Stem Cell Reviews and Reports

, Volume 11, Issue 2, pp 205–218 | Cite as

Pluripotent Stem Cells for Schwann Cell Engineering

  • Ming-San Ma
  • Erik Boddeke
  • Sjef CoprayEmail author


Tissue engineering of Schwann cells (SCs) can serve a number of purposes, such as in vitro SC-related disease modeling, treatment of peripheral nerve diseases or peripheral nerve injury, and, potentially, treatment of CNS diseases. SCs can be generated from autologous stem cells in vitro by recapitulating the various stages of in vivo neural crest formation and SC differentiation. In this review, we survey the cellular and molecular mechanisms underlying these in vivo processes. We then focus on the current in vitro strategies for generating SCs from two sources of pluripotent stem cells, namely embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). Different methods for SC engineering from ESCs and iPSCs are reviewed and suggestions are proposed for optimizing the existing protocols. Potential safety issues regarding the clinical application of iPSC-derived SCs are discussed as well. Lastly, we will address future aspects of SC engineering.


Induced pluripotent stem cells iPSC Schwann cell Peripheral nerve Myelination Mesenchymal stem cells Reprogramming Differentiation Neural crest 


Conflict of Interest

The authors declare no potential conflict of interests


  1. 1.
    Jessen, K. R., & Mirsky, R. (2005). The origin and development of glial cells in peripheral nerves. Nature Reviews Neuroscience, 6, 671–682.PubMedCrossRefGoogle Scholar
  2. 2.
    Kamholz, J., Menichella, D., Jani, A., et al. (2000). Charcot-Marie-Tooth disease type 1: molecular pathogenesis to gene therapy. Brain, 123(Pt 2), 222–233.PubMedCrossRefGoogle Scholar
  3. 3.
    Stadtfeld, M., & Hochedlinger, K. (2010). Induced pluripotency: history, mechanisms, and applications. Genes and Development, 24, 2239–2263.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Eser, F., Bodur, H., & Atan, Ç. (2009). Etiological factors of traumatic peripheral nerve injuries. Neurology India, 57(4), 434–437.PubMedCrossRefGoogle Scholar
  5. 5.
    Novak, C. B., Anastakis, D. J., Beaton, D. E., Mackinnon, S. E., & Katz, J. (2011). Biomedical and psychosocial factors associated with disability after peripheral nerve injury. Journal of Bone and Joint Surgery, 93(10), 929–936.PubMedCrossRefGoogle Scholar
  6. 6.
    Fawcett, J., & Keynes, R. J. (1990). Peripheral nerve regeneration. Annual Review of Neuroscience, 13, 43–60.PubMedCrossRefGoogle Scholar
  7. 7.
    Terenghi, G. (1999). Peripheral nerve regeneration and neurotrophic factors. Journal of Anatomy, 194(Pt 1), 1–14.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Frostick, S. P., Yin, Q., & Kemp, G. J. (1998). Schwann cells, neurotrophic factors, and peripheral nerve regeneration. Microsurgery, 18(7), 397–405.PubMedCrossRefGoogle Scholar
  9. 9.
    Jessen, K., & Mirsky, R. (2002). Signals that determine Schwann cell identity. Journal of Anatomy, 200(4), 367–376.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Hadlock, T., Elisseeff, J., Langer, R., Vacanti, J., & Cheney, M. (1998). A tissue-engineered conduit for peripheral nerve repair. Archives of Otolaryngology Head and Neck Surgery, 124(10), 1081–1086.PubMedCrossRefGoogle Scholar
  11. 11.
    Fansa, H., Keilhoff, G., Wolf, G., & Schneider, W. (2001). Tissue engineering of peripheral nerves: a comparison of venous and acellular muscle grafts with cultured Schwann cells. Plastic and Reconstructive Surgery, 107(2), 485–494. discussion 495–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Frerichs, O., Fansa, H., Schicht, C., Wolf, G., Schneider, W., & Keilhoff, G. (2002). Reconstruction of peripheral nerves using acellular nerve grafts with implanted cultured Schwann cells. Microsurgery, 22(7), 311–315.PubMedCrossRefGoogle Scholar
  13. 13.
    Rodríguez, F. J., Verdú, E., Ceballos, D., & Navarro, X. (2000). Nerve guides seeded with autologous Schwann cells improve nerve regeneration. Experimental Neurology, 161(2), 571–584.PubMedCrossRefGoogle Scholar
  14. 14.
    Schlosshauer, B., Müller, E., Schröder, B., Planck, H., & Müller, H. (2003). Rat Schwann cells in bioresorbable nerve guides to promote and accelerate axonal regeneration. Brain Research, 963(1), 321–326.PubMedCrossRefGoogle Scholar
  15. 15.
    Evans, G. R., Brandt, K., Katz, S., et al. (2002). Bioactive poly (L-lactic acid) conduits seeded with Schwann cells for peripheral nerve regeneration. Biomaterials, 23(3), 841–848.PubMedCrossRefGoogle Scholar
  16. 16.
    Fansa, H., & Keilhoff, G. (2004). Comparison of different biogenic matrices seeded with cultured Schwann cells for bridging peripheral nerve defects. Neurological Research, 26(2), 167–173.PubMedCrossRefGoogle Scholar
  17. 17.
    Keirstead, H. S., Nistor, G., Bernal, G., et al. (2005). Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. Journal of Neuroscience, 25(19), 4694–4705.PubMedCrossRefGoogle Scholar
  18. 18.
    Totoiu, M. O., Nistor, G. I., Lane, T. E., & Keirstead, H. S. (2004). Remyelination, axonal sparing, and locomotor recovery following transplantation of glial-committed progenitor cells into the MHV model of multiple sclerosis. Experimental Neurology, 187(2), 254–265.PubMedCrossRefGoogle Scholar
  19. 19.
    Blakemore, W. (1977). Remyelination of CNS axons by Schwann cells transplanted from the sciatic nerve. Nature, 266, 68–69.PubMedCrossRefGoogle Scholar
  20. 20.
