1. National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; 2. Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
Many neurodegenerative disorders such as Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and others often occur as a result of progressive loss of structure or function of neurons. Recently, many groups were able to generate neural cells, either differentiated from induced pluripotent stem cells (iPSCs) or converted from somatic cells. Advances in converted neural cells have opened a new era to ease applications for modeling diseases and screening drugs. In addition, the converted neural cells also hold the promise for cell replacement therapy (Kikuchi et al., 2011; Krencik et al., 2011; Kriks et al., 2011; Nori et al., 2011; Rhee et al., 2011; Schwartz et al., 2012). Here we will mainly discuss most recent progress on using converted functional neural cells to treat neurological diseases and highlight potential clinical challenges and future perspectives.
Barrilleaux, B., and Knoepfler, P.S. (2011). Inducing iPSCs to escape the dish. Cell Stem Cell 9, 103-111 . doi: 10.1016/j.stem.2011.07.006
2
Berke, J.D., and Hyman, S.E. (2000). Addiction, dopamine, and the molecular mechanisms of memory. Neuron 25, 515-532 . doi: 10.1016/S0896-6273(00)81056-9
3
Bjorklund, L.M., Sanchez-Pernaute, R., Chung, S., Andersson, T., Chen, I.Y., McNaught, K.S., Brownell, A.L., Jenkins, B.G., Wahlestedt, C., Kim, K.S., . (2002). Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc Natl Acad Sci USA 99, 2344-2349 . doi: 10.1073/pnas.022438099
4
Boillee, S., Vande Velde, C., and Cleveland, D.W. (2006). ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron 52, 39-59 . doi: 10.1016/j.neuron.2006.09.018
5
Brennand, K.J., Simone, A., Jou, J., Gelboin-Burkhart, C., Tran, N., Sangar, S., Li, Y., Mu, Y., Chen, G., Yu, D., . (2011). Modelling schizophrenia using human induced pluripotent stem cells. Nature 473, 221-225 . doi: 10.1038/nature09915
6
Cai, J., Yang, M., Poremsky, E., Kidd, S., Schneider, J.S., and Iacovitti, L. (2010). Dopaminergic neurons derived from human induced pluripotent stem cells survive and integrate into 6-OHDA-lesioned rats. Stem Cells Dev 19, 1017-1023 . doi: 10.1089/scd.2009.0319
7
Caiazzo, M., Dell'Anno, M.T., Dvoretskova, E., Lazarevic, D., Taverna, S., Leo, D., Sotnikova, T.D., Menegon, A., Roncaglia, P., Colciago, G., . (2011). Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature 476, 224-227 . doi: 10.1038/nature10284
8
Chen, S.J., Chang, C.M., Tsai, S.K., Chang, Y.L., Chou, S.J., Huang, S.S., Tai, L.K., Chen, Y.C., Ku, H.H., Li, H.Y., . (2010). Functional improvement of focal cerebral ischemia injury by subdural transplantation of induced pluripotent stem cells with fibrin glue. Stem Cells Dev 19, 1757-1767 . doi: 10.1089/scd.2009.0452
9
Cleveland, D.W., and Rothstein, J.D. (2001). From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS. Nat Rev Neurosci 2, 806-819 . doi: 10.1038/35097565
10
Davis, H., Guo, X., Lambert, S., Stancescu, M., and Hickman, J.J. (2011). Small molecule induction of human umbilical stem cells into myelin basic protein positive oligodendrocytes in a defined three-dimensional environment. ACS Chemical Neuroscience 3, 31-39 . doi: 10.1021/cn200082q
11
Deleidi, M., Hargus, G., Hallett, P., Osborn, T., and Isacson, O. (2011). Development of histocompatible primate-induced pluripotent stem cells for neural transplantation. Stem Cells 29, 1052-1063 . doi: 10.1002/stem.662
12
Devine, M.J., Ryten, M., Vodicka, P., Thomson, A.J., Burdon, T., Houlden, H., Cavaleri, F., Nagano, M., Drummond, N.J., Taanman, J.W., . (2011). Parkinson's disease induced pluripotent stem cells with triplication of the alpha-synuclein locus. Nat Commun 2, 440. doi: 10.1038/ncomms1453
13
Dimos, J.T., Rodolfa, K.T., Niakan, K.K., Weisenthal, L.M., Mitsumoto, H., Chung, W., Croft, G.F., Saphier, G., Leibel, R., Goland, R., . (2008). Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321, 1218-1221 . doi: 10.1126/science.1158799
14
Dolmetsch, R., and Geschwind, D.H. (2011). The human brain in a dish: the promise of iPSC-derived neurons. Cell 145, 831-834 . doi: 10.1016/j.cell.2011.05.034
15
Donnan, G.A., Fisher, M., Macleod, M., and Davis, S.M. (2008). Stroke. Lancet 371, 1612-1623 . doi: 10.1016/S0140-6736(08)60694-7
Fujioka, T., Shimizu, N., Yoshino, K., Miyoshi, H., and Nakamura, Y. (2010). Establishment of induced pluripotent stem cells from human neonatal tissues. Human cell. Off J Human Cell Res Soc 23, 113-118 .
