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Stem/Precursor Cell-Based CNS Therapy: The Importance of Circumventing Immune Suppression by Transplanting Autologous Cells

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Abstract

Stem/precursor cell (SPC) therapy for neurodegeneration and neurotrauma has enormous therapeutic potential, but despite ongoing research efforts the success of clinical trials remains limited. Therapies that utilize immune suppression in combination with SPC transplantation have thus far failed to consider the beneficial role of the immune system in central nervous system (CNS) recovery. Systemic immune suppression may prevent neural repair, and in some cases exacerbate the underlying disorder. Until about a decade ago, immunosuppression for CNS disorders was viewed as a therapeutic target, based on the perception that all immune activity in the CNS was destructive. However, recent studies show that the infiltration of blood-borne immune cells into the CNS following neurotrauma and during chronic neurodegeneration promote CNS protection and regeneration. In the context of SPC therapies, although immune suppression prevents rejection of non-autologous cell grafts, it also prevents the restorative immune response by eliminating the immune mediated guidance cues that are required for SPCs to migrate to the location they are needed, and preventing SPC-mediated immunomodulation. This article argues in favor of transplanting autologous SPCs, particularly bone marrow derived cells. The therapeutic use of autologous SPCs for neural repair circumvents the need for concomitant immune suppression, exploits the immunomodulatory capacity of these cells, and maintains the immune niche that supports neural repair and is required to guide these cells to their appropriate locations. Overall, such an approach accommodates the requirements for translational therapeutics, and provides a standardized platform for reconciling the inherent controversies in the science.

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References

  1. Mathews, D. J., Sugarman, J., Bok, H., et al. (2008). Cell-based interventions for neurologic conditions: ethical challenges for early human trials. Neurology, 71(4), 288–293.

    Article  PubMed  CAS  Google Scholar 

  2. Hyun, I., Lindvall, O., Ahrlund-Richter, L., et al. (2008). New ISSCR guidelines underscore major principles for responsible translational stem cell research. Cell Stem Cell, 3(6), 607–609.

    Article  PubMed  CAS  Google Scholar 

  3. Kulbatski, I., Mothe, A. J., Nomura, H., & Tator, C. H. (2005). Endogenous and exogenous CNS derived stem/progenitor cell approaches for neurotrauma. Current Drug Targets, 6(1), 111–126.

    Article  PubMed  CAS  Google Scholar 

  4. Parr, A. M., Tator, C. H., & Keating, A. (2007). Bone marrow-derived mesenchymal stromal cells for the repair of central nervous system injury. Bone Marrow Transplantation, 40(7), 609–619.

    Article  PubMed  CAS  Google Scholar 

  5. Zhang, S. C. (2003). Embryonic stem cells for neural replacement therapy: prospects and challenges. Journal of Hematotherapy and Stem Cell Research, 12(6), 625–634.

    Article  PubMed  Google Scholar 

  6. McDonald, J. W., Becker, D., Holekamp, T. F., et al. (2004). Repair of the injured spinal cord and the potential of embryonic stem cell transplantation. Journal of Neurotrauma, 21(4), 383–393.

    Article  PubMed  Google Scholar 

  7. Horner, P. J., Power, A. E., Kempermann, G., et al. (2000). Proliferation and differentiation of progenitor cells throughout the intact adult rat spinal cord. Journal of Neuroscience, 20(6), 2218–2228.

    PubMed  CAS  Google Scholar 

  8. Johansson, C. B., Momma, S., Clarke, D. L., Risling, M., Lendahl, U., & Frisen, J. (1999). Identification of a neural stem cell in the adult mammalian central nervous system. Cell, 96(1), 25–34.

    Article  PubMed  CAS  Google Scholar 

  9. Johansson, C. B., Svensson, M., Wallstedt, L., Janson, A. M., & Frisén, J. (1999). Neural stem cells in the adult human brain. Experimental Cell Research, 253(2), 733–736.

    Article  PubMed  CAS  Google Scholar 

  10. Namiki, J., & Tator, C. H. (1999). Cell proliferation and nestin expression in the ependyma of the adult rat spinal cord after injury. Journal of Neuropathology and Experimental Neurology, 58(5), 489–498.

    Article  PubMed  CAS  Google Scholar 

  11. Temple, S., & Alvarez-Buylla, A. (1999). Stem cells in the adult mammalian central nervous system. Current Opinion in Neurobiology, 9(1), 135–141.

    Article  PubMed  CAS  Google Scholar 

  12. Weiss, S., Dunne, C., Hewson, J., et al. (1996). Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis. Journal of Neuroscience, 16(23), 7599–7609.

