iPSC-derived neural precursor cells: potential for cell transplantation therapy in spinal cord injury

Review

Abstract

A number of studies have demonstrated that transplantation of neural precursor cells (NPCs) promotes functional recovery after spinal cord injury (SCI). However, the NPCs had been mostly harvested from embryonic stem cells or fetal tissue, raising the ethical concern. Yamanaka and his colleagues established induced pluripotent stem cells (iPSCs) which could be generated from somatic cells, and this innovative development has made rapid progression in the field of SCI regeneration. We and other groups succeeded in producing NPCs from iPSCs, and demonstrated beneficial effects after transplantation for animal models of SCI. In particular, efficacy of human iPSC–NPCs in non-human primate SCI models fostered momentum of clinical application for SCI patients. At the same time, however, artificial induction methods in iPSC technology created alternative issues including genetic and epigenetic abnormalities, and tumorigenicity after transplantation. To overcome these problems, it is critically important to select origins of somatic cells, use integration-free system during transfection of reprogramming factors, and thoroughly investigate the characteristics of iPSC–NPCs with respect to quality management. Moreover, since most of the previous studies have focused on subacute phase of SCI, establishment of effective NPC transplantation should be evaluated for chronic phase hereafter. Our group is currently preparing clinical-grade human iPSC–NPCs, and will move forward toward clinical study for subacute SCI patients soon in the near future.

Keywords

Central nervous system Stem cell graft Regeneration Mechanisms for functional recovery Safety issue 

Notes

Acknowledgements

We appreciate the help of Drs. Masaya Nakamura, RyoYamaguchi, Munehisa Shinozaki, Keiko Sugai, Kota Kojima, who all members of the spinal cord research team in the Department of Physiology and Orthopaedic Surgery. This work was supported by Research Center Network for Realization of Regenerative Medicine the Japan Agency for Medical Research and Development (AMED) (to H.O.). H.O. is a founding scientist of SanBio Co. Ltd and K Pharma Inc. N.N. has no conflict of interest.

