Abstract
Cell therapy plays an important role in multidisciplinary management of the two major forms of central nervous system (CNS) injury, traumatic brain injury and spinal cord injury, which are caused by external physical trauma. Cell therapy for CNS disorders involves the use of cells of neural or non-neural origin to replace, repair, or enhance the function of the damaged nervous system and is usually achieved by transplantation of the cells, which are isolated and may be modified, e.g., by genetic engineering, when it may be referred to as gene therapy. Because the adult brain cells have a limited capacity to migrate to and regenerate at sites of injury, the use of embryonic stem cells that can be differentiated into various cell types as well as the use of neural stem cells has been explored. Preclinical studies and clinical trials are reviewed. Advantages as well as limitations are discussed. Cell therapy is promising for the treatment of CNS injury because it targets multiple mechanisms in a sustained manner. It can provide repair and regeneration of damaged tissues as well as prolonged release of neuroprotective and other therapeutic substances.
Similar content being viewed by others
References
Jain, K. K. (2009). Cell therapy: Technologies, markets & companies. Basel, Switzerland: Jain PharmaBiotech Publications.
Jain, K. K. (2008). Neuroprotection in traumatic brain injury. Drug Discovery Today, 13, 1082–1089. doi:10.1016/j.drudis.2008.09.006.
Maegele, M., & Schaefer, U. (2008). Stem cell-based cellular replacement strategies following traumatic brain injury (TBI). Minimally Invasive Therapy and Allied Technologies, 17, 119–131. doi:10.1080/13645700801970087.
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, 609–619. doi:10.1038/sj.bmt.1705757.
Weidenfeller, C., Svendsen, C. N., & Shusta, E. V. (2007). Differentiating embryonic neural progenitor cells induce blood–brain barrier properties. Journal of Neurochemistry, 101, 555–565. doi:10.1111/j.1471-4159.2006.04394.x.
Watson, D. J., Longhi, L., Lee, E. B., et al. (2003). Genetically modified NT2 N human neuronal cells mediate long-term gene expression as CNS grafts in vivo and improve functional cognitive outcome following experimental traumatic brain injury. Journal of Neuropathology and Experimental Neurology, 62, 368–380.
Longhi, L., Watson, D. J., Saatman, K. E., et al. (2004). Ex vivo gene therapy using targeted engraftment of NGF expressing human NT2 N neurons attenuates cognitive deficits following traumatic brain injury in mice. Journal of Neurotrauma, 21, 1723–1736.
Shen, F., Wen, L., Yang, X., & Liu, W. (2007). The potential application of gene therapy in the treatment of traumatic brain injury. Neurosurgical Review, 30, 291–298. doi:10.1007/s10143-007-0094-4.
Harting, M. T., Baumgartner, J. E., Worth, L. L., et al. (2008). Cell therapies for traumatic brain injury. Neurosurgical Focus, 24, E18. doi:10.3171/FOC/2008/24/3-4/E17.
Harting, M. T., Jimenez, F., Adams, S. D., et al. (2008). Acute, regional inflammatory response after traumatic brain injury: Implications for cellular therapy. Surgery, 144, 803–813. doi:10.1016/j.surg.2008.05.017.
Molcanyi, M., Riess, P., Bentz, K., et al. (2007). Trauma-associated inflammatory response impairs embryonic stem cell survival and integration after implantation into injured rat brain. Journal of Neurotrauma, 24, 625–637. doi:10.1089/neu.2006.0180.
Tate, C. C., Shear, D. A., Tate, M. C., et al. (2009). Laminin and fibronectin scaffolds enhance neural stem cell transplantation into the injured brain. Journal of Tissue Engineering and Regenerative Medicine. doi:10.1002/term.154.
Sykova, E., & Jendelova, P. (2007). In vivo tracking of stem cells in brain and spinal cord injury. Progress in Brain Research, 161C, 367–383. doi:10.1016/S0079-6123(06)61026-1.
Meletis, K., Barnabé-Heider, F., Carlén, M., et al. (2008). Spinal cord injury reveals multilineage differentiation of ependymal cells. PLoS Biology, 6(7), e182. doi:10.1371/journal.pbio.0060182.
Li, Y., Carlstedt, T., Berthold, C. H., & Raisman, G. (2004). Interaction of transplanted olfactory-ensheathing cells and host astrocytic processes provides a bridge for axons to regenerate across the dorsal root entry zone. Experimental Neurology, 188, 300–308. doi:10.1016/j.expneurol.2004.04.021.
Collazos-Castro, J., Muneton-Gomez, V., & Nieto-Sampedro, M. (2005). Olfactory glia transplantation into cervical spinal cord contusion injuries. Journal of Neurosurgery Spine, 3, 308–317.
Mackay-Sim, A., Féron, F., Cochrane, J., et al. (2008). Autologous olfactory ensheathing cell transplantation in human paraplegia: A 3-year clinical trial. Brain, 131, 2376–2386. doi:10.1093/brain/awn173.