    PubMed  CAS  Google Scholar 

  13. Shihabuddin, L. S., Horner, P. J., Ray, J., & Gage, F. H. (2000). Adult spinal cord stem cells generate neurons after transplantation in the adult dentate gyrus. Journal of Neuroscience, 20(23), 8727–8735.

    PubMed  CAS  Google Scholar 

  14. Suhonen, J. O., Peterson, D. A., Ray, J., & Gage, F. H. (1996). Differentiation of adult hippocampus-derived progenitors into olfactory neurons in vivo. Nature, 383(6601), 624–627.

    Article  PubMed  CAS  Google Scholar 

  15. Cao, Q. L., Zhang, Y. P., Howard, R. M., Walters, W. M., Tsoulfas, P., & Whittemore, S. R. (2001). Pluripotent stem cells engrafted into the normal or lesioned adult rat spinal cord are restricted to a glial lineage. Experimental Neurology, 167(1), 48–58.

    Article  PubMed  CAS  Google Scholar 

  16. Ajami, B., Bennett, J. L., Krieger, C., Tetzlaff, W., & Rossi, F. M. (2007). Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nature Neuroscience, 10(12), 1538–1543.

    Article  PubMed  CAS  Google Scholar 

  17. Butovsky, O., Kunis, G., Koronyo-Hamaoui, M., & Schwartz, M. (2007). Selective ablation of bone marrow-derived dendritic cells increases amyloid plaques in a mouse Alzheimer’s disease model. European Journal of Neuroscience, 26, 413–416.

    Article  PubMed  Google Scholar 

  18. Linington, C., Berger, T., Perry, L., et al. (1993). T cells specific for the myelin oligodendrocyte glycoprotein mediate an unusual autoimmune inflammatory response in the central nervous system. European Journal of Immunology, 23(6), 1364–1372.

    Article  PubMed  CAS  Google Scholar 

  19. Malm, T. M., Koistinaho, M., Parepalo, M., et al. (2005). Bone-marrow-derived cells contribute to the recruitment of microglial cells in response to beta-amyloid deposition in APP/PS1 double transgenic Alzheimer mice. Neurobiology of Disease, 18(1), 134–142.

    Article  PubMed  CAS  Google Scholar 

  20. Mildner, A., Schmidt, H., Nitsche, M., et al. (2007). Microglia in the adult brain arise from Ly-6ChiCCR2+monocytes only under defined host conditions. Nature Neuroscience, 10(12), 1544–1553.

    Article  PubMed  CAS  Google Scholar 

  21. Schwartz, M., & Moalem, G. (2001). Beneficial immune activity after CNS injury: prospects for vaccination. Journal of Neuroimmunology, 113, 185–192.

    Article  PubMed  CAS  Google Scholar 

  22. Simard, A. R., Soulet, D., Gowing, G., Julien, J. P., & Rivest, S. (2006). Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease. Neuron, 49, 489–502.

    Article  PubMed  CAS  Google Scholar 

  23. Ziv, Y., Avidan, H., Pluchino, S., Martino, G., & Schwartz, M. (2006). Synergy between immune cells and adult neural stem/progenitor cells promotes functional recovery from spinal cord injury. Proceedings of the National Academy of Sciences of the United States of America, 103, 13174–13179.

    Article  PubMed  CAS  Google Scholar 

  24. Ziv, Y., Ron, N., Butovsky, O., et al. (2006). Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nature Neuroscience, 9(2), 268–275.

    Article  PubMed  CAS  Google Scholar 

  25. Beers, D. R., Henkel, J. S., Zhao, W., Wang, J., & Appel, S. H. (2008). CD4+T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS. Proceedings of the National Academy of Sciences of the United States of America, 105, 15558–15563.

    Article  PubMed  Google Scholar 

  26. Chiu, I. M., Chen, A., Zheng, Y., et al. (2008). T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS. Proceedings of the National Academy of Sciences of the United States of America, 105, 17913–17918.

    Article  PubMed  Google Scholar 

  27. Popovich, P. G., Guan, Z., Wei, P., Huitinga, I., van Rooijen, N., & Stokes, B. T. (1999). Depletion of hematogenous macrophages promotes partial hindlimb recovery and neuroanatomical repair after experimental spinal cord injury. Experimental Neurology, 158(2), 351–365.