References

  1. 1.
    Lee BB, Cripps RA, Fitzharris M, Wing PC (2014) The global map for traumatic spinal cord injury epidemiology: update 2011, global incidence rate. Spinal Cord 52(2):110–116PubMedCrossRefGoogle Scholar
  2. 2.
    Fehlings MG, Wilson JR, Cho N (2014) Methylprednisolone for the treatment of acute spinal cord injury: counterpoint. Neurosurgery 61(Suppl 1):36–42PubMedCrossRefGoogle Scholar
  3. 3.
    Hurlbert RJ (2014) Methylprednisolone for the treatment of acute spinal cord injury: point. Neurosurgery 61(Suppl 1):32–35PubMedCrossRefGoogle Scholar
  4. 4.
    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(5):861–872PubMedCrossRefGoogle Scholar
  5. 5.
    Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663–676PubMedCrossRefGoogle Scholar
  6. 6.
    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(3):523–533PubMedCrossRefGoogle Scholar
  7. 7.
    Tator CH, Fehlings MG (1991) Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascular mechanisms. J Neurosurg 75(1):15–26PubMedCrossRefGoogle Scholar
  8. 8.
    Wilson JR, Forgione N, Fehlings MG (2013) Emerging therapies for acute traumatic spinal cord injury. CMAJ 185(6):485–492PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Reynolds BA, Tetzlaff W, Weiss S (1992) A multipotent EGF-responsive striatal embryonic progenitor cell produces neurons and astrocytes. J Neurosci 12(11):4565–4574PubMedGoogle Scholar
  10. 10.
    Frisen J, Johansson CB, Torok C, Risling M, Lendahl U (1995) Rapid, widespread, and longlasting induction of nestin contributes to the generation of glial scar tissue after CNS injury. J Cell Biol 131(2):453–464PubMedCrossRefGoogle Scholar
  11. 11.
    Nakamura M, Houghtling RA, MacArthur L, Bayer BM, Bregman BS (2003) Differences in cytokine gene expression profile between acute and secondary injury in adult rat spinal cord. Exp Neurol 184(1):313–325PubMedCrossRefGoogle Scholar
  12. 12.
    Ogawa Y, Sawamoto K, Miyata T, Miyao S, Watanabe M, Nakamura M, Bregman BS, Koike M, Uchiyama Y, Toyama Y, Okano H (2002) Transplantation of in vitro-expanded fetal neural progenitor cells results in neurogenesis and functional recovery after spinal cord contusion injury in adult rats. J Neurosci Res 69(6):925–933PubMedCrossRefGoogle Scholar
  13. 13.
    Karimi-Abdolrezaee S, Eftekharpour E, Wang J, Morshead CM, Fehlings MG (2006) Delayed transplantation of adult neural precursor cells promotes remyelination and functional neurological recovery after spinal cord injury. J Neurosci 26(13):3377–3389PubMedCrossRefGoogle Scholar
  14. 14.
    McDonald JW, Liu XZ, Qu Y, Liu S, Mickey SK, Turetsky D, Gottlieb DI, Choi DW (1999) Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord. Nat Med 5(12):1410–1412PubMedCrossRefGoogle Scholar
  15. 15.
    Okada Y, Matsumoto A, Shimazaki T, Enoki R, Koizumi A, Ishii S, Itoyama Y, Sobue G, Okano H (2008) Spatiotemporal recapitulation of central nervous system development by murine embryonic stem cell-derived neural stem/progenitor cells. Stem Cells 26(12):3086–3098PubMedCrossRefGoogle Scholar
  16. 16.
    Kumagai G, Okada Y, Yamane J, Nagoshi N, Kitamura K, Mukaino M, Tsuji O, Fujiyoshi K, Katoh H, Okada S, Shibata S, Matsuzaki Y, Toh S, Toyama Y, Nakamura M, Okano H (2009) Roles of ES cell-derived gliogenic neural stem/progenitor cells in functional recovery after spinal cord injury. PloS One 4(11):e7706PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    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 USA 102(39):14069–14074PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Kimura M, Inoko H, Katsuki M, Ando A, Sato T, Hirose T, Takashima H, Inayama S, Okano H, Takamatsu K et al (1985) Molecular genetic analysis of myelin-deficient mice: shiverer mutant mice show deletion in gene(s) coding for myelin basic protein. J Neurochem 44(3):692–696PubMedCrossRefGoogle Scholar
  19. 19.
    Mikoshiba K, Okano H, Tamura T, Ikenaka K (1991) Structure and function of myelin protein genes. Annu Rev Neurosci 14:201–217PubMedCrossRefGoogle Scholar
  20. 20.
