Human induced pluripotent stem cells are a novel source of neural progenitor cells (iNPCs) that migrate and integrate in the rodent spinal cord

Journal of Comparative Neurology

Volumn 522, Issue 12, 2014, Pages 2707-2728

  Sareen, Dhruv ^a   Gowing, Geneviève ^a   Sahabian, Anais ^a   Staggenborg, Kevin ^a   Paradis, Renée ^a   Avalos, Pablo ^a   Latter, Jessica ^a   Ornelas, Loren ^a   Garcia, Leslie ^a   Svendsen, Clive N ^a  

^a CEDARS SINAI MEDICAL CENTER   (United States)

Author keywords

ALS; Astrocytes; Cell transplantation; Human iPS cells; Neural progenitor cells; Regenerative therapy

Indexed keywords

EPIDERMAL GROWTH FACTOR; FIBROBLAST GROWTH FACTOR 2; RETINOIC ACID; AQUAPORIN 4; KI 67 ANTIGEN; NERVE PROTEIN; TRANSCRIPTOME;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; CELL INTEGRATION; CELL MATURATION; CELL MIGRATION; CELL SURVIVAL; CELL TRANSFORMATION; CELLULAR PARAMETERS; CONTROLLED STUDY; CULTURE TECHNIQUE; EZ SPHERE; FETUS; HUMAN; HUMAN CELL; MACROGLIA; MALE; NERVE CELL DIFFERENTIATION; NERVE CELL GROWTH; NERVE REGENERATION; NEURAL STEM CELL; NEURAL STEM CELL TRANSPLANTATION; NONHUMAN; NUCLEOTIDE SEQUENCE; NUDE RAT; PHENOTYPE; PLURIPOTENT STEM CELL; RAT; SPINAL CORD; SUSPENSION CELL CULTURE; TRANSCRIPTOMICS; ANALYSIS OF VARIANCE; ANIMAL; ASTROCYTE; CELL DIFFERENTIATION; CELL MOTION; CYTOLOGY; METABOLISM; NERVE CELL; PHYSIOLOGY; SURGERY; TRANSPLANTATION;

ANALYSIS OF VARIANCE; ANIMALS; AQUAPORIN 4; ASTROCYTES; CELL DIFFERENTIATION; CELL MOVEMENT; HUMANS; INDUCED PLURIPOTENT STEM CELLS; KI-67 ANTIGEN; NERVE TISSUE PROTEINS; NEURAL STEM CELLS; NEURONS; RATS; RATS, NUDE; SPINAL CORD; TRANSCRIPTOME;

EID: 84911998212     PISSN: 00219967     EISSN: 10969861     Source Type: Journal    
DOI: 10.1002/cne.23578     Document Type: Article

References (102)

1. Andres RH, Horie N, Slikker W, Keren-Gill H, Zhan K, Sun G, Manley NC, Pereira MP, Sheikh LA, McMillan EL, Schaar BT, Svendsen CN, Bliss TM, Steinberg GK. 2011. Human neural stem cells enhance structural plasticity and axonal transport in the ischaemic brain. Brain 134:1777-1789.
2. Araki R, Uda M, Hoki Y, Sunayama M, Nakamura M, Ando S, Sugiura M, Ideno H, Shimada A, Nifuji A, Abe M. 2013. Negligible immunogenicity of terminally differentiated cells derived from induced pluripotent or embryonic stem cells. Nature 494:100-104.
3. Azienda Ospedaliera Santa Maria TI, Azienda Ospedaliero Universitaria Maggiore della Carita, Universitá di Padova I. 2012. Human neural stem cell transplantation in amyotrophic lateral sclerosis (ALS) (hNSCALS). ClinicalTrials.gov [Internet] Bethesda, MD: National Library of Medicine (US) 2000 [cited 2012 July 11] Available from: http://www. clinicaltrials.gov/ct2/show/NCT01640067 NLM Identifier:NCT01640067.
4. Baharvand H, Mehrjardi NZ, Hatami M, Kiani S, Rao M, Haghighi MM. 2007. Neural differentiation from human embryonic stem cells in a defined adherent culture condition. Int J Dev Biol 51:371-378.