Kang, S. K., Shin, M. J., & Jung, J. S. (2006). Autologous adipose tissue-derived stromal cells for treatment of spinal cord injury. Stem Cells and Development, 15, 583–594. doi:10.1089/scd.2006.15.583.
Keirstead, H. S., Nistor, G., Berna, G., et al. (2005). Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. The Journal of Neuroscience, 25, 4694–4705. doi:10.1523/JNEUROSCI.0311-05.2005.
Davies, J. E., Huang, C., Proschel, C., et al. (2006). Astrocytes derived from glial-restricted precursors promote spinal cord repair. Journal of Biology (Online), 5, 7. doi:10.1186/jbiol35.
Ronsyn, M. W., Daans, J., Spaepen, G., et al. (2007). Plasmid-based genetic modification of human bone marrow-derived stromal cells: Analysis of cell survival and transgene expression after transplantation in rat spinal cord. BMC Biotechnology, 7, 90. doi:10.1186/1472-6750-7-90.
Cummings, B. J., Uchida, N., Tamaki, S. J., et al. (2005). Human neural stem cells differentiate and promote locomotor recovery in spinal cord-injured mice. Proceedings of the National Academy of Sciences of the United States of America, 102, 14069–14074. doi:10.1073/pnas.0507063102.
Yan, J., Xu, L., Welsh, A. M., et al. (2007). Extensive neuronal differentiation of human neural stem cell grafts in adult rat spinal cord. PLoS Medicine, 4, e39. doi:10.1371/journal.pmed.0040039.
Pallini, R., Vitiani, L., Bez, A., et al. (2005). Homologous transplantation of neural stem cells to the injured spinal cord of mice. Neurosurgery, 57, 1014–1025. doi:10.1227/01.NEU.0000180058.58372.4c.
Lu, P., Yang, H., Jones, L. L., et al. (2004). Combinatorial therapy with neurotrophins and cAMP promotes axonal regeneration beyond sites of spinal cord injury. The Journal of Neuroscience, 24, 6402–6409. doi:10.1523/JNEUROSCI.1492-04.2004.
Hofstetter, C., Holmstrom, N., Lilja, J., et al. (2005). Allodynia limits the usefulness of intraspinal neural stem cell grafts and directed differentiation improves outcome. Nature Neuroscience, 8, 346–353. doi:10.1038/nn1405.
Ziv, Y., Avidan, H., Pluchino, S., et al. (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. doi:10.1073/pnas.0603747103.
Teng, Y. D., Lavik, E. B., Qu, X., et al. (2002). Functional recovery following traumatic spinal cord injury mediated by a unique polymer scaffold seeded with neural stem cells. Proceedings of the National Academy of Sciences of the United States of America, 99, 3024–3029. doi:10.1073/pnas.052678899.
Cao, Q., Xu, X. M., Devries, W. H., et al. (2005). Functional recovery in traumatic spinal cord injury after transplantation of multineurotrophin-expressing glial-restricted precursor cells. The Journal of Neuroscience, 25, 6947–6957. doi:10.1523/JNEUROSCI.1065-05.2005.
Lepore, A. C., Bakshi, A., Swanger, S. A., et al. (2005). Neural precursor cells can be delivered into the injured cervical spinal cord by intrathecal injection at the lumbar cord. Brain Research, 1045, 206–216.
Callera, F., & de Melo, C. (2007). Magnetic resonance tracking of magnetically labeled autologous bone marrow CD34+ cells transplanted into the spinal cord via lumbar puncture technique in patients with chronic spinal cord injury: CD34+ cells’ migration into the injured site. Stem Cells and Development, 16, 461–466. doi:10.1089/scd.2007.0083.
Fujiwara, Y., Tanaka, N., Ishida, O., et al. (2004). Intravenously injected neural progenitor cells of transgenic rats can migrate to the injured spinal cord and differentiate into neurons, astrocytes and oligodendrocytes. Neuroscience Letters, 366, 287–291. doi:10.1016/j.neulet.2004.05.080.
Deda, H., Inci, M., Kurekci, A., et al. (2008). Treatment of chronic spinal cord injured patients with autologous bone marrow-derived hematopoietic stem cell transplantation: 1-year follow-up. Cytotherapy, 10, 565–574. doi:10.1080/14653240802241797.
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. doi:10.1089/ten.2005.11.913.
Ronsyn, M. W., Berneman, Z. N., Van Tendeloo, V. F., et al. (2008). Can cell therapy heal a spinal cord injury? Spinal Cord, 46, 532–539. doi:10.1038/sc.2008.13.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Jain, K.K. Cell Therapy for CNS Trauma. Mol Biotechnol 42, 367–376 (2009). https://doi.org/10.1007/s12033-009-9166-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12033-009-9166-8