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Stem Cell Based Strategies for Spinal Cord Injury Repair

  • Alexa Reeves
  • Hans S. Keirstead
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 760)

Abstract

As our understanding and ability to direct the differentiation of stem cells grows, specific targets and strategies to incorporate them are essential to define. Any cell-based transplantation strategy is fundamentally a combination therapy as either phenotypic or trophic mechanisms may contribute to functional recovery of the injured spinal cord. Both the transplant population as well as the recipient site will guide the growth factor expression profile and the phenotype of the transplanted cells. Although the use of high purity populations derived from stem cells will result in more regulated repair mechanisms, multiple challenges to the use of stem cell based strategies for SCI remain.

Keywords

Stem Cell Spinal Cord Injury Neural Stem Cell Spinal Muscular Atrophy Human Embryonic Stem Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Sekhon LH, Fehlings MG. Epidemiology, demographics, and pathophysiology of acute spinal cord injury. Spine 2001; 26(24 Suppl):S2–S12.PubMedCrossRefGoogle Scholar
  2. 2.
    Schoenfeld AJ, McCriskin B, Hsiao M et al. Incidence and epidemiology of spinal cord injury within a closed American population: the United States military (2000–2009). Spinal Cord 2011; 49(8):874–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Dodwell ER, Kwon BK, Hughes B et al. Spinal column and spinal cord injuries in mountain bikers: a 13-year review. Am J Sports Med 2010; 38(8):1647–1652.PubMedCrossRefGoogle Scholar
  4. 4.
    Fehlings MG, Wilson JR. Timing of surgical intervention in spinal trauma: what does the evidence indicate? Spine 2010; 35(21 Suppl):S159–S160.PubMedCrossRefGoogle Scholar
  5. 5.
    Biering-Sørensen F, Bickenbach JE, Masry ElWS et al. ISCoS-WHO collaboration. International Perspectives of Spinal Cord Injury (IPSCI) report. Spinal Cord 2011; 49(6):679–83.PubMedCrossRefGoogle Scholar
  6. 6.
    Nayak MS, Kim Y, Goldman M et al. Cellular therapies in motor neuron diseases. Biochim Biophys Acta 2006; 1762(11–12):1128–1138.PubMedCrossRefGoogle Scholar
  7. 7.
    Lin VW, Cardenas DD. Spinal cord medicine. Demos Medical Pub 2003; 1043.Google Scholar
  8. 8.
    Sendtner M. Therapy development in spinal muscular atrophy. Nat Neurosci 2010; 13(7):795–799.PubMedCrossRefGoogle Scholar
  9. 9.
    Ebert AD, Yu J, Rose FF et al. Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 2009; 457(7227):277–280.PubMedCrossRefGoogle Scholar
  10. 10.
    Jaenisch R, Young R. Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming. Cell 2008; 132(4):567–582.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Park I, Zhao R, West JA et al. Reprogramming of human somatic cells to pluripotency with defined factors. Nature 2008; 451(7175):141–146.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Takahashi K, Tanabe K, Ohnuki M et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007; 131(5):861–872.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Wyatt TJ, Keirstead HS. Stem cell-derived neurotrophic support for the neuromuscular junction in spinal muscular atrophy. Expert Opin Biol Ther 2010; 10(11):1587–1594.PubMedCrossRefGoogle Scholar
  14. 14.
    Niibe K, Kawamura Y, Araki D et al. Purified mesenchymal stem cells are an efficient source for iPS cell induction. PLoS ONE 2011; 6(3):e17610.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Doi A, Park I, Wen B et al. Differential methylation of tissue-and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts. Nat Genet 2009; 41(12):1350–1353.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Okita K, Matsumura Y, Sato Y et al. A more efficient method to generate integration-free human iPS cells. Nat Methods 2011; 8(5):409–12.PubMedCrossRefGoogle Scholar