5. Bain G, Kitchens D, Yao M, Huettner JE, Gottlieb DI. 1995. Embryonic stem cells express neuronal properties in vitro. Dev Biol 168:342-357.
6. Blum B, Benvenisty N. 2009. The tumorigenicity of diploid and aneuploid human pluripotent stem cells. Cell Cycle 8:3822-3830.
7. Bonnamain V, Neveu I, Naveilhan P. 2012. Neural stem/progenitor cells as a promising candidate for regenerative therapy of the central nervous system. Front Cell Neurosci 6:17.
8. Bonzo JA, Ferry CH, Matsubara T, Kim JH, Gonzalez FJ. 2012. Suppression of hepatocyte proliferation by hepatocyte nuclear factor 4alpha in adult mice. J Biol Chem 287:7345-7356.
9. Bushong EA, Martone ME, Ellisman MH. 2004. Maturation of astrocyte morphology and the establishment of astrocyte domains during postnatal hippocampal development. Int J Dev Neurosci 22:73-86.
10. Chetty S, Pagliuca FW, Honore C, Kweudjeu A, Rezania A, Melton DA. 2013. A simple tool to improve pluripotent stem cell differentiation. Nat Methods 10:553-556.
11. Conti L, Cattaneo E. 2010. Neural stem cell systems: physiological players or in vitro entities? Nat Rev Neurosci 11:176-187.
12. Cummings BJ, Uchida N, Tamaki SJ, Salazar DL, Hooshmand M, Summers R, Gage FH, Anderson AJ. 2005. Human neural stem cells differentiate and promote locomotor recovery in spinal cord-injured mice. Proc Natl Acad Sci U S A 102:14069-14074.
13. Daadi MM, Maag AL, Steinberg GK. 2008. Adherent selfrenewable human embryonic stem cell-derived neural stem cell line: functional engraftment in experimental stroke model. PLoS One 3:e1644.
14. Di Giorgio FP, Carrasco MA, Siao MC, Maniatis T, Eggan K. 2007. Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nat Neurosci 10:608-614.
15. Ebert AD, Beres AJ, Barber AE, Svendsen CN. 2008. Human neural progenitor cells over-expressing IGF-1 protect dopamine neurons and restore function in a rat model of Parkinson's disease. Exp Neurol 209:213-223.
16. Ebert AD, Shelley BC, Hurley AM, Onorati M, Castiglioni V, Patitucci TN, Svendsen SP, Mattis VB, McGivern JV, Schwab AJ, Sareen D, Kim HW, Cattaneo E, Svendsen CN. 2013. EZ spheres: a stable and expandable culture system for the generation of pre-rosette multipotent stem cells from human ESCs and iPSCs. Stem Cell Res 10:417-427.
17. Fraichard A, Chassande O, Bilbaut G, Dehay C, Savatier P, Samarut J. 1995. In vitro differentiation of embryonic stem cells into glial cells and functional neurons. J Cell Sci 108(Pt 10):3181-3188.
18. Ghosh Z, Huang M, Hu S, Wilson KD, Dey D, Wu JC. 2011. Dissecting the oncogenic and tumorigenic potential of differentiated human induced pluripotent stem cells and human embryonic stem cells. Cancer Res 71:5030-5039.
19. Glass JD, Boulis NM, Johe K, Rutkove SB, Federici T, Polak M, Kelly C, Feldman EL. 2012. Lumbar intraspinal injection of neural stem cells in patients with amyotrophic lateral sclerosis: results of a phase I trial in 12 patients. Stem Cells 30:1144-1151.
20. Gowing G, Svendsen CN. 2011. Stem cell transplantation for motor neuron disease: current approaches and future perspectives. Neurotherapeutics 8:591-606.
21. Gowing G, Shelley B, Staggenborg K, Hurley A, Avalos P, Victoroff J, Latter J, Garcia L, Svendsen CN. 2013. Glial cell line-derived neurotrophic factor-secreting human neural progenitors show long-term survival, maturation into astrocytes, and no tumor formation following transplantation into the spinal cord of immunocompromised rats. Neuroreport [Epub ahead of print].