18
Grskovic, M., Javaherian, A., Strulovici, B., and Daley, G.Q. (2011). Induced pluripotent stem cells--opportunities for disease modelling and drug discovery. Nat Rev Drug Discov 10, 915-929 .
19
Han, S.S., Williams, L.A., and Eggan, K.C. (2011). Constructing and deconstructing stem cell models of neurological disease. Neuron 70, 626-644 . doi: 10.1016/j.neuron.2011.05.003
20
Hargus, G., Cooper, O., Deleidi, M., Levy, A., Lee, K., Marlow, E., Yow, A., Soldner, F., Hockemeyer, D., Hallett, P.J., . (2010). Differentiated Parkinson patient-derived induced pluripotent stem cells grow in the adult rodent brain and reduce motor asymmetry in Parkinsonian rats. Proc Natl Acad Sci USA 107, 15921-15926 . doi: 10.1073/pnas.1010209107
21
Hayashi, K., Hashimoto, M., Koda, M., Naito, A.T., Murata, A., Okawa, A., Takahashi, K., and Yamazaki, M. (2011). Increase of sensitivity to mechanical stimulus after transplantation of murine induced pluripotent stem cell-derived astrocytes in a rat spinal cord injury model.J Neurosurg Spine 15, 582-593 . doi: 10.3171/2011.7.SPINE10775
22
Hockemeyer, D., and Jaenisch, R. (2010). Gene targeting in human pluripotent cells. Cold Spring Harb Symp Quant Biol 75, 201-209 . doi: 10.1101/sqb.2010.75.021
23
Huse, D.M., Schulman, K., Orsini, L., Castelli-Haley, J., Kennedy, S., and Lenhart, G. (2005). Burden of illness in Parkinson's disease. Movement disorders. Off J Move Dis Soc 20, 1449-1454 .
24
Ilieva, H., Polymenidou, M., and Cleveland, D.W. (2009). Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J Cell Biol 187, 761-772 . doi: 10.1083/jcb.200908164
Jensen, M.B., Yan, H., Krishnaney-Davison, R., Al Sawaf, A., and Zhang, S.C. (2011). Survival and differentiation of transplanted neural stem cells derived from human induced pluripotent stem cells in a rat stroke model. J Stroke Cerebrovasc Dis: the official journal of National Stroke Association .
27
Karumbayaram, S., Novitch, B.G., Patterson, M., Umbach, J.A., Richter, L., Lindgren, A., Conway, A.E., Clark, A.T., Goldman, S.A., Plath, K., . (2009). Directed differentiation of human-induced pluripotent stem cells generates active motor neurons. Stem Cells 27, 806-811 . doi: 10.1002/stem.31
28
Kawai, H., Yamashita, T., Ohta, Y., Deguchi, K., Nagotani, S., Zhang, X., Ikeda, Y., Matsuura, T., and Abe, K. (2010). Tridermal tumorigenesis of induced pluripotent stem cells transplanted in ischemic brain. J Cerebral Blood Flow Met: official journal of the International Society of Cerebral Blood Flow and Metabolism 30, 1487-1493 .
29
Kikuchi, T., Morizane, A., Doi, D., Onoe, H., Hayashi, T., Kawasaki, T., Saiki, H., Miyamoto, S., and Takahashi, J. (2011). Survival of human induced pluripotent stem cell-derived midbrain dopaminergic neurons in the brain of a primate model of Parkinson's disease. J Parkinson's Dis , 395-412 .