  17. 17.
    Stadtfeld M, Nagaya M, Utikal J et al. Induced pluripotent stem cells generated without viral integration. Science 2008; 322(5903):945–949.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Yamanaka S. A fresh look at iPS cells. Cell 2009; 137(1):13–17.PubMedCrossRefGoogle Scholar
  19. 19.
    Tsuji O, Miura K, Okada Y et al. Therapeutic potential of appropriately evaluated safe-induced pluripotent stem cells for spinal cord injury. Proc Natl Acad Sci U S A 2010; 107(28):12704–12709.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Iwanami A, Kaneko S, Nakamura M et al. Transplantation of human neural stem cells for spinal cord injury in primates. J Neurosci Res 2005; 80(2):182–190.PubMedCrossRefGoogle Scholar
  21. 21.
    Yamane J, Nakamura M, Iwanami A et al. Transplantation of galectin-1-expressing human neural stem cells into the injured spinal cord of adult common marmosets. J Neurosci Res 2010; 88(7):1394–1405.PubMedGoogle Scholar
  22. 22.
    Snyder EY, Deitcher DL, Walsh C et al. Multipotent neural cell lines can engraft and participate in development of mouse cerebellum. Cell 1992; 68(1):33–51.PubMedCrossRefGoogle Scholar
  23. 23.
    Lois C, Alvarez-Buylla A. Proliferating subventricular zone cells in the adult mammalian forebrain can differentiate into neurons and glia. Proc Natl Acad Sci U S A 1993; 90(5):2074–2077.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Mayer-Proschel M, Kalyani AJ, Mujtaba T et al. Isolation of lineage-restricted neuronal precursors from multipotent neuroepithelial stem cells. Neuron 1997; 19(4):773–785.PubMedCrossRefGoogle Scholar
  25. 25.
    Shi J, Marinovich A, Barres BA. Purification and characterization of adult oligodendrocyte precursor cells from the rat optic nerve. J Neurosci 1998; 18(12):4627–4636.PubMedCrossRefGoogle Scholar
  26. 26.
    Caldwell MA, He X, Wilkie N et al. Growth factors regulate the survival and fate of cells derived from human neurospheres. Nat Biotechnol 2001; 19(5):475–479.PubMedCrossRefGoogle Scholar
  27. 27.
    Nunes MC, Roy NS, Keyoung HM et al. Identification and isolation of multipotential neural progenitor cells from the subcortical white matter of the adult human brain. Nat Med 2003; 9(4):439–447.PubMedCrossRefGoogle Scholar
  28. 28.
    Lladó J, Haenggeli C, Maragakis NJ et al. Neural stem cells protect against glutamate-induced excitotoxicity and promote survival of injured motor neurons through the secretion of neurotrophic factors. Mol Cell Neurosci 2004; 27(3):322–331.PubMedCrossRefGoogle Scholar
  29. 29.
    Lu P, Jones LL, Snyder EY et al. Neural stem cells constitutively secrete neurotrophic factors and promote extensive host axonal growth after spinal cord injury. Exp Neurol 2003; 181(2):115–129.PubMedCrossRefGoogle Scholar
  30. 30.
    Doetsch F, Caillé I, Lim DA et al. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 1999; 97(6):703–716.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Wright LS, Prowse KR, Wallace K et al. Human progenitor cells isolated from the developing cortex undergo decreased neurogenesis and eventual senescence following expansion in vitro. Exp Cell Res 2006; 312(11):2107–2120.PubMedCrossRefGoogle Scholar
  32. 32.
    Einstein O, Karussis D, Grigoriadis N et al. Intraventricular transplantation of neural precursor cell spheres attenuates acute experimental allergic encephalomyelitis. Mol Cell Neurosci 2003; 24(4):1074–1082.PubMedCrossRefGoogle Scholar
  33. 33.
    Ben-Hur T, Einstein O, Mizrachi-Kol R et al. Transplanted multipotential neural precursor cells migrate into the inflamed white matter in response to experimental autoimmune encephalomyelitis. Glia 2003; 41(1):73–80.PubMedCrossRefGoogle Scholar