22. Guan K, Chang H, Rolletschek A, Wobus AM. 2001. Embryonic stem cell-derived neurogenesis. Retinoic acid induction and lineage selection of neuronal cells. Cell Tissue Res 305:171-176.
23. Guzman R, Uchida N, Bliss TM, He D, Christopherson KK, Stellwagen D, Capela A, Greve J, Malenka RC, Moseley ME, Palmer TD, Steinberg GK. 2007. Long-term monitoring of transplanted human neural stem cells in developmental and pathological contexts with MRI. Proc Natl Acad Sci U S A 104:10211-10216.
24. Haidet-Phillips AM, Hester ME, Miranda CJ, Meyer K, Braun L, Frakes A, Song S, Likhite S, Murtha MJ, Foust KD, Rao M, Eagle A, Kammesheidt A, Christensen A, Mendell JR, Burghes AH, Kaspar BK. 2011. Astrocytes from familial and sporadic ALS patients are toxic to motor neurons. Nat Biotechnol 29:824-828.
25. Jiang P, Chen C, Wang R, Chechneva OV, Chung SH, Rao MS, Pleasure DE, Liu Y, Zhang Q, Deng W. 2013. hESCderived Olig21 progenitors generate a subtype of astroglia with protective effects against ischaemic brain injury. Nat Commun 4:2196.
26. Juopperi TA, Kim WR, Chiang CH, Yu H, Margolis RL, Ross CA, Ming GL, Song H. 2012. Astrocytes generated from patient induced pluripotent stem cells recapitulate features of Huntington's disease patient cells. Mol Brain 5:17.
27. Kaneko S, Yamanaka S. 2013. To be immunogenic, or not to be: that's the iPSC question. Cell Stem Cell 12:385-386.
28. Kawai H, Yamashita T, Ohta Y, Deguchi K, Nagotani S, Zhang X, Ikeda Y, Matsuura T, Abe K. 2010. Tridermal tumorigenesis of induced pluripotent stem cells transplanted in ischemic brain. J Cereb Blood Flow Metab 30:1487-1493.
29. Kelly S, Bliss TM, Shah AK, Sun GH, Ma M, Foo WC, Masel J, Yenari MA, Weissman IL, Uchida N, Palmer T, Steinberg GK. 2004. Transplanted human fetal neural stem cells survive, migrate, and differentiate in ischemic rat cerebral cortex. Proc Natl Acad Sci U S A 101:11839-11844.
30. Klein SM, Behrstock S, McHugh J, Hoffmann K, Wallace K, Suzuki M, Aebischer P, Svendsen CN. 2005. GDNF delivery using human neural progenitor cells in a rat model of ALS. Hum Gene Ther 16:509-521.
31. Kobayashi Y, Okada Y, Itakura G, Iwai H, Nishimura S, Yasuda A, Nori S, Hikishima K, Konomi T, Fujiyoshi K, Tsuji O, Toyama Y, Yamanaka S, Nakamura M, Okano H. 2012. Pre-evaluated safe human iPSC-derived neural stem cells promote functional recovery after spinal cord injury in common marmoset without tumorigenicity. PLoS One 7: e52787.
32. Koch P, Opitz T, Steinbeck JA, Ladewig J, Brustle O. 2009. 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 106:3225-3230.
33. Krencik R, Zhang SC. 2011. Directed differentiation of functional astroglial subtypes from human pluripotent stem cells. Nat Protoc 6:1710-1717.
34. Krencik R, Weick JP, Liu Y, Zhang ZJ, Zhang SC. 2011. Specification of transplantable astroglial subtypes from human pluripotent stem cells. Nat Biotechnol 29:528-534.
35. Kriegstein A, Alvarez-Buylla A. 2009. The glial nature of embryonic and adult neural stem cells. Annu Rev Neurosci 32:149-184.
36. 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. 2011. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease. Nature 480:547-551.