30
Kim, H.W., and Svendsen, C.N. (2011). Gene editing in stem cells hits the target. Cell Stem Cell 9, 93-94 . doi: 10.1016/j.stem.2011.07.011
31
Kim, J., Efe, J.A., Zhu, S., Talantova, M., Yuan, X., Wang, S., Lipton, S.A., Zhang, K., and Ding, S. (2011a). Direct reprogramming of mouse fibroblasts to neural progenitors. Proc Natl Acad Sci USA 108, 7838-7843 . doi: 10.1073/pnas.1103113108
32
Kim, J., Su, S.C., Wang, H., Cheng, A.W., Cassady, J.P., Lodato, M.A., Lengner, C.J., Chung, C.Y., Dawlaty, M.M., Tsai, L.H., . (2011b). Functional integration of dopaminergic neurons directly converted from mouse fibroblasts. Cell Stem Cell 9, 413-419 . doi: 10.1016/j.stem.2011.09.011
33
Kim, J.H., Auerbach, J.M., Rodriguez-Gomez, J.A., Velasco, I., Gavin, D., Lumelsky, N., Lee, S.H., Nguyen, J., Sanchez-Pernaute, R., Bankiewicz, K., . (2002). Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease. Nature 418, 50-56 . doi: 10.1038/nature00900
34
Kim, K.Y., Hysolli, E., and Park, I.H. (2011c). Neuronal maturation defect in induced pluripotent stem cells from patients with Rett syndrome. Proc Natl Acad Sci USA 108, 14169-14174 . doi: 10.1073/pnas.1018979108
35
Koch, P., Breuer, P., Peitz, M., Jungverdorben, J., Kesavan, J., Poppe, D., Doerr, J., Ladewig, J., Mertens, J., Tuting, T., . (2011). Excitation-induced ataxin-3 aggregation in neurons from patients with Machado-Joseph disease. Nature 480, 543-546 .
36
Krencik, R., Weick, J.P., Liu, Y., Zhang, Z.J., and Zhang, S.C. (2011). Specification of transplantable astroglial subtypes from human pluripotent stem cells. Nat Biotechnol 29, 528-534 . doi: 10.1038/nbt.1877
37
Kriks, S., Shim, J.W., Piao, J., Ganat, Y.M., Wakeman, D.R., Xie, Z., Carrillo-Reid, L., Auyeung, G., Antonacci, C., Buch, A., . (2011). Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease. Nature 480, 547-551 .
38
Lee, S.T., Chu, K., Jung, K.H., Song, Y.M., Jeon, D., Kim, S.U., Kim, M., Lee, S.K., and Roh, J.K. (2011). Direct generation of neurosphere-like cells from human dermal fibroblasts. PLoS ONE 6, e21801. doi: 10.1371/journal.pone.0021801
39
Lindvall, O., and Bj?rklund, A. (2011). Cell therapeutics in Parkinson’s disease. Neurotherapeutics 8, 539-548 . doi: 10.1007/s13311-011-0069-6
40
Liu, G.H., Sancho-Martinez, I., and Izpisua Belmonte, J.C. (2012a). Cut and Paste: restoring cellular function by gene correction. CellRes 22, 283-284 . doi: 10.1038/cr.2011.192
41
Liu, G.H., Suzuki, K., Qu, J., Sancho-Martinez, I., Yi, F., Li, M., Kumar, S., Nivet, E., Kim, J., Soligalla, R.D., . (2011). Targeted gene correction of laminopathy-associated LMNA mutations in patient-specific iPSCs. Cell Stem Cell 8, 688-694 . doi: 10.1016/j.stem.2011.04.019
42
Liu, X., Li, F., Stubblefield, E.A., Blanchard, B., Richards, T.L., Larson, G.A., He, Y., Huang, Q., Tan, A.C., Zhang, D., . (2012b). Direct reprogramming of human fibroblasts into dopaminergic neuron-like cells. Cell Res 22, 321-332 . doi: 10.1038/cr.2011.181
43
Lujan, E., Chanda, S., Ahlenius, H., Sudhof, T.C., and Wernig, M. (2012). Direct conversion of mouse fibroblasts to self-renewing, tripotent neural precursor cells. Proc National Acad Sci USA . doi: 10.1073/pnas.1121003109 pmid:10.1073/pnas.1121003109" target="blank">. doi: 10.1073/pnas.1121003109