  34. 34.
    Pluchino S, Quattrini A, Brambilla E et al. Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature 2003; 422(6933):688–694.PubMedCrossRefGoogle Scholar
  35. 35.
    Bulte JWM, Ben-Hur T, Miller BR et al. MR microscopy of magnetically labeled neurospheres transplanted into the Lewis EAE rat brain. Magn Reson Med 2003; 50(1):201–205.PubMedCrossRefGoogle Scholar
  36. 36.
    Yoon SH, Shim YS, Park YH et al. Complete spinal cord injury treatment using autologous bone marrow cell transplantation and bone marrow stimulation with granulocyte macrophage-colony stimulating factor: Phase I/II clinical trial. Stem Cells 2007; 25(8):2066–2073.PubMedCrossRefGoogle Scholar
  37. 37.
    Callera F, doNascimento RX. Delivery of autologous bone marrow precursor cells into the spinal cord via lumbar puncture technique in patients with spinal cord injury: a preliminary safety study. Exp Hematol 2006; 34(2):130–131.PubMedCrossRefGoogle Scholar
  38. 38.
    Akiyama Y, Radtke C, Kocsis JD. Remyelination of the rat spinal cord by transplantation of identified bone marrow stromal cells. J Neurosci 2002; 22(15):6623–6630.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Koda M, Okada S, Nakayama T et al. Hematopoietic stem cell and marrow stromal cell for spinal cord injury in mice. Neuroreport 2005; 16(16):1763–1767.PubMedCrossRefGoogle Scholar
  40. 40.
    Hofstetter CP, Holmström NAV, Lilja JA et al. Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome. Nat Neurosci 2005; 8(3):346–353.PubMedCrossRefGoogle Scholar
  41. 41.
    Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005; 105(4):1815–1822.PubMedCrossRefGoogle Scholar
  42. 42.
    Song S, Kamath S, Mosquera D et al. Expression of brain natriuretic peptide by human bone marrow stromal cells. Exp Neurol 2004; 185(1):191–197.PubMedCrossRefGoogle Scholar
  43. 43.
    Lu P, Jones LL, Tuszynski MH. BDNF-expressing marrow stromal cells support extensive axonal growth at sites of spinal cord injury. Exp Neurol 2005; 191(2):344–360.PubMedCrossRefGoogle Scholar
  44. 44.
    Thomson JA, Itskovitz-Eldor J, Shapiro SS et al. Embryonic stem cell lines derived from human blastocysts. Science 1998; 282(5391):1145–1147.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Coutts M, Keirstead HS. Stem cells for the treatment of spinal cord injury. Exp Neurol 2008; 209(2): 368–377.PubMedCrossRefGoogle Scholar
  46. 46.
    Billon N, Jolicoeur C, Raff M. Generation and characterization of oligodendrocytes from lineage-selectable embryonic stem cells in vitro. Methods Mol Biol 2006; 330:15–32.PubMedGoogle Scholar
  47. 47.
    Finley MF, Kulkarni N, Huettner JE. Synapse formation and establishment of neuronal polarity by P19 embryonic carcinoma cells and embryonic stem cells. J Neurosci 1996; 16(3):1056–1065.PubMedCrossRefGoogle Scholar
  48. 48.
    Deshpande DM, Kim Y, Martinez T et al. Recovery from paralysis in adult rats using embryonic stem cells Ann Neurol 2006; 60(1):32–44.PubMedCrossRefGoogle Scholar
  49. 49.
    Carpenter MK, Inokuma MS, Denham J et al. Enrichment of neurons and neural precursors from human embryonic stem cells. Exp Neurol 2001; 172(2):383–397.PubMedCrossRefGoogle Scholar
  50. 50.
    Li X, Du Z, Zarnowska ED et al. Specification of motoneurons from human embryonic stem cells. Nat Biotechnol 2005; 23(2):215–221.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Keirstead HS, Nistor G, Bernal G et al. Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci 2005; 25(19):4694–4705.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Rossi SL, Nistor G, Wyatt T et al. Histological and functional benefit following transplantation of motor neuron progenitors to the injured rat spinal cord. PLoS ONE. 2010; 5(7):e11852.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Schultz SS, Lucas PA. Human stem cells isolated from adult skeletal muscle differentiate into neural phenotypes. J Neurosci Methods 2006; 152(1–2):144–155.PubMedCrossRefGoogle Scholar