    Duncan, I., Aguayo, A., Bunge, R., & Wood, P. (1981). Transplantation of rat Schwann cells grown in tissue culture into the mouse spinal cord. Journal of Neurological Sciences, 49(2), 241–252.CrossRefGoogle Scholar
  21. 21.
    Itoyama, Y., Webster, H. D., Richardson, E. P., & Trapp, B. D. (1983). Schwann cell remyelination of demyelinated axons in spinal cord multiple sclerosis lesions. Annals of Neurology, 14(3), 339–346.PubMedCrossRefGoogle Scholar
  22. 22.
    Baron-Van Evercooren, A., Gansmuller, A., Duhamel, E., Pascal, F., & Gumpel, M. (1992). Repair of a myelin lesion by Schwann cells transplanted in the adult mouse spinal cord. Journal of Neuroimmunology, 40(2), 235–242.PubMedCrossRefGoogle Scholar
  23. 23.
    Blakemore, W., Olby, N., & Franklin, R. (1995). The use of transplanted glial cells to reconstruct glial environments in the CNS. Brain Pathology, 5(4), 443–450.PubMedCrossRefGoogle Scholar
  24. 24.
    Honmou, O., Felts, P. A., Waxman, S. G., & Kocsis, J. D. (1996). Restoration of normal conduction properties in demyelinated spinal cord axons in the adult rat by transplantation of exogenous Schwann cells. Journal of Neuroscience, 16(10), 3199–3208.PubMedCentralPubMedGoogle Scholar
  25. 25.
    Iwashita, Y., Fawcett, J. W., Crang, A., Franklin, R. J., & Blakemore, W. F. (2000). Schwann cells transplanted into normal and X-irradiated adult white matter do not migrate extensively and show poor long-term survival. Experimental Neurology, 164(2), 292–302.PubMedCrossRefGoogle Scholar
  26. 26.
    Dezawa, M., Takahashi, I., Esaki, M., Takano, M., & Sawada, H. (2001). Sciatic nerve regeneration in rats induced by transplantation of in vitro differentiated bone-marrow stromal cells. European Journal of Neuroscience, 14(11), 1771–1776.PubMedCrossRefGoogle Scholar
  27. 27.
    Shimizu, S., Kitada, M., Ishikawa, H., Itokazu, Y., Wakao, S., & Dezawa, M. (2007). Peripheral nerve regeneration by the in vitro differentiated-human bone marrow stromal cells with Schwann cell property. Biochemical and Biophysical Research Communications, 359(4), 915–920.PubMedCrossRefGoogle Scholar
  28. 28.
    Wakao, S., Hayashi, T., Kitada, M., et al. (2010). Long-term observation of auto-cell transplantation in non-human primate reveals safety and efficiency of bone marrow stromal cell-derived Schwann cells in peripheral nerve regeneration. Experimental Neurology, 223(2), 537–547.PubMedCrossRefGoogle Scholar
  29. 29.
    Mimura, T., Dezawa, M., Kanno, H., Sawada, H., & Yamamoto, I. (2004). Peripheral nerve regeneration by transplantation of bone marrow stromal cell-derived Schwann cells in adult rats. Journal of Neurosurgery, 101(5), 806–812.PubMedCrossRefGoogle Scholar
  30. 30.
    Tohill, M., Mantovani, C., Wiberg, M., & Terenghi, G. (2004). Rat bone marrow mesenchymal stem cells express glial markers and stimulate nerve regeneration. Neuroscience Letters, 362(3), 200–203.PubMedCrossRefGoogle Scholar
  31. 31.
    Tohill, M. P., Mann, D. J., Mantovani, C. M., Wiberg, M., & Terenghi, G. (2004). Green fluorescent protein is a stable morphological marker for Schwann cell transplants in bioengineered nerve conduits. Tissue Engineering, 10(9–10), 1359–1367.PubMedCrossRefGoogle Scholar
  32. 32.
    Caddick, J., Kingham, P. J., Gardiner, N. J., Wiberg, M., & Terenghi, G. (2006). Phenotypic and functional characteristics of mesenchymal stem cells differentiated along a Schwann cell lineage. Glia, 54(8), 840–849.PubMedCrossRefGoogle Scholar
  33. 33.
    Brohlin, M., Mahay, D., Novikov, L. N., et al. (2009). Characterisation of human mesenchymal stem cells following differentiation into Schwann cell-like cells. Neuroscience Research, 64(1), 41–49.PubMedCrossRefGoogle Scholar
  34. 34.
    Kingham, P. J., Kalbermatten, D. F., Mahay, D., Armstrong, S. J., Wiberg, M., & Terenghi, G. (2007). Adipose-derived stem cells differentiate into a Schwann cell phenotype and promote neurite outgrowth in vitro. Experimental Neurology, 207(2), 267–274.PubMedCrossRefGoogle Scholar
  35. 35.
    Xu, Y., Liu, L., Li, Y., et al. (2008). Myelin-forming ability of Schwann cell-like cells induced from rat adipose-derived stem cells in vitro. Brain Research, 1239, 49–55.PubMedCrossRefGoogle Scholar
  36. 36.
    Jiang, L., Zhu, J. K., Liu, X. L., Xiang, P., Hu, J., & Yu, W. H. (2008). Differentiation of rat adipose tissue-derived stem cells into Schwann-like cells in vitro. Neuroreport, 19(10), 1015–1019.PubMedCrossRefGoogle Scholar
  37. 37.
    Radtke, C., Schmitz, B., Spies, M., Kocsis, J., & Vogt, P. (2009). Peripheral glial cell differentiation from neurospheres derived from adipose mesenchymal stem cells. International Journal of Developmental Neuroscience, 27(8), 817–823.PubMedCrossRefGoogle Scholar
  38. 38.