37. Lee MK, Tuttle JB, Rebhun LI, Cleveland DW, Frankfurter A. 1990. The expression and posttranslational modification of a neuron-specific beta-tubulin isotype during chick embryogenesis. Cell Motil Cytoskeleton 17:118-132.
38. Lee G, Ramirez CN, Kim H, Zeltner N, Liu B, Radu C, Bhinder B, Kim YJ, Choi IY, Mukherjee-Clavin B, Djaballah H, Studer L. 2012. Large-scale screening using familial dysautonomia induced pluripotent stem cells identifies compounds that rescue IKBKAP expression. Nat Biotechnol 30:1244-1248.
39. Lepore AC, Rauck B, Dejea C, Pardo AC, Rao MS, Rothstein JD, Maragakis NJ. 2008. Focal transplantation-based astrocyte replacement is neuroprotective in a model of motor neuron disease. Nat Neurosci 11:1294-1301.
40. Lepore AC, O'Donnell J, Kim AS, Williams T, Tuteja A, Rao MS, Kelley LL, Campanelli JT, Maragakis NJ. 2011. Human glial-restricted progenitor transplantation into cervical spinal cord of the SOD1 mouse model of ALS. PLoS One 6:e25968.
41. Li XJ, Du ZW, Zarnowska ED, Pankratz M, Hansen LO, Pearce RA, Zhang SC. 2005. Specification of motoneurons from human embryonic stem cells. Nat Biotechnol 23:215-221.
42. Liao CW, Fan CK, Kao TC, Ji DD, Su KE, Lin YH, Cho WL. 2008. Brain injury-associated biomarkers of TGF-beta1, S100B, GFAP, NF-L, tTG, AbetaPP, and tau were concomitantly enhanced and the UPS was impaired during acute brain injury caused by Toxocara canis in mice. BMC Infect Dis 8:84.
43. Liu P, Chen S, Li X, Qin L, Huang K, Wang L, Huang W, Li S, Jia B, Zhong M, Pan G, Cai J, Pei D. 2013. Low immunogenicity of neural progenitor cells differentiated from induced pluripotent stem cells derived from less immunogenic somatic cells. PLoS One 8:e69617.
44. Livak KJ, Schmittgen TD. 2001. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25:402-408.
45. Lobo MV, Alonso FJ, Redondo C, Lopez-Toledano MA, Caso E, Herranz AS, Paino CL, Reimers D, Bazan E. 2003. Cellular characterization of epidermal growth factor-expanded free-floating neurospheres. J Histochem Cytochem 51:89-103.
46. Luong MX, Auerbach J, Crook JM, Daheron L, Hei D, Lomax G, Loring JF, Ludwig T, Schlaeger TM, Smith KP, Stacey G, Xu RH, Zeng F. 2011. A call for standardized naming and reporting of human ESC and iPSC lines. Cell Stem Cell 8:357-359.
47. Mattis VB, Wakeman DR, Tom C, Dodiya HB, Yeung SY, Tran AH, Bernau K, Ornelas L, Sahabian A, Reidling J, Sareen D, Thompson LM, Kordower JH, Svendsen CN. 2014. Neonatal immune-tolerance in mice does not prevent xenograft rejection. Exp Neurol 254:90-98.
48. Messam CA, Hou J, Major EO. 2000. Coexpression of nestin in neural and glial cells in the developing human CNS defined by a human-specific anti-nestin antibody. Exp Neurol 161:585-596.
49. Miller GM, Gowing G, Svendsen S, Svendsen CN. 2014. The past, present and future of stem cell clinical trials for ALS. Exp Neurol (in press).
50. Muller FJ, Schuldt BM, Williams R, Mason D, Altun G, Papapetrou EP, Danner S, Goldmann JE, Herbst A, Schmidt NO, Aldenhoff JB, Laurent LC, Loring JF. 2011. A bioinformatic assay for pluripotency in human cells. Nat Methods 8:315-317.
51. Nagai M, Re DB, Nagata T, Chalazonitis A, Jessell TM, Wichterle H, Przedborski S. 2007. Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat Neurosci 10:615-622.