    Article  PubMed  CAS  Google Scholar 

  28. Stirling, D. P., Khodarahmi, K., Liu, J., et al. (2004). Minocycline treatment reduces delayed oligodendrocyte death, attenuates axonal dieback, and improves functional outcome after spinal cord injury. Journal of Neuroscience, 24(9), 2182–2190.

    Article  PubMed  CAS  Google Scholar 

  29. Moalem, G., Leibowitz-Amit, R., Yoles, E., Mor, F., Cohen, I. R., & Schwartz, M. (1999). Autoimmune T cells protect neurons from secondary degeneration after central nervous system axotomy. Nature Medicine, 5(1), 49–55.

    Article  PubMed  CAS  Google Scholar 

  30. Bechmann, I., & Nitsch, R. (2001). Plasticity following lesion: help and harm from the immune system. Restorative Neurology and Neuroscience, 19, 189–198.

    PubMed  CAS  Google Scholar 

  31. Hofstetter, H. H., Sewell, D. L., Liu, F., et al. (2003). Autoreactive T cells promote post-traumatic healing in the central nervous system. Journal of Neuroimmunology, 134(1–2), 25–34.

    Article  PubMed  CAS  Google Scholar 

  32. Gris, D., Marsh, D. R., Oatway, M. A., et al. (2004). Transient blockade of the CD11d/CD18 integrin reduces secondary damage after spinal cord injury, improving sensory, autonomic, and motor function. Journal of Neuroscience, 24(16), 4043–4051.

    Article  PubMed  CAS  Google Scholar 

  33. Mabon, P. J., Weaver, L. C., & Dekaban, G. A. (2000). Inhibition of monocyte/macrophage migration to a spinal cord injury site by an antibody to the integrin alphaD: a potential new anti-inflammatory treatment. Experimental Neurology, 166, 52–64.

    Article  PubMed  CAS  Google Scholar 

  34. Popovich, P. G., & Hickey, W. F. (2001). Bone marrow chimeric rats reveal the unique distribution of resident and recruited macrophages in the contused rat spinal cord. Journal of Neuropathology and Experimental Neurology, 60, 676–685.

    PubMed  CAS  Google Scholar 

  35. Popovich, P. G., Guan, Z., McGaughy, V., Fisher, L., Hickey, W. F., & Basso, D. M. (2002). The neuropathological and behavioral consequences of intraspinal microglial/macrophage activation. Journal of Neuropathology and Experimental Neurology, 61(7), 623–633.

    PubMed  CAS  Google Scholar 

  36. Meda, L., Cassatella, M. A., Szendrei, G. I., et al. (1995). Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature, 374(6523), 647–650.

    Article  PubMed  CAS  Google Scholar 

  37. Majed, H. H., Chandran, S., Niclou, S. P., et al. (2006). A novel role for Sema3A in neuroprotection from injury mediated by activated microglia. Journal of Neuroscience, 26(6), 1730–1738.

    Article  PubMed  CAS  Google Scholar 

  38. Block, M. I., Zecca, L., & Hong, J. S. (2007). Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nature Reviews. Neuroscience, 8, 57–69.

    Article  PubMed  CAS  Google Scholar 

  39. Chao, C. C., Hu, S., Molitor, T. W., Shaskan, E. G., & Peterson, P. K. (1992). Activated microglia mediate neuronal cell injury via a nitric oxide mechanism. Journal of Immunology, 149, 2736–2741.

    CAS  Google Scholar 

  40. Leon, S., Yin, Y., Nguyen, J., Irwin, N., & Benowitz, L. I. (2000). Lens injury stimulates axon regeneration in the mature rat optic nerve. Journal of Neuroscience, 20, 4615–4626.

    PubMed  CAS  Google Scholar 

  41. Glezer, I., Simard, A. R., & Rivest, S. (2007). Neuroprotective role of the innate immune system by microglia. Neuroscience, 147, 867–883.

    Article  PubMed  CAS  Google Scholar 

  42. Neumann, J., Gunzer, M., Gutzeit, H. O., Ullrich, O., Reymann, K. G., & Dinkel, K. (2006). Microglia provide neuroprotection after ischemia. FASEB Journal, 20(6), 714–716.

    PubMed  CAS  Google Scholar 

  43. Simard, A. R., Soulet, D., Gowing, G., Julien, J. P., & Rivest, S. (2006). Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease. Neuron, 49, 489–502.

    Article  PubMed  CAS  Google Scholar 

  44. Polazzi, E., Gianni, T., & Contestabile, A. (2001). Microglial cells protect cerebellar granule neurons from apoptosis: evidence for reciprocal signaling. Glia, 36, 271–280.