    Roach A, Boylan K, Horvath S, Prusiner SB, Hood LE (1983) Characterization of cloned cDNA representing rat myelin basic protein: absence of expression in brain of shiverer mutant mice. Cell 34(3):799–806PubMedCrossRefGoogle Scholar
  21. 21.
    Yasuda A, Tsuji O, Shibata S, Nori S, Takano M, Kobayashi Y, Takahashi Y, Fujiyoshi K, Hara CM, Miyawaki A, Okano HJ, Toyama Y, Nakamura M, Okano H (2011) Significance of remyelination by neural stem/progenitor cells transplanted into the injured spinal cord. Stem Cells 29(12):1983–1994PubMedCrossRefGoogle Scholar
  22. 22.
    Barnabe-Heider F, Frisen J (2008) Stem cells for spinal cord repair. Cell Stem Cell 3(1):16–24PubMedCrossRefGoogle Scholar
  23. 23.
    Keirstead HS, Nistor G, Bernal G, Totoiu M, Cloutier F, Sharp K, Steward O (2005) Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci 25(19):4694–4705PubMedCrossRefGoogle Scholar
  24. 24.
    Kumamaru H, Ohkawa Y, Saiwai H, Yamada H, Kubota K, Kobayakawa K, Akashi K, Okano H, Iwamoto Y, Okada S (2012) Direct isolation and RNA-seq reveal environment-dependent properties of engrafted neural stem/progenitor cells. Nat Commun 3:1140PubMedCrossRefGoogle Scholar
  25. 25.
    Nishimura S, Yasuda A, Iwai H, Takano M, Kobayashi Y, Nori S, Tsuji O, Fujiyoshi K, Ebise H, Toyama Y, Okano H, Nakamura M (2013) Time-dependent changes in the microenvironment of injured spinal cord affects the therapeutic potential of neural stem cell transplantation for spinal cord injury. Mol Brain 6:3PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Abematsu M, Tsujimura K, Yamano M, Saito M, Kohno K, Kohyama J, Namihira M, Komiya S, Nakashima K (2010) Neurons derived from transplanted neural stem cells restore disrupted neuronal circuitry in a mouse model of spinal cord injury. J Clin Investig 120(9):3255–3266PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Okano H, Yamanaka S (2014) iPS cell technologies: significance and applications to CNS regeneration and disease. Mol Brain 7:22PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Miura K, Okada Y, Aoi T, Okada A, Takahashi K, Okita K, Nakagawa M, Koyanagi M, Tanabe K, Ohnuki M, Ogawa D, Ikeda E, Okano H, Yamanaka S (2009) Variation in the safety of induced pluripotent stem cell lines. Nat Biotechnol 27(8):743–745PubMedCrossRefGoogle Scholar
  29. 29.
    Okita K, Ichisaka T, Yamanaka S (2007) Generation of germline-competent induced pluripotent stem cells. Nature 448(7151):313–317PubMedCrossRefGoogle Scholar
  30. 30.
    Kang E, Wang X, Tippner-Hedges R, Ma H, Folmes CD, Gutierrez NM, Lee Y, Van Dyken C, Ahmed R, Li Y, Koski A, Hayama T, Luo S, Harding CO, Amato P, Jensen J, Battaglia D, Lee D, Wu D, Terzic A, Wolf DP, Huang T, Mitalipov S (2016) Age-related accumulation of somatic mitochondrial DNA mutations in adult-derived human iPSCs. Cell Stem Cell 18(5):625–636PubMedCrossRefGoogle Scholar
  31. 31.
    Tsuji O, Miura K, Okada Y, Fujiyoshi K, Mukaino M, Nagoshi N, Kitamura K, Kumagai G, Nishino M, Tomisato S, Higashi H, Nagai T, Katoh H, Kohda K, Matsuzaki Y, Yuzaki M, Ikeda E, Toyama Y, Nakamura M, Yamanaka S, Okano H (2010) Therapeutic potential of appropriately evaluated safe-induced pluripotent stem cells for spinal cord injury. Proc Natl Acad Sci USA 107(28):12704–12709PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Woltjen K, Michael IP, Mohseni P, Desai R, Mileikovsky M, Hamalainen R, Cowling R, Wang W, Liu P, Gertsenstein M, Kaji K, Sung HK, Nagy A (2009) piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 458(7239):766–770PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Salewski RP, Buttigieg J, Mitchell RA, van der Kooy D, Nagy A, Fehlings MG (2013) The generation of definitive neural stem cells from PiggyBac transposon-induced pluripotent stem cells can be enhanced by induction of the NOTCH signaling pathway. Stem Cells Dev 22(3):383–396PubMedCrossRefGoogle Scholar
  34. 34.
    Salewski RP, Mitchell RA, Li L, Shen C, Milekovskaia M, Nagy A, Fehlings MG (2015) Transplantation of induced pluripotent stem cell-derived neural stem cells mediate functional recovery following thoracic spinal cord injury through remyelination of axons. Stem Cells Trans Med 4(7):743–754CrossRefGoogle Scholar
  35. 35.