52. Neuralstem Inc., Emory University. 2011. Human spinal cord derived neural stem cell transplantation for the treatment of amyotrophic lateral sclerosis (ALS). Clinical-Trials.gov [Internet] Bethesda, MD: National Library of Medicine (US) 2000 [cited 2013 May 8] Available from: http://www.clinicaltrials.gov/ct2/show/NCT01348451 NLM Identifier: NCT01348451.
53. Nichols NL, Gowing G, Satriotomo I, Nashold LJ, Dale EA, Suzuki M, Avalos P, Mulcrone PL, McHugh J, Svendsen CN, Mitchell GS. 2013. Intermittent hypoxia and stem cell implants preserve breathing capacity in a rodent model of amyotrophic lateral sclerosis. Am J Respir Crit Care Med 187:535-542.
54. Novitch BG, Wichterle H, Jessell TM, Sockanathan S. 2003. A requirement for retinoic acid-mediated transcriptional activation in ventral neural patterning and motor neuron specification. Neuron 40:81-95.
55. Oberheim NA, Wang X, Goldman S, Nedergaard M. 2006. Astrocytic complexity distinguishes the human brain. Trends Neurosci 29:547-553.
56. Okano H, Nakamura M, Yoshida K, Okada Y, Tsuji O, Nori S, Ikeda E, Yamanaka S, Miura K. 2013. Steps toward safe cell therapy using induced pluripotent stem cells. Circ Res 112:523-533.
57. Okita K, Matsumura Y, Sato Y, Okada A, Morizane A, Okamoto S, Hong H, Nakagawa M, Tanabe K, Tezuka K, Shibata T, Kunisada T, Takahashi M, Takahashi J, Saji H, Yamanaka S. 2011a. A more efficient method to generate integration-free human iPS cells. Nat Methods 8:409-412.
58. Okita K, Nagata N, Yamanaka S. 2011b. Immunogenicity of induced pluripotent stem cells. Circ Res 109:720-721.
59. Ostenfeld T, Caldwell MA, Prowse KR, Linskens MH, Jauniaux E, Svendsen CN. 2000. Human neural precursor cells express low levels of telomerase in vitro and show diminishing cell proliferation with extensive axonal outgrowth following transplantation. Exp Neurol 164:215-226.
60. Pierani A, Brenner-Morton S, Chiang C, Jessell TM. 1999. A sonic hedgehog-independent, retinoid-activated pathway of neurogenesis in the ventral spinal cord. Cell 97:903-915.
61. Piltti KM, Salazar DL, Uchida N, Cummings BJ, Anderson AJ. 2013. Safety of epicenter versus intact parenchyma as a transplantation site for human neural stem cells for spinal cord injury therapy. Stem Cells Transl Med 2:204-216.
62. ReNeuron Limited. 2010. Pilot investigation of stem cells in stroke (PISCES). ClinicalTrials.gov [Internet] Bethesda, MD: National Library of Medicine (US) 2000 [cited 2013 March 27] Available from: http://www.clinicaltrials.gov/ct2/show/NCT01151124 NLM Identifier: NCT01151124.
63. Robberecht W, Philips T. 2013. The changing scene of amyotrophic lateral sclerosis. Nat Rev Neurosci 14:248-264.
64. Robinton DA, Daley GQ. 2012. The promise of induced pluripotent stem cells in research and therapy. Nature 481:295-305.
65. Rohwedel J, Guan K, Wobus AM. 1999. Induction of cellular differentiation by retinoic acid in vitro. Cells Tissues Organs 165:190-202.
66. Salazar DL, Uchida N, Hamers FP, Cummings BJ, Anderson AJ. 2010. Human neural stem cells differentiate and promote locomotor recovery in an early chronic spinal cord injury NOD-scid mouse model. PLoS One 5: e12272.
67. Sareen D, van Ginkel PR, Takach JC, Mohiuddin A, Darjatmoko SR, Albert DM, Polans AS. 2006. Mitochondria as the primary target of resveratrol-induced apoptosis in human retinoblastoma cells. Invest Ophthalmol Vis Sci 47:3708-3716.