    Article  PubMed  CAS  Google Scholar 

  45. Rapalino, O., Lazarov-Spiegler, O., Agranov, E., et al. (1998). Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats. Nature Medicine, 4(7), 814–821.

    Article  PubMed  CAS  Google Scholar 

  46. Ben-Hur, T. (2008). Immunomodulation by neural stem cells. Journal of the Neurological Sciences, 265, 102–104.

    Article  PubMed  CAS  Google Scholar 

  47. Karussis, D., Kassis, I., Kurkalli, B. G., & Slavin, S. (2008). Immunomodulation and neuroprotection with mesenchymal bone marrow stem cells (MSCs): a proposed treatment for multiple sclerosis and other neuroimmunological/neurodegenerative diseases. Journal of the Neurological Sciences, 265(1–2), 131–135.

    Article  PubMed  CAS  Google Scholar 

  48. Ting, A. E., Mays, R. W., Frey, M. R., Van’t Hof, W., Medicetty, S., & Deans, R. (2008). Therapeutic pathways of adult stem cell repair. Critical Reviews in Oncology/hematology, 65(1), 81–93.

    Article  PubMed  Google Scholar 

  49. Ben-Hur, T., Ben-Menachem, O., Furer, V., Einstein, O., Mizrachi-Kol, R., & Grigoriadis, N. (2003). Effects of proinflammatory cytokines on growth, fate, and motility of multipotential neural precursor cell. Molecular and Cellular Neurosciences, 24, 623–631.

    Article  PubMed  CAS  Google Scholar 

  50. Belmadani, A., Tran, P. B., Ren, D., & Miller, R. J. (2006). Chemokines regulate the migration of neural progenitors to sites of neuroinflammation. Journal of Neuroscience, 26, 3182–3191.

    Article  PubMed  CAS  Google Scholar 

  51. Lalive, P. H., Paglinawan, R., Biollaz, G., et al. (2005). TGF-beta-treated microglia induce oligodendrocyte precursor cell chemotaxis through the HGF-c-Met pathway. European Journal of Immunology, 35, 727–737.

    Article  PubMed  CAS  Google Scholar 

  52. Armstrong, R. C., Harvath, L., & Dubois-Dalcq, M. E. (1990). Type 1 astrocytes and oligodendrocyte-type 2 astrocyte glial progenitors migrate toward distinct molecules. Journal of Neuroscience Research, 27, 400–407.

    Article  PubMed  CAS  Google Scholar 

  53. Imitola, J., Raddassi, K., Park, K. I., et al. (2003). Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1alpha/CXC chemokine receptor 4 pathway. Proceedings of the National Academy of Sciences of the United States of America, 101, 18117–18122.

    Article  CAS  Google Scholar 

  54. Nasef, A., Ashammakhi, N., & Fouillard, L. (2008). Immunomodulatory effect of mesenchymal stromal cells: possible mechanisms. Regeneración Médica, 3(4), 531–46.

    CAS  Google Scholar 

  55. Einstein, O., Fainstein, N., Vaknin, I., et al. (2007). Neural precursors attenuate autoimmune encephalomyelitis by peripheral immunosuppression. Annals of Neurology, 61, 209–218.

    Article  PubMed  CAS  Google Scholar 

  56. Zappia, E., Casazza, S., Pedemonte, E., et al. (2005). Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood, 106, 1755–1761.

    Article  PubMed  CAS  Google Scholar 

  57. Aggarwal, S., & Pittenger, M. F. (2005). Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood, 105, 1815–1822.

    Article  PubMed  CAS  Google Scholar 

  58. Le Blanc, K., Rasmusson, I., Gotherstrom, C., et al. (2004). Mesenchymal stem cells inhibit the expression of CD25 (interleukin-2 receptor) and CD38 on phytohaemagglutinin-activated lymphocytes. Scandinavian Journal of Immunology, 60, 307–315.

    Article  PubMed  Google Scholar 

  59. Smyth, M. J., Dunn, G. P., & Schreiber, R. D. (2006). Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Advances in Immunology, 90, 1–50.

    Article  PubMed  CAS  Google Scholar 

  60. Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J., & Schreiber, R. D. (2002). Cancer immunoediting: from immunosurveillance to tumor escape. Nature Immunology, 3(11), 991–998.

    Article  PubMed  CAS  Google Scholar 

  61. Schwartz, M., & Ziv, Y. (2008). Immunity to self and self-maintenance: what can tumor immunology teach us about ALS and Alzheimer’s disease? Trends in Pharmacological Sciences, 29(6), 287–293.