    Nori S, Okada Y, Yasuda A, Tsuji O, Takahashi Y, Kobayashi Y, Fujiyoshi K, Koike M, Uchiyama Y, Ikeda E, Toyama Y, Yamanaka S, Nakamura M, Okano H (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(40):16825–16830PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    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(12):e52787PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Lu P, Wang Y, Graham L, McHale K, Gao M, Wu D, Brock J, Blesch A, Rosenzweig ES, Havton LA, Zheng B, Conner JM, Marsala M, Tuszynski MH (2012) Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell 150(6):1264–1273PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Lu P, Woodruff G, Wang Y, Graham L, Hunt M, Wu D, Boehle E, Ahmad R, Poplawski G, Brock J, Goldstein LS, Tuszynski MH (2014) Long-distance axonal growth from human induced pluripotent stem cells after spinal cord injury. Neuron 83(4):789–796PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Tashiro S, Nishimura S, Iwai H, Sugai K, Zhang L, Shinozaki M, Iwanami A, Toyama Y, Liu M, Okano H, Nakamura M (2016) Functional recovery from neural stem/progenitor cell transplantation combined with treadmill training in mice with chronic spinal cord injury. Sci Rep 6:30898PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Tashiro S, Shinozaki M, Mukaino M, Renault-Mihara F, Toyama Y, Liu M, Nakamura M, Okano H (2015) BDNF induced by treadmill training contributes to the suppression of spasticity and allodynia after spinal cord injury via upregulation of KCC2. Neurorehabilit Neural Repair 29(7):677–689CrossRefGoogle Scholar
  41. 41.
    Ruzicka J, Machova-Urdzikova L, Gillick J, Amemori T, Romanyuk N, Karova K, Zaviskova K, Dubisova J, Kubinova S, Murali R, Sykova E, Jhanwar-Uniyal M, Jendelova P (2017) A comparative study of three different types of stem cells for treatment of rat spinal cord injury. Cell Transpl 26(4):585–603CrossRefGoogle Scholar
  42. 42.
    Fujimoto Y, Abematsu M, Falk A, Tsujimura K, Sanosaka T, Juliandi B, Semi K, Namihira M, Komiya S, Smith A, Nakashima K (2012) Treatment of a mouse model of spinal cord injury by transplantation of human induced pluripotent stem cell-derived long-term self-renewing neuroepithelial-like stem cells. Stem Cells 30(6):1163–1173PubMedCrossRefGoogle Scholar
  43. 43.
    Oh J, Lee KI, Kim HT, You Y, do Yoon H, Song KY, Cheong E, Ha Y, Hwang DY (2015) Human-induced pluripotent stem cells generated from intervertebral disc cells improve neurologic functions in spinal cord injury. Stem Cell Res Ther 6:125PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Romanyuk N, Amemori T, Turnovcova K, Prochazka P, Onteniente B, Sykova E, Jendelova P (2015) Beneficial effect of human induced pluripotent stem cell-derived neural precursors in spinal cord injury repair. Cell Transpl 24(9):1781–1797CrossRefGoogle Scholar
  45. 45.
    Pomeshchik Y, Puttonen KA, Kidin I, Ruponen M, Lehtonen S, Malm T, Akesson E, Hovatta O, Koistinaho J (2015) Transplanted human induced pluripotent stem cell-derived neural progenitor cells do not promote functional recovery of pharmacologically immunosuppressed mice with contusion spinal cord injury. Cell Transpl 24(9):1799–1812CrossRefGoogle Scholar
  46. 46.
    Sekhon LH, Fehlings MG (2001) Epidemiology, demographics, and pathophysiology of acute spinal cord injury. Spine 26(24 Suppl):S2–S12PubMedCrossRefGoogle Scholar
  47. 47.
    Kwon BK, Okon EB, Tsai E, Beattie MS, Bresnahan JC, Magnuson DK, Reier PJ, McTigue DM, Popovich PG, Blight AR, Oudega M, Guest JD, Weaver LC, Fehlings MG, Tetzlaff W (2011) A grading system to evaluate objectively the strength of pre-clinical data of acute neuroprotective therapies for clinical translation in spinal cord injury. J Neurotrauma 28(8):1525–1543PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Doulames VM, Plant GW (2016) Induced pluripotent stem cell therapies for cervical spinal cord injury. Int J Mol Sci 17(4):530PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Hodgetts SI, Edel M, Harvey AR (2015) The state of play with iPSCs and spinal cord injury models. J Clin Med 4(1):193–203PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Li