68. Sareen D, McMillan E, Ebert AD, Shelley BC, Johnson JA, Meisner LF, Svendsen CN. 2009. Chromosome 7 and 19 trisomy in cultured human neural progenitor cells. PLoS One 4:e7630.
69. Sareen D, Ebert AD, Heins BM, McGivern JV, Ornelas L, Svendsen CN. 2012. Inhibition of apoptosis blocks human motor neuron cell death in a stem cell model of spinal muscular atrophy. PLoS One 7:e39113.
70. Sareen D, O'Rourke JG, Meera P, Muhammad AK, Grant S, Simpkinson M, Bell S, Carmona S, Ornelas L, Sahabian A, Gendron T, Petrucelli L, Baughn M, Ravits J, Harms MB, Rigo F, Bennett CF, Otis TS, Svendsen CN, Baloh RH. 2013. Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion. Sci Transl Med 5:208ra149.
71. Schmittgen TD, Livak KJ. 2008. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 3:1101-1108.
72. Smith SB, Brodjian S, Desai S, Sarthy V. 1997. Glial fibrillary acidic protein (GFAP) is synthesized in the early stages of the photoreceptor cell degeneration of the mivit/mivit (vitiligo) mouse. Exp Eye Res 64:645-650.
73. Sockanathan S, Jessell TM. 1998. Motor neuron-derived retinoid signaling specifies the subtype identity of spinal motor neurons. Cell 94:503-514.
74. StemCells I. 2006. Study of HuCNS-SC cells in patients with infantile or late infantile neuronal ceroid lipofuscinosis (NCL). ClinicalTrials.gov [Internet] Bethesda, MD: National Library of Medicine (US) 2000 [cited 2010 November 5] Available from: http://www.clinicaltrials.gov/ct2/show/NCT00337636 NLM Identifier: NCT00337636.
75. StemCells I. 2011. Long-term follow-up study of human stem cells transplanted in subjects with connatal Pelizaeus-Merzbacher disease (PMD). ClinicalTrials.gov [Internet] Bethesda, MD: National Library of Medicine (US) 2000-[cited 2012 November 7] Available from: http://www.clinicaltrials.gov/ct2/show/NCT01391637 NLM Identifier:NCT01391637.
76. StemCells I. 2012. Long-term follow-up of transplanted human central nervous system stem cells (HuCNS-SC) in spinal cord trauma subjects. ClinicalTrials.gov [Internet] Bethesda, MD: National Library of Medicine (US) 2000-[cited 2012 November] Available from: http://www.clinicaltrials.gov/ct2/show/NCT01725880 NLM Identifier: NCT01725880.
77. Strubing C, Ahnert-Hilger G, Shan J, Wiedenmann B, Hescheler J, Wobus AM. 1995. Differentiation of pluripotent embryonic stem cells into the neuronal lineage in vitro gives rise to mature inhibitory and excitatory neurons. Mech Dev 53:275-287.
78. Sun Y, Pollard S, Conti L, Toselli M, Biella G, Parkin G, Willatt L, Falk A, Cattaneo E, Smith A. 2008. Long-term tripotent differentiation capacity of human neural stem (NS) cells in adherent culture. Mol Cell Neurosci 38:245-258.
79. Suzuki M, Svendsen CN. 2008. Combining growth factor and stem cell therapy for amyotrophic lateral sclerosis. Trends Neurosci 31:192-198.
80. Suzuki M, McHugh J, Tork C, Shelley B, Klein SM, Aebischer P, Svendsen CN. 2007. GDNF secreting human neural progenitor cells protect dying motor neurons, but not their projection to muscle, in a rat model of familial ALS. PLoS One 2:e689.
81. Svendsen CN, Caldwell MA, Shen J, ter Borg MG, Rosser AE, Tyers P, Karmiol S, Dunnett SB. 1997. Long-term survival of human central nervous system progenitor cells transplanted into a rat model of Parkinson's disease. Exp Neurol 148:135-146.