    Chi, G. F., Kim, M., Kim, D., Jiang, M. H., & Son, Y. (2010). Schwann cells differentiated from spheroid-forming cells of rat subcutaneous fat tissue myelinate axons in the spinal cord injury. Experimental Neurology, 222(2), 304–317.PubMedCrossRefGoogle Scholar
  39. 39.
    Fernandes, K. J., McKenzie, I. A., Mill, P., et al. (2004). A dermal niche for multipotent adult skin-derived precursor cells. Nature Cell Biology, 6(11), 1082–1093.PubMedCrossRefGoogle Scholar
  40. 40.
    Toma, J. G., McKenzie, I. A., Bagli, D., & Miller, F. D. (2005). Isolation and characterization of multipotent skin-derived precursors from human skin. Stem Cells, 23(6), 727–737.PubMedCrossRefGoogle Scholar
  41. 41.
    McKenzie, I. A., Biernaskie, J., Toma, J. G., Midha, R., & Miller, F. D. (2006). Skin-derived precursors generate myelinating Schwann cells for the injured and dysmyelinated nervous system. Journal of Neuroscience, 26(24), 6651–6660.PubMedCrossRefGoogle Scholar
  42. 42.
    Sieber-Blum, M., Grim, M., Hu, Y., & Szeder, V. (2004). Pluripotent neural crest stem cells in the adult hair follicle. Developmental Dynamics, 231(2), 258–269.PubMedCrossRefGoogle Scholar
  43. 43.
    Amoh, Y., Li, L., Katsuoka, K., Penman, S., & Hoffman, R. M. (2005). Multipotent nestin-positive, keratin-negative hair-follicle bulge stem cells can form neurons. Proceedings of the National academy of Sciences of the United States of America, 102(15), 5530–5534.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Krause, M. P., Dworski, S., Feinberg, K., et al. (2014). Direct genesis of functional rodent and human Schwann cells from skin mesenchymal precursors. Stem Cell Reports, 3(1), 85–100.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Amoh, Y., Li, L., Katsuoka, K., & Hoffman, R. M. (2009). Multipotent nestin-expressing hair follicle stem cells. Journal of Dermatology, 36(1), 1–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Biernaskie, J. A., McKenzie, I. A., Toma, J. G., & Miller, F. D. (2007). Isolation of skin-derived precursors (SKPs) and differentiation and enrichment of their Schwann cell progeny. Nature Protocols, 1(6), 2803–2812.CrossRefGoogle Scholar
  47. 47.
    Biernaskie, J., Sparling, J. S., Liu, J., et al. (2007). Skin-derived precursors generate myelinating Schwann cells that promote remyelination and functional recovery after contusion spinal cord injury. Journal of Neuroscience, 27(36), 9545–9559.PubMedCrossRefGoogle Scholar
  48. 48.
    Heine, W., Conant, K., Griffin, J. W., & Höke, A. (2004). Transplanted neural stem cells promote axonal regeneration through chronically denervated peripheral nerves. Experimental Neurology, 189(2), 231–240.PubMedCrossRefGoogle Scholar
  49. 49.
    Murakami, T., Fujimoto, Y., Yasunaga, Y., et al. (2003). Transplanted neuronal progenitor cells in a peripheral nerve gap promote nerve repair. Brain Research, 974(1), 17–24.PubMedCrossRefGoogle Scholar
  50. 50.
    Evans, M. J., & Kaufman, M. H. (1981). Establishment in culture of pluripotential cells from mouse embryos. Nature, 292(5819), 154–156.PubMedCrossRefGoogle Scholar
  51. 51.
    Martin, G. R. (1981). Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proceedings of the National Academy of Sciences, 78(12), 7634–7638.CrossRefGoogle Scholar
  52. 52.
    Itskovitz-Eldor, J., Schuldiner, M., Karsenti, D., et al. (2000). Differentiation of human embryonic stem cells into embryoid bodies comprising the three embryonic germ layers. Molecular Medicine, 6(2), 88–95.PubMedCentralPubMedGoogle Scholar
  53. 53.
    Biswas, A., & Hutchins, R. (2007). Embryonic stem cells. Stem Cells and Development, 16(2), 213–222.PubMedCrossRefGoogle Scholar
  54. 54.
    Thomson, J. A., Itskovitz-Eldor, J., Shapiro, S. S., et al. (1998). Embryonic stem cell lines derived from human blastocysts. Science, 282(5391), 1145–1147.PubMedCrossRefGoogle Scholar
  55. 55.
    Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4), 663–676.PubMedCrossRefGoogle Scholar
  56. 56.
    Takahashi, K., Tanabe, K., Ohnuki, M., et al. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131(5), 861–872.PubMedCrossRefGoogle Scholar
  57. 57.
    Maherali, N., Sridharan, R., Xie, W., et al. (2007). Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell, 1(1), 55–70.PubMedCrossRefGoogle Scholar
  58. 58.
    Okita, K., Ichisaka, T., & Yamanaka, S. (2007). Generation of germline-competent induced pluripotent stem cells. Nature, 448(7151), 313–317.PubMedCrossRefGoogle Scholar
  59. 59.
    Wernig, M., Zhao, J., Pruszak, J., et al. (2008). Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson’s disease. Proceedings of the National Academy of Sciences, 105(15), 5856–5861.CrossRefGoogle Scholar
  60. 60.
    Hanna, J., Wernig, M., Markoulaki, S., et al. (2007). Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science, 318(5858), 1920–1923.PubMedCrossRefGoogle Scholar
  61. 61.
    Du, Z., & Zhang, S. (2004). Neural differentiation from embryonic stem cells: which way? Stem Cells and Development, 13(4), 372–381.PubMedCrossRefGoogle Scholar
  62. 62.
    Villanueva, S., Glavic, A., Ruiz, P., & Mayor, R. (2002). Posteriorization by FGF, Wnt, and retinoic acid is required for neural crest induction. Developmental Biology, 241(2), 289–301.PubMedCrossRefGoogle Scholar
  63. 63.