K, Javed E, Scura D, Hala TJ, Seetharam S, Falnikar A, Richard JP, Chorath A, Maragakis NJ, Wright MC, Lepore AC (2015) Human iPS cell-derived astrocyte transplants preserve respiratory function after spinal cord injury. Exp Neurol 271:479–492PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Nutt SE, Chang EA, Suhr ST, Schlosser LO, Mondello SE, Moritz CT, Cibelli JB, Horner PJ (2013) Caudalized human iPSC-derived neural progenitor cells produce neurons and glia but fail to restore function in an early chronic spinal cord injury model. Exp Neurol 248:491–503PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Nakagawa M, Koyanagi M, Tanabe K, Takahashi K, Ichisaka T, Aoi T, Okita K, Mochiduki Y, Takizawa N, Yamanaka S (2008) Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol 26(1):101–106PubMedCrossRefGoogle Scholar
  53. 53.
    Nori S, Okada Y, Nishimura S, Sasaki T, Itakura G, Kobayashi Y, Renault-Mihara F, Shimizu A, Koya I, Yoshida R, Kudoh J, Koike M, Uchiyama Y, Ikeda E, Toyama Y, Nakamura M, Okano H (2015) Long-term safety issues of iPSC-based cell therapy in a spinal cord injury model: oncogenic transformation with epithelial–mesenchymal transition. Stem Cell Rep 4(3):360–373CrossRefGoogle Scholar
  54. 54.
    Itakura G, Kobayashi Y, Nishimura S, Iwai H, Takano M, Iwanami A, Toyama Y, Okano H, Nakamura M (2015) Controlling immune rejection is a fail-safe system against potential tumorigenicity after human iPSC-derived neural stem cell transplantation. PloS One 10(2):e0116413PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Okubo T, Iwanami A, Kohyama J, Itakura G, Kawabata S, Nishiyama Y, Sugai K, Ozaki M, Iida T, Matsubayashi K, Matsumoto M, Nakamura M, Okano H (2016) Pretreatment with a gamma-secretase inhibitor prevents tumor-like overgrowth in human iPSC-derived transplants for spinal cord injury. Stem Cell Rep 7(4):649–663CrossRefGoogle Scholar
  56. 56.
    Wang S, Bates J, Li X, Schanz S, Chandler-Militello D, Levine C, Maherali N, Studer L, Hochedlinger K, Windrem M, Goldman SA (2013) Human iPSC-derived oligodendrocyte progenitor cells can myelinate and rescue a mouse model of congenital hypomyelination. Cell Stem Cell 12(2):252–264PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Numasawa-Kuroiwa Y, Okada Y, Shibata S, Kishi N, Akamatsu W, Shoji M, Nakanishi A, Oyama M, Osaka H, Inoue K, Takahashi K, Yamanaka S, Kosaki K, Takahashi T, Okano H (2014) Involvement of ER stress in dysmyelination of Pelizaeus–Merzbacher disease with PLP1 missense mutations shown by iPSC-derived oligodendrocytes. Stem Cell Rep 2(5):648–661CrossRefGoogle Scholar
  58. 58.
    Kawabata S, Takano M, Numasawa-Kuroiwa Y, Itakura G, Kobayashi Y, Nishiyama Y, Sugai K, Nishimura S, Iwai H, Isoda M, Shibata S, Kohyama J, Iwanami A, Toyama Y, Matsumoto M, Nakamura M, Okano H (2016) Grafted human iPS cell-derived oligodendrocyte precursor cells contribute to robust remyelination of demyelinated axons after spinal cord injury. Stem Cell Rep 6(1):1–8CrossRefGoogle Scholar
  59. 59.
    All AH, Gharibani P, Gupta S, Bazley FA, Pashai N, Chou BK, Shah S, Resar LM, Cheng L, Gearhart JD, Kerr CL (2015) Early intervention for spinal cord injury with human induced pluripotent stem cells oligodendrocyte progenitors. PloS One 10(1):e0116933PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Iwai H, Shimada H, Nishimura S, Kobayashi Y, Itakura G, Hori K, Hikishima K, Ebise H, Negishi N, Shibata S, Habu S, Toyama Y, Nakamura M, Okano H (2015) Allogeneic neural stem/progenitor cells derived from embryonic stem cells promote functional recovery after transplantation into injured spinal cord of nonhuman primates. Stem Cells Trans Med 4(7):708–719CrossRefGoogle Scholar
  61. 61.
    Sugai K, Fukuzawa R, Shofuda T, Fukusumi H, Kawabata S, Nishiyama Y, Higuchi Y, Kawai K, Isoda M, Kanematsu D, Hashimoto-Tamaoki T, Kohyama J, Iwanami A, Suemizu H, Ikeda E, Matsumoto M, Kanemura Y, Nakamura M, Okano H (2016) Pathological classification of human iPSC-derived neural stem/progenitor cells towards safety assessment of transplantation therapy for CNS diseases. Mol Brain 9(1):85PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Kakulas BA, Kaelan C (2015) The neuropathological foundations for the restorative neurology of spinal cord injury. Clin Neurol Neurosurg 129(Suppl 1):S1–S7PubMedCrossRefGoogle Scholar