44
Marchetto, M.C., Carromeu, C., Acab, A., Yu, D., Yeo, G.W., Mu, Y., Chen, G., Gage, F.H., and Muotri, A.R. (2010). A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell 143, 527-539 . doi: 10.1016/j.cell.2010.10.016
45
Nguyen, H.N., Byers, B., Cord, B., Shcheglovitov, A., Byrne, J., Gujar, P., Kee, K., Sch?le, B., Dolmetsch, R.E., Langston, W., . (2011). LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell 8, 267-280 . doi: 10.1016/j.stem.2011.01.013
46
Nori, S., Okada, Y., Yasuda, A., Tsuji, O., Takahashi, Y., Kobayashi, Y., Fujiyoshi, K., Koike, M., Uchiyama, Y., Ikeda, E., . (2011). Grafted human-induced pluripotent stem-cell-derived neurospheres promote motor functional recovery after spinal cord injury in mice. Proc Natl Acad Sci USA 108, 16825-16830 . doi: 10.1073/pnas.1108077108
47
Pan, H., Zhang, W., and Liu, G.H. (2011). Find and replace: editing human genome in pluripotent stem cells. Protein Cell 2, 950-956 . doi: 10.1007/s13238-011-1132-0
48
Park, I.H., Arora, N., Huo, H., Maherali, N., Ahfeldt, T., Shimamura, A., Lensch, M.W., Cowan, C., Hochedlinger, K., and Daley, G.Q. (2008). Disease-specific induced pluripotent stem cells. Cell 134, 877-886 . doi: 10.1016/j.cell.2008.07.041
49
Pasca, S.P., Portmann, T., Voineagu, I., Yazawa, M., Shcheglovitov, A., Pasca, A.M., Cord, B., Palmer, T.D., Chikahisa, S., Nishino, S., . (2011). Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nat Med 17, 1657-1662 . doi: 10.1038/nm.2576
50
Pawitan, J.A. (2011). Prospect of cell therapy for Parkinson's disease. Anat Cell Biol 44, 256-264 . doi: 10.5115/acb.2011.44.4.256
51
Pfisterer, U., Kirkeby, A., Torper, O., Wood, J., Nelander, J., Dufour, A., Bjorklund, A., Lindvall, O., Jakobsson, J., and Parmar, M. (2011). Direct conversion of human fibroblasts to dopaminergic neurons. Proc Natl Acad Sci USA 108, 10343-10348 . doi: 10.1073/pnas.1105135108
52
Qiang, L., Fujita, R., Yamashita, T., Angulo, S., Rhinn, H., Rhee, D., Doege, C., Chau, L., Aubry, L., Vanti, W.B., . (2011). Directed conversion of Alzheimer's disease patient skin fibroblasts into functional neurons. Cell 146, 359-371 . doi: 10.1016/j.cell.2011.07.007
53
Rhee, Y.-H., Ko, J.-Y., Chang, M.-Y., Yi, S.-H., Kim, D., Kim, C.-H., Shim, J.-W., Jo, A.Y., Kim, B.-W., Lee, H., . (2011). Protein-based human iPS cells efficiently generate functional dopamine neurons and can treat a rat model of Parkinson disease. J Clin Invest 121, 2326-2335 . doi: 10.1172/JCI45794
54
Ross, C.A., and Poirier, M.A. (2004). Protein aggregation and neurodegenerative disease. Nat Med 10, S10-S17 . doi: 10.1038/nm1066
55
Roy, N.S., Cleren, C., Singh, S.K., Yang, L., Beal, M.F., and Goldman, S.A. (2006). Functional engraftment of human ES cell-derived dopaminergic neurons enriched by coculture with telomerase-immortalized midbrain astrocytes. Nat Med 12, 1259-1268 . doi: 10.1038/nm1495
56
Sanchez-Pernaute, R., Lee, H., Patterson, M., Reske-Nielsen, C., Yoshizaki, T., Sonntag, K.C., Studer, L., and Isacson, O. (2008). Parthenogenetic dopamine neurons from primate embryonic stem cells restore function in experimental Parkinson's disease. Brain: a journal of neurology 131, 2127-2139 .