82. Svendsen CN, ter Borg MG, Armstrong RJ, Rosser AE, Chandran S, Ostenfeld T, Caldwell MA. 1998. A new method for the rapid and long term growth of human neural precursor cells. J Neurosci Methods 85:141-152.
83. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S. 2007. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861-872.
84. 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. 2002. Engraftment of sorted/expanded human central nervous system stem cells from fetal brain. J Neurosci Res 69:976-986.
85. Taupin P. 2006. HuCNS-SC (StemCells). Curr Opin Mol Ther 8:156-163.
86. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM. 1998. Embryonic stem cell lines derived from human blastocysts. Science 282:1145-1147.
87. 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. 2012. Human neural stem cells induce functional myelination in mice with severe dysmyelination. Sci Transl Med 4:155ra136.
88. Wang S, Girman S, Lu B, Bischoff N, Holmes T, Shearer R, Wright LS, Svendsen CN, Gamm DM, Lund RD. 2008. Long-term vision rescue by human neural progenitors in a rat model of photoreceptor degeneration. Invest Ophthalmol Vis Sci 49:3201-3206.
89. Wichterle H, Lieberam I, Porter JA, Jessell TM. 2002. Directed differentiation of embryonic stem cells into motor neurons. Cell 110:385-397.
90. Windrem MS, Nunes MC, Rashbaum WK, Schwartz TH, Goodman RA, McKhann G, Roy NS, Goldman SA. 2004. Fetal and adult human oligodendrocyte progenitor cell isolates myelinate the congenitally dysmyelinated brain. Nat Med 10:93-97.
91. Wright LS, Li J, Caldwell MA, Wallace K, Johnson JA, Svendsen CN. 2003. Gene expression in human neural stem cells: effects of leukemia inhibitory factor. J Neurochem 86:179-195.
92. Wright LS, Prowse KR, Wallace K, Linskens MH, Svendsen CN. 2006. Human progenitor cells isolated from the developing cortex undergo decreased neurogenesis and eventual senescence following expansion in vitro. Exp Cell Res 312:2107-2120.
93. Yamanaka S. 2012. Induced pluripotent stem cells: past, present, and future. Cell Stem Cell 10:678-684.
94. Yamanaka K, Chun SJ, Boillee S, Fujimori-Tonou N, Yamashita H, Gutmann DH, Takahashi R, Misawa H, Cleveland DW. 2008. Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat Neurosci 11:251-253.
95. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA. 2007. Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917-1920.
96. Yu J, Hu K, Smuga-Otto K, Tian S, Stewart R, Slukvin II, Thomson JA. 2009. Human induced pluripotent stem cells free of vector and transgene sequences. Science 324:797-801.
97. Yuan T, Liao W, Feng NH, Lou YL, Niu X, Zhang AJ, Wang Y, Deng ZF. 2013. Human induced pluripotent stem cellderived neural stem cells survive, migrate, differentiate, and improve neurological function in a rat model of middle cerebral artery occlusion. Stem Cell Res Ther 4:73.
98. Zhang Y, Wang D, Chen M, Yang B, Zhang F, Cao K. 2011. Intramyocardial transplantation of undifferentiated rat induced pluripotent stem cells causes tumorigenesis in the heart. PLoS One 6:e19012.
99. Zhang G, Shang B, Yang P, Cao Z, Pan Y, Zhou Q. 2012. Induced pluripotent stem cell consensus genes: implication for the risk of tumorigenesis and cancers in induced pluripotent stem cell therapy. Stem Cells Dev 21:955-964.
100. Zhao T, Zhang ZN, Rong Z, Xu Y. 2011. Immunogenicity of induced pluripotent stem cells. Nature 474:212-215.
101. Zhou JM, Chu JX, Chen XJ. 2008. An improved protocol that induces human embryonic stem cells to differentiate into neural cells in vitro. Cell Biol Int 32:80-85.
102. Zhou J, Su P, Li D, Tsang S, Duan E, Wang F. 2010. High-efficiency induction of neural conversion in human ESCs and human induced pluripotent stem cells with a single chemical inhibitor of transforming growth factor beta superfamily receptors. Stem Cells 28:1741-1750.