  54. 54.
    Woodbury D, Schwarz EJ, Prockop DJ et al. Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res 2000; 61(4):364–370.PubMedCrossRefGoogle Scholar
  55. 55.
    Lee SH, Lumelsky N, Studer L et al. Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells. Nat Biotechnol 2000; 18(6):675–679.PubMedCrossRefGoogle Scholar
  56. 56.
    Nistor G, Haque N, Carpenter M et al. Human embryonic stem cells differentiate into oligodendrocytes in high purity and myelinate after spinal cord transplantation-2004-Glia-Wiley Online Library. Glia 2005.Google Scholar
  57. 57.
    Zhang YW, Denham J, Thies RS. Oligodendrocyte progenitor cells derived from human embryonic stem cells express neurotrophic factors. Stem Cells Dev 2006; 15(6):943–952.PubMedCrossRefGoogle Scholar
  58. 58.
    Dreyfus CF, Dai X, Lercher LD et al. Expression of neurotrophins in the adult spinal cord in vivo. J Neurosci Res 1999; 56(1):1–7.PubMedCrossRefGoogle Scholar
  59. 59.
    Corti S, Nizzardo M, Nardini M et al. Embryonic stem cell-derived neural stem cells improve spinal muscular atrophy phenotype in mice. Brain 2010; 133(Pt 2):465–481.PubMedCrossRefGoogle Scholar
  60. 60.
    Grumbles RM, Sesodia S, Wood PM et al. Neurotrophic factors improve motoneuron survival and function of muscle reinnervated by embryonic neurons. J Neuropathol Exp Neurol 2009; 68(7):736–746.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Rossi SL, Keirstead HS. Stem cells and spinal cord regeneration. Current Opinion in Biotechnology 2009; 20(5):552–562.PubMedCrossRefGoogle Scholar
  62. 62.
    Sharp J, Keirstead H. Therapeutic applications of oligodendrocyte precursors derived from human embryonic stem cells. Current Opinion in Biotechnology 2007; 18(5):434–440.PubMedCrossRefGoogle Scholar
  63. 63.
    Salazar DL, Uchida N, Hamers FPT et al. Human neural stem cells differentiate and promote locomotor recovery in an early chronic spinal cord injury NOD-scid mouse model. PLoS ONE 2010; 5(8):e12272.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Fawcett JW, Curt A, Steeves JD et al. Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: spontaneous recovery after spinal cord injury and statistical power needed for therapeutic clinical trials. Spinal Cord 2007; 45(3):190–205.PubMedCrossRefGoogle Scholar
  65. 65.
    Steeves JD, Lammertse D, Curt A et al. Guidelines for the conduct of clinical trials for spinal cord injury (SCI) as developed by the ICCP panel: clinical trial outcome measures. Spinal Cord 2007; 45(3):206–221.PubMedCrossRefGoogle Scholar
  66. 66.
    Tuszynski MH, Steeves JD, Fawcett JW et al. Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP Panel: clinical trial inclusion/exclusion criteria and ethics. Spinal Cord 2007; 45(3):222–231.PubMedCrossRefGoogle Scholar
  67. 67.
    Lammertse D, Tuszynski MH, Steeves JD et al. Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: clinical trial design. Spinal Cord 2007; 45(3):232–242.PubMedCrossRefGoogle Scholar
  68. 68.
    Hofstetter CP, Holmstrom NA, Lilja JA et al. Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome. Nat Neurosci 2005; 8:346–353.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2012

Authors and Affiliations

  • Alexa Reeves
    • 1
  • Hans S. Keirstead
    • 2
  1. 1.Department of Neurological SurgeryUniversity of California IrvineOrangeUSA
  2. 2.Reeve Irvine Research CenterUniversity of California IrvineIrvineUSA

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