57
Schwartz, S.D., Hubschman, J.P., Heilwell, G., Franco-Cardenas, V., Pan, C.K., Ostrick, R.M., Mickunas, E., Gay, R., Klimanskaya, I., and Lanza, R. (2012). Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet. Lancet. 2012Jan24 [Epub ahead of print].
58
Seifinejad, A., Tabebordbar, M., Baharvand, H., Boyer, L.A., and Salekdeh, G.H. (2010). Progress and promise towards safe induced pluripotent stem cells for therapy. Stem Cell Rev 6, 297-306 . doi: 10.1007/s12015-010-9121-x
59
Soldner, F., Hockemeyer, D., Beard, C., Gao, Q., Bell, G.W., Cook, E.G., Hargus, G., Blak, A., Cooper, O., Mitalipova, M., . (2009). Parkinson's disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell 136, 964-977 . doi: 10.1016/j.cell.2009.02.013
60
Son, E.Y., Ichida, J.K., Wainger, B.J., Toma, J.S., Rafuse, V.F., Woolf, C.J., and Eggan, K. (2011). Conversion of mouse and human fibroblasts into functional spinal motor neurons. Cell Stem Cell 9, 205-218 . doi: 10.1016/j.stem.2011.07.014
61
Swistowski, A., Peng, J., Liu, Q., Mali, P., Rao, M.S., Cheng, L., and Zeng, X. (2010). Efficient generation of functional dopaminergic neurons from human induced pluripotent stem cells under defined conditions. Stem Cells 28, 1893-1904 . doi: 10.1002/stem.499
62
Tsuji, O., Miura, K., Okada, Y., Fujiyoshi, K., Mukaino, M., Nagoshi, N., Kitamura, K., Kumagai, G., Nishino, M., Tomisato, S., . (2010). Therapeutic potential of appropriately evaluated safe-induced pluripotent stem cells for spinal cord injury. Proc Natl Acad Sci USA 107, 12704-12709 . doi: 10.1073/pnas.0910106107
63
Varela, C., Denis, J.A., Polentes, J., Feyeux, M., Aubert, S., Champon, B., Pietu, G., Peschanski, M., and Lefort, N. (2012). Recurrent genomic instability of chromosome 1q in neural derivatives of human embryonic stem cells. J Clin Invest 122, 569-574 . doi: 10.1172/JCI46268
64
Vierbuchen, T., Ostermeier, A., Pang, Z.P., Kokubu, Y., Sudhof, T.C., and Wernig, M. (2010). Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463, 1035-1041 . doi: 10.1038/nature08797
65
Wernig, M., Benninger, F., Schmandt, T., Rade, M., Tucker, K.L., Bussow, H., Beck, H., and Brustle, O. (2004). Functional integration of embryonic stem cell-derived neurons in vivo. J Neurosci: the official journal of the Society for Neuroscience 24, 5258-5268 .
66
Wernig, M., Zhao, J.-P., Pruszak, J., Hedlund, E., Fu, D., Soldner, F., Broccoli, V., Constantine-Paton, M., Isacson, O., and Jaenisch, R. (2008). Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson's disease. Proc Natl Acad Sci USA 105, 5856-5861 . doi: 10.1073/pnas.0801677105
67
Yagi, T., Ito, D., Okada, Y., Akamatsu, W., Nihei, Y., Yoshizaki, T., Yamanaka, S., Okano, H., and Suzuki, N. (2011). Modeling familial Alzheimer's disease with induced pluripotent stem cells. Human Mol Genet 20, 4530-45839 . doi: 10.1093/hmg/ddr394
68
Yamashita, T., Kawai, H., Tian, F., Ohta, Y., and Abe, K. (2011). Tumorigenic development of induced pluripotent stem cells in ischemic mouse brain. Cell Transplant 20, 883-891 . doi: 10.3727/096368910X539092
69
Yang, D., Zhang, Z.J., Oldenburg, M., Ayala, M., and Zhang, S.C. (2008). Human embryonic stem cell-derived dopaminergic neurons reverse functional deficit in parkinsonian rats. Stem Cells 26, 55-63 . doi: 10.1634/stemcells.2007-0494
70
Zhang, W., Ding, Z., and Liu, G.H. (2012). Evolution of iPSC disease models. Protein Cell. Protein Cell 3, 1-4 .