    Sauka-Spengler, T., & Bronner-Fraser, M. (2008). A gene regulatory network orchestrates neural crest formation. Nature Reviews Molecular Cell Biology, 9(7), 557–568.PubMedCrossRefGoogle Scholar
  64. 64.
    Kalluri, R., & Weinberg, R. A. (2009). The basics of epithelial-mesenchymal transition. Journal of Clinical Investigation, 119(6), 1420–1428.PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Bronner, M. E., & LeDouarin, N. M. (2012). Development and evolution of the neural crest: an overview. Developmental Biology, 366(1), 2–9.PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    Thiery, J. P. (2002). Epithelial–mesenchymal transitions in tumour progression. Nature Reviews Cancer, 2(6), 442–454.PubMedCrossRefGoogle Scholar
  67. 67.
    Peinado, H., Portillo, F., & Cano, A. (2004). Transcriptional regulation of cadherins during development and carcinogenesis. International Journal of Developmental Biology, 48(5–6), 365–375.PubMedCrossRefGoogle Scholar
  68. 68.
    Batlle, E., Sancho, E., Francí, C., et al. (2000). The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nature Cell Biology, 2(2), 84–89.PubMedCrossRefGoogle Scholar
  69. 69.
    Cano, A., Pérez-Moreno, M. A., Rodrigo, I., et al. (2000). The transcription factor snail controls epithelial–mesenchymal transitions by repressing E-cadherin expression. Nature Cell Biology, 2(2), 76–83.PubMedCrossRefGoogle Scholar
  70. 70.
    Hajra, K. M., Chen, D. Y., & Fearon, E. R. (2002). The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer Research, 62(6), 1613–1618.PubMedGoogle Scholar
  71. 71.
    Nieto, M. A. (2002). The snail superfamily of zinc-finger transcription factors. Nature Reviews Molecular Cell Biology, 3(3), 155–166.PubMedCrossRefGoogle Scholar
  72. 72.
    De Craene, B., Gilbert, B., Stove, C., Bruyneel, E., van Roy, F., & Berx, G. (2005). The transcription factor snail induces tumor cell invasion through modulation of the epithelial cell differentiation program. Cancer Research, 65(14), 6237–6244.PubMedCrossRefGoogle Scholar
  73. 73.
    Balzac, F., Avolio, M., Degani, S., et al. (2005). E-cadherin endocytosis regulates the activity of Rap1: a traffic light GTPase at the crossroads between cadherin and integrin function. Journal of Cell Science, 118(20), 4765–4783.PubMedCrossRefGoogle Scholar
  74. 74.
    Thiery, J. P., & Sleeman, J. P. (2006). Complex networks orchestrate epithelial–mesenchymal transitions. Nature Reviews Molecular Cell Biology, 7(2), 131–142.PubMedCrossRefGoogle Scholar
  75. 75.
    Kalcheim, C., & Burstyn-Cohen, T. (2005). Early stages of neural crest ontogeny: formation and regulation of cell delamination. International Journal of Developmental Biology, 49(2–3), 105–116.PubMedCrossRefGoogle Scholar
  76. 76.
    Jessen, K. R., & Mirsky, R. (2005). The origin and development of glial cells in peripheral nerves. Nature Reviews Neuroscience, 6(9), 671–682.PubMedCrossRefGoogle Scholar
  77. 77.
    Mirsky, R., Woodhoo, A., Parkinson, D. B., Arthur‐Farraj, P., Bhaskaran, A., & Jessen, K. R. (2008). Novel signals controlling embryonic Schwann cell development, myelination and dedifferentiation. Journal of the Peripheral Nervous System, 13(2), 122–135.PubMedCrossRefGoogle Scholar
  78. 78.
    Pereira, J. A., Lebrun-Julien, F., & Suter, U. (2012). Molecular mechanisms regulating myelination in the peripheral nervous system. Trends in Neurosciences, 35(2), 123–134.PubMedCrossRefGoogle Scholar
  79. 79.
    Stolt, C. C., & Wegner, M. (2010). SoxE function in vertebrate nervous system development. International Journal of Biochemistry and Cell Biology, 42(3), 437–440.PubMedCrossRefGoogle Scholar
  80. 80.
    Britsch, S., Goerich, D. E., Riethmacher, D., et al. (2001). The transcription factor Sox10 is a key regulator of peripheral glial development. Genes and Development, 15(1), 66–78.PubMedCentralPubMedCrossRefGoogle Scholar
  81. 81.
    Schreiner, S., Cossais, F., Fischer, K., et al. (2007). Hypomorphic Sox10 alleles reveal novel protein functions and unravel developmental differences in glial lineages. Development, 134(18), 3271–3281.PubMedCrossRefGoogle Scholar
  82. 82.
    Inoue, K., Khajavi, M., Ohyama, T., et al. (2004). Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations. Nature Genetics, 36(4), 361–369.PubMedCrossRefGoogle Scholar
  83. 83.
    Finzsch, M., Schreiner, S., Kichko, T., et al. (2010). Sox10 is required for Schwann cell identity and progression beyond the immature Schwann cell stage. Journal of Cell Biology, 189(4), 701–712.PubMedCentralPubMedCrossRefGoogle Scholar
  84. 84.
    Topilko, P., Schneider-Maunoury, S., Levi, G., et al. (1994). Krox-20 controls myelination in the peripheral nervous system. Nature, 371, 396–399.CrossRefGoogle Scholar
  85. 85.
    Nagarajan, R., Svaren, J., Le, N., Araki, T., Watson, M., & Milbrandt, J. (2001). EGR2 mutations in inherited neuropathies dominant-negatively inhibit myelin gene expression. Neuron, 30(2), 355–368.PubMedCrossRefGoogle Scholar
  86. 86.
    Ghislain, J., & Charnay, P. (2006). Control of myelination in Schwann cells: a Krox20 cis-regulatory element integrates Oct6, Brn2 and Sox10 activities. EMBO Reports, 7(1), 52–58.PubMedCentralPubMedCrossRefGoogle Scholar
  87. 87.
