Lee, J. J. Palacino, K. A. Bower, J. Li, M. T. Vanier, D. A. Wenger, R. L. Sidman, E. Y. Snyder, Intrinsic resistance of neural stem cells to toxic metabolites may make them well suited for cell non-autonomous disorders: Evidence from a mouse model of Krabbe leukodystrophy. J. Neurochem. 97, 1585-1599 (2006).
90. D. R. Wakeman, M. R. Hofmann, D. E. Redmond Jr., Y. D. Teng, E. Y. Snyder, Long-term multilayer adherent network (MAN) expansion, maintenance, and characterization, chemical and genetic manipulation, and transplantation of human fetal forebrain neural stem cells. Curr. Protoc. Stem Cell Biol. Chapter 2, Unit2D.3 (2009).
91. J. Wagner, P. Akerud, D. Castro, P. C. Holm, E. Y. Snyder, T. Perlmann, E. Arenas, Induction of a midbrain dopaminergic phenotype in Nurr1-overexpressing neural stem cells by type 1 astrocytes. Nat. Biotechnol. 17, 653-659 (1999).
92. O. Nicole, C. Ali, F. Docagne, L. Plawinski, E. T. MacKenzie, D. Vivien, A. Buisson, Neuroprotection mediated by glial cell line-derived neurotrophic factor: Involvement of a reduction of NMDA-induced calcium influx by the mitogen-activated protein kinase pathway. J. Neurosci. 21, 3024-3033 (2001).
93. 2+ channels and transmitter release. Neuron 32, 99-112 (2001).
94. Y. Lee, B.M.Morrison, Y. Li, S. Lengacher,M.H. Farah, P.N. Hoffman, Y. Liu, A. Tsingalia, L. Jin, P. W. Zhang, L. Pellerin, P. J. Magistretti, J. D. Rothstein, Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature 487, 443-448 (2012).
95. B. D. Yandava, L. L. Billinghurst, E. Y. Snyder, "Global" cell replacement is feasible via neural stem cell transplantation: Evidence from the dysmyelinated shiverer mouse brain. Proc. Natl. Acad. Sci. U.S.A. 96, 7029-7034 (1999).
96. E. Y. Snyder, R. M. Taylor, J. H. Wolfe, Neural progenitor cell engraftment corrects lysosomal storage throughout the MPS VII mouse brain. Nature 374, 367-370 (1995).
97. P. Cartwright, C. McLean, A. Sheppard, D. Rivett, K. Jones, S. Dalton, LIF/STAT3 controls ES cell self-renewal and pluripotency by a Myc-dependent mechanism. Development 132, 885-896 (2005).
98. M. J. Murphy, A. Wilson, A. Trumpp, More than just proliferation: Myc function in stem cells. Trends Cell Biol. 15, 128-137 (2005).
99. P. S. Knoepfler, P. F. Cheng, R. N. Eisenman, N-myc is essential during neurogenesis for the rapid expansion of progenitor cell populations and the inhibition of neuronal differentiation. Genes Dev. 16, 2699-2712 (2002).
100. N. J. Maragakis, M. S. Rao, J. Llado, V. Wong, H. Xue, A. Pardo, J. Herring, D. Kerr, C. Coccia, J. D. Rothstein, Glial restricted precursors protect against chronic glutamate neurotoxicity of motor neurons in vitro. Glia 50, 145-159 (2005).
101. W. Light, A. E. Vernon, A. Lasorella, A. Iavarone, C. LaBonne, Xenopus Id3 is required downstream of Myc for the formation of multipotent neural crest progenitor cells. Development 132, 1831-1841 (2005).
102. E. Y. Snyder, D. L. Deitcher, C. Walsh, S. Arnold-Aldea, E. A. Hartwieg, C. L. Cepko, Multipotent neural cell lines can engraft and participate in development of mouse cerebellum. Cell 68, 33-51 (1992).
103. H. D. Lacorazza, J. D. Flax, E. Y. Snyder, M. Jendoubi, Expression of human β-hexosaminidase α-subunit gene (the gene defect of Tay-Sachs disease) in mouse brains upon engraftment of transduced progenitor cells. Nat. Med. 2, 424-429 (1996).
104. J. D. Rothstein, E. Y. Snyder, Reality and immortality - Neural stem cells for therapies. Nat. Biotechnol. 22, 283-285 (2004).
105. N. S. Roy, T. Nakano, H. M. Keyoung, M. Windrem, W. K. Rashbaum, M. L. Alonso, J. Kang, W. Peng, M. K. Carpenter, J. Lin, M. Nedergaard, S. A. Goldman, Telomerase immortalization of neuronally restricted progenitor cells derived from the human fetal spinal cord. Nat. Biotechnol. 22, 297-305 (2004).
106. V. Ourednik, J. Ourednik, K. I. Park, E. Y. Snyder, Neural stem cells - A versatile tool for cell replacement and gene therapy in the central nervous system. Clin. Genet. 56, 267-278 (1999).
107. V. Ourednik, J. Ourednik, J. D. Flax, W. M. Zawada, C. Hutt, C. Yang, K. I. Park, S. U. Kim, R. L. Sidman, C. R. Freed, E. Y. Snyder, Segregation of human neural stem cells in the developing primate forebrain. Science 293, 1820-1824 (2001).
108. R. E. Coggeshall, H. A. Lekan, Methods for determining numbers of cells and synapses: A case for more uniform standards of review. J. Comp. Neurol. 364, 6-15 (1996).
109. M. Abercrombie, Estimation of nuclear population from microtome sections. Anat. Rec. 94, 239 -247 (1946).
110. P. S. Knoepfler, Why myc? An unexpected ingredient in the stem cell cocktail. Cell Stem Cell 2, 18- 21 (2008).
111. P. S. Knoepfler, X. Y. Zhang, P. F. Cheng, P. R. Gafken, S. B. McMahon, R. N. Eisenman, Myc influences global chromatin structure. EMBO J. 25, 2723-2734 (2006).
112. K. S. Aboody, A. Brown, N. G. Rainov, K. A. Bower, S. Liu, W. Yang, J. E. Small, U. Herrlinger, V. Ourednik, P. M. Black, X. O. Breakefield, E. Y. Snyder, Neural stem cells display extensive tropism for pathology in adult brain: Evidence from intracranial gliomas. Proc. Natl. Acad. Sci. U.S.A. 97, 12846-12851 (2000).