  63. 63.
    Kumamaru H, Saiwai H, Kubota K, Kobayakawa K, Yokota K, Ohkawa Y, Shiba K, Iwamoto Y, Okada S (2013) Therapeutic activities of engrafted neural stem/precursor cells are not dormant in the chronically injured spinal cord. Stem Cells 31(8):1535–1547PubMedCrossRefGoogle Scholar
  64. 64.
    Bradbury EJ, Carter LM (2011) Manipulating the glial scar: chondroitinase ABC as a therapy for spinal cord injury. Brain Res Bull 84(4–5):306–316PubMedCrossRefGoogle Scholar
  65. 65.
    Silver J, Miller JH (2004) Regeneration beyond the glial scar. Nat Rev Neurosci 5(2):146–156PubMedCrossRefGoogle Scholar
  66. 66.
    Coles CH, Shen Y, Tenney AP, Siebold C, Sutton GC, Lu W, Gallagher JT, Jones EY, Flanagan JG, Aricescu AR (2011) Proteoglycan-specific molecular switch for RPTPsigma clustering and neuronal extension. Science 332(6028):484–488PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Okada S, Nakamura M, Katoh H, Miyao T, Shimazaki T, Ishii K, Yamane J, Yoshimura A, Iwamoto Y, Toyama Y, Okano H (2006) Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury. Nat Med 12(7):829–834PubMedCrossRefGoogle Scholar
  68. 68.
    Renault-Mihara F, Okada S, Shibata S, Nakamura M, Toyama Y, Okano H (2008) Spinal cord injury: emerging beneficial role of reactive astrocytes’ migration. Int J Biochem Cell Biol 40(9):1649–1653PubMedCrossRefGoogle Scholar
  69. 69.
    Zhao RR, Fawcett JW (2013) Combination treatment with chondroitinase ABC in spinal cord injury—breaking the barrier. Neurosci Bull 29(4):477–483PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Bradbury EJ, Moon LD, Popat RJ, King VR, Bennett GS, Patel PN, Fawcett JW, McMahon SB (2002) Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature 416(6881):636–640PubMedCrossRefGoogle Scholar
  71. 71.
    Barritt AW, Davies M, Marchand F, Hartley R, Grist J, Yip P, McMahon SB, Bradbury EJ (2006) Chondroitinase ABC promotes sprouting of intact and injured spinal systems after spinal cord injury. J Neurosci 26(42):10856–10867PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Carter LM, Starkey ML, Akrimi SF, Davies M, McMahon SB, Bradbury EJ (2008) The yellow fluorescent protein (YFP-H) mouse reveals neuroprotection as a novel mechanism underlying chondroitinase ABC-mediated repair after spinal cord injury. J Neurosci 28(52):14107–14120PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Karimi-Abdolrezaee S, Schut D, Wang J, Fehlings MG (2012) Chondroitinase and growth factors enhance activation and oligodendrocyte differentiation of endogenous neural precursor cells after spinal cord injury. PloS One 7(5):e37589PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Shinozaki M, Iwanami A, Fujiyoshi K, Tashiro S, Kitamura K, Shibata S, Fujita H, Nakamura M, Okano H (2016) Combined treatment with chondroitinase ABC and treadmill rehabilitation for chronic severe spinal cord injury in adult rats. Neurosci Res 113:37–47PubMedCrossRefGoogle Scholar
  75. 75.
    Ikegami T, Nakamura M, Yamane J, Katoh H, Okada S, Iwanami A, Watanabe K, Ishii K, Kato F, Fujita H, Takahashi T, Okano HJ, Toyama Y, Okano H (2005) Chondroitinase ABC combined with neural stem/progenitor cell transplantation enhances graft cell migration and outgrowth of growth-associated protein-43-positive fibers after rat spinal cord injury. Eur J Neurosci 22(12):3036–3046PubMedCrossRefGoogle Scholar
  76. 76.
    Karimi-Abdolrezaee S, Eftekharpour E, Wang J, Schut D, Fehlings MG (2010) Synergistic effects of transplanted adult neural stem/progenitor cells, chondroitinase, and growth factors promote functional repair and plasticity of the chronically injured spinal cord. J Neurosci 30(5):1657–1676PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of Orthopaedic SurgeryKeio University School of MedicineTokyoJapan
  2. 2.Department of PhysiologyKeio University School of MedicineTokyoJapan

Personalised recommendations