    Warner, L. E., Mancias, P., Butler, I. J., et al. (1998). Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies. Nature Genetics, 18(4), 382–384.PubMedCrossRefGoogle Scholar
  88. 88.
    Timmerman, V., De Jonghe, P., Ceuterick, C., et al. (1999). Novel missense mutation in the early growth response 2 gene associated with Dejerine-Sottas syndrome phenotype. Neurology, 52(9), 1827–1832.PubMedCrossRefGoogle Scholar
  89. 89.
    Boerkoel, C. F., Takashima, H., Bacino, C. A., Daentl, D., & Lupski, J. R. (2001). EGR2 mutation R359W causes a spectrum of Dejerine-Sottas neuropathy. Neurogenetics, 3(3), 153–157.PubMedCrossRefGoogle Scholar
  90. 90.
    Jaegle, M., Ghazvini, M., Mandemakers, W., et al. (2003). The POU proteins Brn-2 and Oct-6 share important functions in Schwann cell development. Genes and Development, 17(11), 1380–1391.PubMedCentralPubMedCrossRefGoogle Scholar
  91. 91.
    Ghislain, J., Desmarquet-Trin-Dinh, C., Jaegle, M., Meijer, D., Charnay, P., & Frain, M. (2002). Characterisation of cis-acting sequences reveals a biphasic, axon-dependent regulation of Krox20 during Schwann cell development. Development, 129(1), 155–166.PubMedGoogle Scholar
  92. 92.
    Kao, S. C., Wu, H., Xie, J., et al. (2009). Calcineurin/NFAT signaling is required for neuregulin-regulated Schwann cell differentiation. Science, 323(5914), 651–654.PubMedCentralPubMedCrossRefGoogle Scholar
  93. 93.
    Jagalur, N. B., Ghazvini, M., Mandemakers, W., et al. (2011). Functional dissection of the Oct6 Schwann cell enhancer reveals an essential role for dimeric Sox10 binding. Journal of Neuroscience, 31(23), 8585–8594.PubMedCentralPubMedCrossRefGoogle Scholar
  94. 94.
    Zorick, T. S., Syroid, D. E., Brown, A., Gridley, T., & Lemke, G. (1999). Krox-20 controls SCIP expression, cell cycle exit and susceptibility to apoptosis in developing myelinating Schwann cells. Development, 126(7), 1397–1406.PubMedGoogle Scholar
  95. 95.
    Peirano, R. I., & Wegner, M. (2000). The glial transcription factor Sox10 binds to DNA both as monomer and dimer with different functional consequences. Nucleic Acids Research, 28(16), 3047–3055.PubMedCentralPubMedCrossRefGoogle Scholar
  96. 96.
    Slutsky, S. G., Kamaraju, A. K., Levy, A. M., Chebath, J., & Revel, M. (2003). Activation of myelin genes during transdifferentiation from melanoma to glial cell phenotype. Journal of Biological Chemistry, 278(11), 8960–8968.PubMedCrossRefGoogle Scholar
  97. 97.
    Bondurand, N., Girard, M., Pingault, V., Lemort, N., Dubourg, O., & Goossens, M. (2001). Human Connexin 32, a gap junction protein altered in the X-linked form of Charcot-Marie-Tooth disease, is directly regulated by the transcription factor SOX10. Human Molecular Genetics, 10(24), 2783–2795.PubMedCrossRefGoogle Scholar
  98. 98.
    Meyer, D., Yamaai, T., Garratt, A., et al. (1997). Isoform-specific expression and function of neuregulin. Development, 124(18), 3575–3586.PubMedGoogle Scholar
  99. 99.
    Marchionni, M. A., Goodearl, A. D., Chen, M. S., et al. (1993). Glial growth factors are alternatively spliced erbB2 ligands expressed in the nervous system. Nature, 362, 312–318.PubMedCrossRefGoogle Scholar
  100. 100.
    Shah, N. M., Marchionni, M. A., Isaacs, I., Stroobant, P., & Anderson, D. J. (1994). Glial growth factor restricts mammalian neural crest stem cells to a glial fate. Cell, 77(3), 349–360.PubMedCrossRefGoogle Scholar
  101. 101.
    Dong, Z., Brennan, A., Liu, N., et al. (1995). Neu differentiation factor is a neuron-glia signal and regulates survival, proliferation, and maturation of rat Schwann cell precursors. Neuron, 15(3), 585–596.PubMedCrossRefGoogle Scholar
  102. 102.
    Jessen, K., & Mirsky, R. (1997). Embryonic Schwann cell development: the biology of Schwann cell precursors and early Schwann cells. Journal of Anatomy, 191(4), 501–505.PubMedCentralPubMedCrossRefGoogle Scholar
  103. 103.
    Nave, K., & Salzer, J. L. (2006). Axonal regulation of myelination by neuregulin 1. Current Opinion in Neurobiology, 16(5), 492–500.PubMedCrossRefGoogle Scholar
  104. 104.
    Monje, P. V., Bartlett Bunge, M., & Wood, P. M. (2006). Cyclic AMP synergistically enhances neuregulin-dependent ERK and Akt activation and cell cycle progression in Schwann cells. Glia, 53(6), 649–659.PubMedCrossRefGoogle Scholar
  105. 105.
    Limpert, A. S., & Carter, B. D. (2010). Axonal neuregulin 1 type III activates NF-kappaB in Schwann cells during myelin formation. Journal of Biological Chemistry, 285(22), 16614–16622.PubMedCentralPubMedCrossRefGoogle Scholar
  106. 106.
    Nickols, J. C., Valentine, W., Kanwal, S., & Carter, B. D. (2003). Activation of the transcription factor NF-κB in Schwann cells is required for peripheral myelin formation. Nature Neuroscience, 6(2), 161–167.PubMedCrossRefGoogle Scholar
  107. 107.
    Arthur‐Farraj, P., Wanek, K., Hantke, J., et al. (2011). Mouse schwann cells need both NRG1 and cyclic AMP to myelinate. Glia, 59(5), 720–733.PubMedCrossRefGoogle Scholar
  108. 108.
