Protein & Cell

, Volume 3, Issue 2, pp 91–97 | Cite as

Converted neural cells: induced to a cure?

  • Weiqi Zhang
  • Shunlei Duan
  • Ying Li
  • Xiuling Xu
  • Jing QuEmail author
  • Weizhou ZhangEmail author
  • Guang-Hui LiuEmail author


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.


converted neural cell pluripotent stem cell transdifferentiation transplantation neurodegenerative diseases 


  1. Barrilleaux, B., and Knoepfler, P.S. (2011). Inducing iPSCs to escape the dish. Cell Stem Cell 9, 103–111.PubMedCentralCrossRefPubMedGoogle Scholar
  2. Berke, J.D., and Hyman, S.E. (2000). Addiction, dopamine, and the molecular mechanisms of memory. Neuron 25, 515–532.CrossRefPubMedGoogle Scholar
  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., et al. (2002). Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc Natl Acad Sci USA 99, 2344–2349.PubMedCentralCrossRefPubMedGoogle Scholar
  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.CrossRefPubMedGoogle Scholar
  5. Brennand, K.J., Simone, A., Jou, J., Gelboin-Burkhart, C., Tran, N., Sangar, S., Li, Y., Mu, Y., Chen, G., Yu, D., et al. (2011). Modelling schizophrenia using human induced pluripotent stem cells. Nature 473, 221–225.PubMedCentralCrossRefPubMedGoogle Scholar
  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.PubMedCentralCrossRefPubMedGoogle Scholar
  7. Caiazzo, M., Dell’Anno, M.T., Dvoretskova, E., Lazarevic, D., Taverna, S., Leo, D., Sotnikova, T.D., Menegon, A., Roncaglia, P., Colciago, G., et al. (2011). Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature 476, 224–227.CrossRefPubMedGoogle Scholar
  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., et al. (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.CrossRefPubMedGoogle Scholar
  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.CrossRefPubMedGoogle Scholar
  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.PubMedCentralCrossRefPubMedGoogle Scholar
  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.PubMedCentralCrossRefPubMedGoogle Scholar
  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., et al. (2011). Parkinson’s disease induced pluripotent stem cells with triplication of the alpha-synuclein locus. Nat Commun 2, 440.PubMedCentralCrossRefPubMedGoogle Scholar
  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., et al. (2008). Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321, 1218–1221.CrossRefPubMedGoogle Scholar
  14. Dolmetsch, R., and Geschwind, D.H. (2011). The human brain in a dish: the promise of iPSC-derived neurons. Cell 145, 831–834.PubMedCentralCrossRefPubMedGoogle Scholar
  15. Donnan, G.A., Fisher, M., Macleod, M., and Davis, S.M. (2008). Stroke. Lancet 371, 1612–1623.CrossRefPubMedGoogle Scholar
  16. Ebert, A.D., Yu, J., Rose, F.F. Jr, Mattis, V.B., Lorson, C.L., Thomson, J.A., and Svendsen, C.N. (2009). Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 457, 277–280.PubMedCentralCrossRefPubMedGoogle Scholar
  17. 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.Google Scholar
  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.PubMedGoogle Scholar
  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.CrossRefPubMedGoogle Scholar
  20. Hargus, G., Cooper, O., Deleidi, M., Levy, A., Lee, K., Marlow, E., Yow, A., Soldner, F., Hockemeyer, D., Hallett, P.J., et al. (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.PubMedCentralCrossRefPubMedGoogle Scholar
  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.CrossRefPubMedGoogle Scholar
  22. Hockemeyer, D., and Jaenisch, R. (2010). Gene targeting in human pluripotent cells. Cold Spring Harb Symp Quant Biol 75, 201–209.CrossRefPubMedGoogle Scholar
  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.CrossRefGoogle Scholar
  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.PubMedCentralCrossRefPubMedGoogle Scholar
  25. Israel, M.A., Yuan, S.H., Bardy, C., Reyna, S.M., Mu, Y., Herrera, C., Hefferan, M.P., Van Gorp, S., Nazor, K.L., Boscolo, F.S., et al. (2012). Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature 482, 216–220.PubMedCentralPubMedGoogle Scholar
  26. 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.Google Scholar
  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., et al. (2009). Directed differentiation of human-induced pluripotent stem cells generates active motor neurons. Stem Cells 27, 806–811.PubMedCentralCrossRefPubMedGoogle Scholar
  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.CrossRefGoogle Scholar
  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.Google Scholar
  30. Kim, H.W., and Svendsen, C.N. (2011). Gene editing in stem cells hits the target. Cell Stem Cell 9, 93–94.CrossRefPubMedGoogle Scholar
  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.PubMedCentralCrossRefPubMedGoogle Scholar
  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., et al. (2011b). Functional integration of dopaminergic neurons directly converted from mouse fibroblasts. Cell Stem Cell 9, 413–419.PubMedCentralCrossRefPubMedGoogle Scholar
  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., et al. (2002). Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson’s disease. Nature 418, 50–56.CrossRefPubMedGoogle Scholar
  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.PubMedCentralCrossRefPubMedGoogle Scholar
  35. Koch, P., Breuer, P., Peitz, M., Jungverdorben, J., Kesavan, J., Poppe, D., Doerr, J., Ladewig, J., Mertens, J., Tuting, T., et al. (2011). Excitation-induced ataxin-3 aggregation in neurons from patients with Machado-Joseph disease. Nature 480, 543–546.PubMedGoogle Scholar