    Article  PubMed  CAS  Google Scholar 

  62. Baker, M. (2009). Tumors spark stem-cell review. Nature, 457(7232), 941.

    Article  PubMed  CAS  Google Scholar 

  63. Amariglio, N., Hirshberg, A., Scheithauer, B. W., et al. (2009). Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS Medicine, 6(2), e1000029.

    Article  PubMed  CAS  Google Scholar 

  64. Lee, H., Park, J., Forget, B. G., & Gaines, P. (2009). Induced pluripotent stem cells in regenerative medicine: an argument for continued research on human embryonic stem cells. Regeneración Médica, 4(5), 759–769.

    Google Scholar 

  65. Rolletschek, A., & Wobus, A. M. (2009). Induced human pluripotent stem cells: promises and open questions. Biological Chemistry, 390(9), 845–849.

    Article  PubMed  CAS  Google Scholar 

  66. Jalving, M., & Shepers, H. (2009). Induced pluripotent stem cells: will they be safe? Current Opinion in Molecular Therapeutics, 11(4), 383–393.

    PubMed  CAS  Google Scholar 

  67. Mahmood, A., Lu, D., Lu, M., & Chopp, M. (2003). Treatment of traumatic brain injury in adult rats with intravenous administration of human bone marrow stromal cells. Neurosurgery, 53, 697–702.

    Article  PubMed  Google Scholar 

  68. Mahmood, A., Lu, D., Qu, C., Goussev, A., & Chopp, M. (2005). Human marrow stromal cell treatment provides long-lasting benefit after traumatic brain injury in rats. Neurosurgery, 57, 1026–1031. discussion 1026–1031.

    Article  PubMed  Google Scholar 

  69. Zhang, J., Li, Y., Chen, J., et al. (2005). Human bone marrow stromal cell treatment improves neurological functional recovery in EAE mice. Experimental Neurology, 195, 16–26.

    Article  PubMed  CAS  Google Scholar 

  70. Uccelli, A., Zappia, E., Benvenuto, F., Frassoni, F., & Mancardi, G. (2006). Stem cells in inflammatory demyelinating disorders: a dual role for immunosuppression and neuroprotection. Expert Opinion on Biological Therapy, 6, 17–22.

    Article  PubMed  CAS  Google Scholar 

  71. Mansilla, E., Marin, G. H., Sturla, F., et al. (2005). Human mesenchymal stem cells are tolerized by mice and improve skin and spinal cord injuries. Transplantation Proceedings, 37, 292–294.

    Article  PubMed  CAS  Google Scholar 

  72. Syková, E., Homola, A., Mazanec, R., et al. (2006). Autologous bone marrow transplantation in patients with subacute and chronic spinal cord injury. Cell Transplantation, 15, 675–687.

    Article  PubMed  Google Scholar 

  73. Himes, B. T., Neuhuber, B., Coleman, C., et al. (2006). Recovery of function following grafting of human bone marrow-derived stromal cells into the injured spinal cord. Neurorehabil Neural Repair, 20, 278–296.

    Article  PubMed  Google Scholar 

  74. Park, H. C., Shim, Y. S., Ha, Y., et al. (2005). Treatment of complete spinal cord injury patients by autologous bone marrow cell transplantation and administration of granulocyte-macrophage colony stimulating factor. Tissue Engineering, 11, 913–922.

    Article  PubMed  CAS  Google Scholar 

  75. Li, Y., & Chopp, M. (2009). Marrow stromal cell transplantation in stroke and traumatic brain injury. Neuroscience Letters, 456(3), 120–123.

    Article  PubMed  CAS  Google Scholar 

  76. Slavin, S., Kurkalli, B. G., & Karussis, D. (2008). The potential use of adult stem cells for the treatment of multiple sclerosis and other neurodegenerative disorders. Clinical Neurology and Neurosurgery, 110(9), 943–946.

    Article  PubMed  Google Scholar 

  77. Tator, C. H. (2006). Review of treatment trials in human spinal cord injury: issues, difficulties, and recommendations. Neurosurgery, 59, 957–982. discussion 982–987.

    PubMed  Google Scholar 

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Acknowledgements

The author would like to thank Prof. Michal Schwartz for her support, scientific advice, and intellectual contribution to this article.

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Kulbatski, I. Stem/Precursor Cell-Based CNS Therapy: The Importance of Circumventing Immune Suppression by Transplanting Autologous Cells. Stem Cell Rev and Rep 6, 405–410 (2010). https://doi.org/10.1007/s12015-010-9141-6

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