    Svaren, J., & Meijer, D. (2008). The molecular machinery of myelin gene transcription in Schwann cells. Glia, 56(14), 1541–1551.PubMedCentralPubMedCrossRefGoogle Scholar
  109. 109.
    Fregien, N. L., White, L. A., Bunge, M. B., & Wood, P. M. (2005). Forskolin increases neuregulin receptors in human Schwann cells without increasing receptor mRNA. Glia, 49(1), 24–35.PubMedCrossRefGoogle Scholar
  110. 110.
    Sheean, M. E., McShane, E., Cheret, C., et al. (2014). Activation of MAPK overrides the termination of myelin growth and replaces Nrg1/ErbB3 signals during Schwann cell development and myelination. Genes and Development, 28(3), 290–303.PubMedCentralPubMedCrossRefGoogle Scholar
  111. 111.
    Cornbrooks, C. J., Carey, D. J., McDonald, J. A., Timpl, R., & Bunge, R. P. (1983). In vivo and in vitro observations on laminin production by Schwann cells. Proceedings of the National academy of Sciences of the United States of America, 80(12), 3850–3854.PubMedCentralPubMedCrossRefGoogle Scholar
  112. 112.
    Patton, B. L., Miner, J. H., Chiu, A. Y., & Sanes, J. R. (1997). Distribution and function of laminins in the neuromuscular system of developing, adult, and mutant mice. Journal of Cell Biology, 139(6), 1507–1521.PubMedCentralPubMedCrossRefGoogle Scholar
  113. 113.
    Chen, Z., Yu, W., & Strickland, S. (2007). Peripheral regeneration. Annual Review of Neuroscience, 30, 209–233.PubMedCrossRefGoogle Scholar
  114. 114.
    Yu, W. M., Feltri, M. L., Wrabetz, L., Strickland, S., & Chen, Z. L. (2005). Schwann cell-specific ablation of laminin gamma1 causes apoptosis and prevents proliferation. Journal of Neuroscience, 25(18), 4463–4472.PubMedCentralPubMedCrossRefGoogle Scholar
  115. 115.
    Hossain, S., de la Cruz‐Morcillo, M., Sanchez‐Prieto, R., & Almazan, G. (2012). Mitogen-activated protein kinase p38 regulates krox-20 to direct schwann cell differentiation and peripheral myelination. Glia, 60(7), 1130–1144.PubMedCrossRefGoogle Scholar
  116. 116.
    Erceg, S., Ronaghi, M., & Stojković, M. (2009). Human embryonic stem cell differentiation toward regional specific neural precursors. Stem Cells, 27(1), 78–87.PubMedCentralPubMedCrossRefGoogle Scholar
  117. 117.
    Denham, M., & Dottori, M. (2009). Signals involved in neural differentiation of human embryonic stem cells. Neurosignals, 17(4), 234–241.PubMedCrossRefGoogle Scholar
  118. 118.
    Lee, G., Kim, H., Elkabetz, Y., et al. (2007). Isolation and directed differentiation of neural crest stem cells derived from human embryonic stem cells. Natural Biotechnology, 25(12).Google Scholar
  119. 119.
    Monsoro-Burq, A. H., Fletcher, R. B., & Harland, R. M. (2003). Neural crest induction by paraxial mesoderm in Xenopus embryos requires FGF signals. Development, 130(14), 3111–3124.PubMedCrossRefGoogle Scholar
  120. 120.
    Kawaguchi, J., Nichols, J., Gierl, M. S., Faial, T., & Smith, A. (2010). Isolation and propagation of enteric neural crest progenitor cells from mouse embryonic stem cells and embryos. Development, 137(5), 693–704.PubMedCentralPubMedCrossRefGoogle Scholar
  121. 121.
    ten Berge, D., Koole, W., Fuerer, C., Fish, M., Eroglu, E., & Nusse, R. (2008). Wnt signaling mediates self-organization and axis formation in embryoid bodies. Cell Stem Cell, 3(5), 508–518.PubMedCentralPubMedCrossRefGoogle Scholar
  122. 122.
    Jessell, T. M. (2000). Neuronal specification in the spinal cord: inductive signals and transcriptional codes. Nature Reviews Genetics, 1(1), 20–29.PubMedCrossRefGoogle Scholar
  123. 123.
    Mizuseki, K., Sakamoto, T., Watanabe, K., et al. (2003). Generation of neural crest-derived peripheral neurons and floor plate cells from mouse and primate embryonic stem cells. Proceedings of the National academy of Sciences of the United States of America, 100(10), 5828–5833.PubMedCentralPubMedCrossRefGoogle Scholar
  124. 124.
    Okawa, T., Kamiya, H., Himeno, T., et al. (2013). Transplantation of neural crest-like cells derived from induced pluripotent stem cells improves diabetic polyneuropathy in mice. Cell Transplantation, 22(10), 1767–1783.PubMedCrossRefGoogle Scholar
  125. 125.
    Haastert, K., Mauritz, C., Chaturvedi, S., & Grothe, C. (2007). Human and rat adult Schwann cell cultures: fast and efficient enrichment and highly effective non-viral transfection protocol. Nature Protocols, 2(1), 99–104.PubMedCrossRefGoogle Scholar
  126. 126.
    Kalcheim, C., & Gendreau, M. (1988). Brain-derived neurotrophic factor stimulates survival and neuronal differentiation in cultured avian neural crest. Developmental Brain Research, 41(1), 79–86.CrossRefGoogle Scholar
  127. 127.
    Yu, D., Lee, K., Lee, J., et al. (2004). Changes of gene expression profiles during neuronal differentiation of central nervous system precursors treated with ascorbic acid. Journal of Neuroscience Research, 78(1), 29–37.PubMedCrossRefGoogle Scholar
  128. 128.