  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.PubMedCentralCrossRefPubMedGoogle Scholar
  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., et al. (2011). Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease. Nature 480, 547–551.PubMedCentralPubMedGoogle Scholar
  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.PubMedCentralCrossRefPubMedGoogle Scholar
  39. Lindvall, O., and Björklund, A. (2011). Cell therapeutics in Parkinson’s disease. Neurotherapeutics 8, 539–548.PubMedCentralCrossRefPubMedGoogle Scholar
  40. Liu, G.H., Sancho-Martinez, I., and Izpisua Belmonte, J.C. (2012a). Cut and Paste: restoring cellular function by gene correction. Ce Res 22, 283–284.CrossRefGoogle Scholar
  41. Liu, G.H., Suzuki, K., Qu, J., Sancho-Martinez, I., Yi, F., Li, M., Kumar, S., Nivet, E., Kim, J., Soligalla, R.D., et al. (2011). Targeted gene correction of laminopathy-associated LMNA mutations in patient-specific iPSCs. Cell Stem Cell 8, 688–694.PubMedCentralCrossRefPubMedGoogle Scholar
  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., et al. (2012b). Direct reprogramming of human fibroblasts into dopaminergic neuron-like cells. Cell Res 22, 321–332.PubMedCentralCrossRefPubMedGoogle Scholar
  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.Google Scholar
  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.PubMedCentralCrossRefPubMedGoogle Scholar
  45. Nguyen, H.N., Byers, B., Cord, B., Shcheglovitov, A., Byrne, J., Gujar, P., Kee, K., Schüle, B., Dolmetsch, R.E., Langston, W., et al. (2011). LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell 8, 267–280.PubMedCentralCrossRefPubMedGoogle Scholar
  46. Nori, S., Okada, Y., Yasuda, A., Tsuji, O., Takahashi, Y., Kobayashi, Y., Fujiyoshi, K., Koike, M., Uchiyama, Y., Ikeda, E., et al. (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.PubMedCentralCrossRefPubMedGoogle Scholar
  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.CrossRefPubMedGoogle Scholar
  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.PubMedCentralCrossRefPubMedGoogle Scholar
  49. Pasca, S.P., Portmann, T., Voineagu, I., Yazawa, M., Shcheglovitov, A., Pasca, A.M., Cord, B., Palmer, T.D., Chikahisa, S., Nishino, S., et al. (2011). Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nat Med 17, 1657–1662.PubMedCentralCrossRefPubMedGoogle Scholar
  50. Pawitan, J.A. (2011). Prospect of cell therapy for Parkinson’s disease. Anat Cell Biol 44, 256–264.PubMedCentralCrossRefPubMedGoogle Scholar
  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.PubMedCentralCrossRefPubMedGoogle Scholar
  52. Qiang, L., Fujita, R., Yamashita, T., Angulo, S., Rhinn, H., Rhee, D., Doege, C., Chau, L., Aubry, L., Vanti, W.B., et al. (2011). Directed conversion of Alzheimer’s disease patient skin fibroblasts into functional neurons. Cell 146, 359–371.PubMedCentralCrossRefPubMedGoogle Scholar
  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., et al. (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.PubMedCentralCrossRefPubMedGoogle Scholar
  54. Ross, C.A., and Poirier, M.A. (2004). Protein aggregation and neurodegenerative disease. Nat Med 10, S10–S17.CrossRefPubMedGoogle Scholar
  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.CrossRefPubMedGoogle Scholar
  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.CrossRefGoogle Scholar
  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. 2012 Jan 24 [Epub ahead of print].Google Scholar
  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.CrossRefPubMedGoogle Scholar
  59. Soldner, F., Hockemeyer, D., Beard, C., Gao, Q., Bell, G.W., Cook, E.G., Hargus, G., Blak, A., Cooper, O., Mitalipova, M., et al. (2009). Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell 136, 964–977.PubMedCentralCrossRefPubMedGoogle Scholar
  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.PubMedCentralCrossRefPubMedGoogle Scholar
  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.PubMedCentralCrossRefPubMedGoogle Scholar
  62. Tsuji, O., Miura, K., Okada, Y., Fujiyoshi, K., Mukaino, M., Nagoshi, N., Kitamura, K., Kumagai, G., Nishino, M., Tomisato, S., et al. (2010). Therapeutic potential of appropriately evaluated safe-induced pluripotent stem cells for spinal cord injury. Proc Natl Acad Sci USA 107, 12704–12709.PubMedCentralCrossRefPubMedGoogle Scholar
  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.PubMedCentralCrossRefPubMedGoogle Scholar
  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.PubMedCentralCrossRefPubMedGoogle Scholar
  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.CrossRefGoogle Scholar
  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.PubMedCentralCrossRefPubMedGoogle Scholar
  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.CrossRefGoogle Scholar
  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.CrossRefPubMedGoogle Scholar
  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.PubMedCentralCrossRefPubMedGoogle Scholar
  70. Zhang, W., Ding, Z., and Liu, G.H. (2012). Evolution of iPSC disease models. Protein Cell. Protein Cell 3, 1–4.CrossRefPubMedGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.National Laboratory of Biomacromolecules, Institute of BiophysicsChinese Academy of SciencesBeijingChina
  2. 2.Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of MedicineUniversity of CaliforniaSan Diego, La JollaUSA

Personalised recommendations