    Eldridge, C. F., Bunge, M. B., Bunge, R. P., & Wood, P. M. (1987). Differentiation of axon-related Schwann cells in vitro. I. Ascorbic acid regulates basal lamina assembly and myelin formation. Journal of Cell Biology, 105(2), 1023–1034.PubMedCrossRefGoogle Scholar
  129. 129.
    Pomp, O., Brokhman, I., Ben-Dor, I., Reubinoff, B., & Goldstein, R. S. (2005). Generation of peripheral sensory and sympathetic neurons and neural crest cells from human embryonic stem cells. Stem Cells, 23(7), 923–930.PubMedCrossRefGoogle Scholar
  130. 130.
    Motohashi, T., Aoki, H., Chiba, K., Yoshimura, N., & Kunisada, T. (2007). Multipotent cell fate of neural crest-like cells derived from embryonic stem cells. Stem Cells, 25(2), 402–410.PubMedCrossRefGoogle Scholar
  131. 131.
    Rathjen, J., Haines, B. P., Hudson, K. M., Nesci, A., Dunn, S., & Rathjen, P. D. (2002). Directed differentiation of pluripotent cells to neural lineages: homogeneous formation and differentiation of a neurectoderm population. Development, 129(11), 2649–2661.PubMedGoogle Scholar
  132. 132.
    Zhou, Y., & Snead, M. L. (2008). Derivation of cranial neural crest-like cells from human embryonic stem cells. Biochemical and Biophysical Research Communications, 376(3), 542–547.PubMedCentralPubMedCrossRefGoogle Scholar
  133. 133.
    Jiang, X., Gwye, Y., McKeown, S. J., Bronner-Fraser, M., Lutzko, C., & Lawlor, E. R. (2009). Isolation and characterization of neural crest stem cells derived from in vitro-differentiated human embryonic stem cells. Stem Cells and Development, 18(7), 1059–1070.PubMedCrossRefGoogle Scholar
  134. 134.
    Lee, G., Chambers, S. M., Tomishima, M. J., & Studer, L. (2010). Derivation of neural crest cells from human pluripotent stem cells. Nature Protocols, 5(4), 688–701.PubMedCrossRefGoogle Scholar
  135. 135.
    Ziegler, L., Grigoryan, S., Yang, I. H., Thakor, N. V., & Goldstein, R. S. (2011). Efficient generation of Schwann cells from human embryonic stem cell-derived neurospheres. Stem Cell Reviews and Reports, 7(2), 394–403.PubMedCrossRefGoogle Scholar
  136. 136.
    Cui, L., Jiang, J., Wei, L., et al. (2008). Transplantation of embryonic stem cells improves nerve repair and functional recovery after severe sciatic nerve axotomy in rats. Stem Cells, 26(5), 1356–1365.PubMedCrossRefGoogle Scholar
  137. 137.
    Chin, M. H., Mason, M. J., Xie, W., et al. (2009). Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures. Cell Stem Cell, 5(1), 111–123.PubMedCentralPubMedCrossRefGoogle Scholar
  138. 138.
    Doi, A., Park, I., Wen, B., et al. (2009). Differential methylation of tissue-and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts. Nature Genetics, 41(12), 1350–1353.PubMedCentralPubMedCrossRefGoogle Scholar
  139. 139.
    Liu, Q., Spusta, S. C., Mi, R., et al. (2012). Human neural crest stem cells derived from human ESCs and induced pluripotent stem cells: induction, maintenance, and differentiation into functional schwann cells. Stem Cells Translational Medicine, 1(4), 266–278.PubMedCentralPubMedCrossRefGoogle Scholar
  140. 140.
    Menendez, L., Kulik, M. J., Page, A. T., et al. (2013). Directed differentiation of human pluripotent cells to neural crest stem cells. Nature Protocols, 8(1), 203–212.PubMedCrossRefGoogle Scholar
  141. 141.
    Wang, A., Tang, Z., Park, I., et al. (2011). Induced pluripotent stem cells for neural tissue engineering. Biomaterials, 32(22), 5023–5032.PubMedCentralPubMedCrossRefGoogle Scholar
  142. 142.
    Uemura, T., Takamatsu, K., Ikeda, M., et al. (2012). Transplantation of induced pluripotent stem cell-derived neurospheres for peripheral nerve repair. Biochemical and Biophysical Research Communications, 419(1), 130–135.PubMedCrossRefGoogle Scholar
  143. 143.
    Ikeda, M., Uemura, T., Takamatsu, K., et al. (2013). Acceleration of peripheral nerve regeneration using nerve conduits in combination with induced pluripotent stem cell technology and a basic fibroblast growth factor drug delivery system. Journal of Biomedical Materials Research Part A.Google Scholar
  144. 144.
    Pomp, O., Brokhman, I., Ziegler, L., et al. (2008). PA6-induced human embryonic stem cell-derived neurospheres: a new source of human peripheral sensory neurons and neural crest cells. Brain Research, 1230, 50–60.PubMedCrossRefGoogle Scholar
  145. 145.
    Nakagawa, M., Koyanagi, M., Tanabe, K., et al. (2008). Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nature Biotechnology, 26(1), 101–106.PubMedCrossRefGoogle Scholar
  146. 146.
    Melino, G. (2011). p63 is a suppressor of tumorigenesis and metastasis interacting with mutant p53. Cell Death and Differentiation, 18(9), 1487–1499.PubMedCentralPubMedCrossRefGoogle Scholar
  147. 147.
    Koyanagi, M., Takahashi, J., Arakawa, Y., et al. (2008). Inhibition of the Rho/ROCK pathway reduces apoptosis during transplantation of embryonic stem cell-derived neural precursors. Journal of Neuroscience Research, 86(2), 270–280.PubMedCrossRefGoogle Scholar
  148. 148.
    Huangfu, D., Osafune, K., Maehr, R., et al. (2008). Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nature Biotechnology, 26(11), 1269–1275.PubMedCrossRefGoogle Scholar
  149. 149.
    Wernig, M., Meissner, A., Foreman, R., et al. (2007). In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature, 448(7151), 318–324.PubMedCrossRefGoogle Scholar
  150. 150.
    Stadtfeld, M., Nagaya, M., Utikal, J., Weir, G., & Hochedlinger, K. (2008). Induced pluripotent stem cells generated without viral integration. Science, 322(5903), 945–949.PubMedCentralPubMedCrossRefGoogle Scholar
  151. 151.
    Okita, K., Nakagawa, M., Hyenjong, H., Ichisaka, T., & Yamanaka, S. (2008). Generation of mouse induced pluripotent stem cells without viral vectors. Science, 322(5903), 949–953.PubMedCrossRefGoogle Scholar
  152. 152.
    Zhou, H., Wu, S., Joo, J. Y., et al. (2009). Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell, 4(5), 381–384.PubMedCrossRefGoogle Scholar
  153. 153.
    Kim, D., Kim, C., Moon, J., et al. (2009). Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell, 4(6), 472.PubMedCentralPubMedCrossRefGoogle Scholar
  154. 154.
    Warren, L., Manos, P. D., Ahfeldt, T., et al. (2010). Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell, 7(5), 618–630.PubMedCentralPubMedCrossRefGoogle Scholar
  155. 155.
    Desponts, C., Ding, S. (2010). Using small molecules to improve generation of induced pluripotent stem cells from somatic cells. Cellular Programming and Reprogramming, 207–218.Google Scholar
  156. 156.
    Woltjen, K., Michael, I. P., Mohseni, P., et al. (2009). PiggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature, 458(7239), 766–770.PubMedCentralPubMedCrossRefGoogle Scholar
  157. 157.
    Kaji, K., Norrby, K., Paca, A., Mileikovsky, M., Mohseni, P., & Woltjen, K. (2009). Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature, 458(7239), 771–775.PubMedCentralPubMedCrossRefGoogle Scholar
  158. 158.
    Jia, F., Wilson, K. D., Sun, N., et al. (2010). A nonviral minicircle vector for deriving human iPS cells. Nature Methods, 7(3), 197–199.PubMedCentralPubMedCrossRefGoogle Scholar
  159. 159.
    Yu, J., Hu, K., Smuga-Otto, K., et al. (2009). Human induced pluripotent stem cells free of vector and transgene sequences. Science, 324(5928), 797–801.PubMedCentralPubMedCrossRefGoogle Scholar
  160. 160.
    Chou, B., Mali, P., Huang, X., et al. (2011). Efficient human iPS cell derivation by a non-integrating plasmid from blood cells with unique epigenetic and gene expression signatures. Cell Research, 21(3), 518–529.PubMedCentralPubMedCrossRefGoogle Scholar
  161. 161.
    Ban, H., Nishishita, N., Fusaki, N., et al. (2011). Efficient generation of transgene-free human induced pluripotent stem cells (iPSCs) by temperature-sensitive Sendai virus vectors. Proceedings of the National Academy of Sciences, 108(34), 14234–14239.CrossRefGoogle Scholar
  162. 162.
    Li, J., Christophersen, N. S., Hall, V., Soulet, D., & Brundin, P. (2008). Critical issues of clinical human embryonic stem cell therapy for brain repair. Trends in Neurosciences, 31(3), 146–153.PubMedCrossRefGoogle Scholar
  163. 163.
    Yamanaka, S., Tanabe, K. (2009). Method for producing induced pluripotent stem cells, US Patent App. 13/059,188.Google Scholar
  164. 164.
    Kawasaki, H., Mizuseki, K., Nishikawa, S., et al. (2000). Induction of midbrain dopaminergic neurons from ES cells by stromal cell–derived inducing activity. Neuron, 28(1), 31–40.PubMedCrossRefGoogle Scholar
  165. 165.
    Chambers, S. M., Qi, Y., Mica, Y., et al. (2012). Combined small-molecule inhibition accelerates developmental timing and converts human pluripotent stem cells into nociceptors. Nature Biotechnology, 30(7), 715–720.PubMedCentralPubMedCrossRefGoogle Scholar
  166. 166.
    Kreitzer, F. R., Salomonis, N., Sheehan, A., et al. (2013). A robust method to derive functional neural crest cells from human pluripotent stem cells. American Journal of Stem Cells, 2(2), 119.PubMedCentralPubMedGoogle Scholar
  167. 167.
    Vierbuchen, T., Ostermeier, A., Pang, Z. P., Kokubu, Y., Südhof, T. C., & Wernig, M. (2010). Direct conversion of fibroblasts to functional neurons by defined factors. Nature, 463(7284), 1035–1041.PubMedCentralPubMedCrossRefGoogle Scholar
  168. 168.
    Yang, N., Zuchero, J. B., Ahlenius, H., et al. (2013). Generation of oligodendroglial cells by direct lineage conversion. Nature Biotechnology, 31(5), 434–439.PubMedCentralPubMedCrossRefGoogle Scholar
  169. 169.
    Najm, F. J., Lager, A. M., Zaremba, A., et al. (2013). Transcription factor-mediated reprogramming of fibroblasts to expandable, myelinogenic oligodendrocyte progenitor cells. Nature Biotechnology, 31(5), 426–433.PubMedCentralPubMedCrossRefGoogle Scholar
  170. 170.
    Parkinson, D. B., Bhaskaran, A., Droggiti, A., et al. (2004). Krox-20 inhibits Jun-NH2-terminal kinase/c-Jun to control Schwann cell proliferation and death. Journal of Cell Biology, 164(3), 385–394.PubMedCentralPubMedCrossRefGoogle Scholar
  171. 171.
    Ryu, E. J., Wang, J. Y., Le, N., et al. (2007). Misexpression of Pou3f1 results in peripheral nerve hypomyelination and axonal loss. Journal of Neuroscience, 27(43), 11552–11559.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Neuroscience, Section Medical Physiology, University Medical Center GroningenUniversity of GroningenGroningenThe Netherlands

Personalised recommendations