Skip to main content

Advertisement

SpringerLink
Log in

Gene-Modified Stem Cells for Spinal Cord Injury: a Promising Better Alternative Therapy

  • Published:
Stem Cell Reviews and Reports Aims and scope Submit manuscript

Abstract

Stem cell therapy holds great promise for the treatment of spinal cord injury (SCI), which can reverse neurodegeneration and promote tissue regeneration via its pluripotency and ability to secrete neurotrophic factors. Although various stem cell-based approaches have shown certain therapeutic effects when applied to the treatment of SCI, their clinical efficacies have been disappointing. Thus, it is an urgent need to further enhance the neurological benefits of stem cells through bioengineering strategies including genetic engineering. In this review, we summarize the progress of stem cell therapy for SCI and the prospect of genetically modified stem cells, focusing on the genome editing tools and functional molecules involved in SCI repair, trying to provide a deeper understanding of genetically modified stem cell therapy and more applicable clinical strategies for SCI repair.

Graphical abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data Availability

All data generated or analyzed during this study are included in this published article. The datasets analyzed during the study are available from the corresponding author on reasonable request.

Abbreviations

SCI:

Spinal cord injury

MSCs:

Mesenchymal stem cells

HUCMSCs:

Human umbilical cord derived mesenchymal stem cells

NSCs:

Neural stem cells

IPSCs:

Induced pluripotent stem cells

ESCs:

Embryonic stem cells

BMSCs:

Bone marrow stromal cells

HSPCs:

Hematopoietic stem and progenitor cells

VEGF:

Vascular endothelial growth factor

NGF:

Nerve growth factor

GDNF:

Glial cell derived neurotrophic factor

BDNF:

Brain-derived neurotrophic factor

BFGF:

Basic fibroblast growth factor

NT-3:

Neurotrophin-3

NT-4/5:

Neurotrophin-4/5

LIF:

Leukemia inhibitory factor

SSN:

Site-specific nucleases

HR:

Homologous recombination

DSBs:

Double-strand breaks

NHEJ:

Non-homologous end joining

ZFNs:

Zinc finger nucleases

TALENs:

Transcription activator-like effector nucleases

CRISPR:

Clustered regularly interspaced short palindromic repeats

IVT mRNA:

In vitro-transcribed mRNA

CNS:

Central nervous system

LTR:

Long terminal repeats

LV:

Lentivirus

Ngb:

Neuroglobin

ROS:

Reactive oxygen species

AAV:

Adeno-associated virus

ITRs:

Inverted terminal repeats

RNP:

Ribonucleoprotein

DOTMA:

N - [1-(2,3-dioleyloxy) propyl]-N,N,N-trimethylammonium chloride

DOTAP:

1,2-dioleoyl-3-trimethylammoniumpropane

CHO:

Cholesterol

DOPE:

Diolelphophatidylethanolamine

DOPC:

Dioleylphosphatidylcholine

LNPs:

Lipid nanoparticles

PEG:

Polyethylene glycol

DOGSDSO:

1′,2′ dioleoyl-sn-glycero-3′-succinyl-2-hydroxyethyl disulfide ornithine conjugate

PEI:

Polyethylenimine

CPPs:

Cell-penetrating peptides

NAs:

Neural aggregates

CST:

Corticospinal tract

References

  1. Anjum, A., Yazid, M. D., Fauzi Daud, M., Idris, J., Ng, A. M. H., Selvi Naicker, A., et al. (2020). Spinal cord injury: Pathophysiology, multimolecular interactions, and underlying recovery mechanisms. International Journal of Molecular Sciences, 21(20), 7533.

  2. (2014). Spinal cord injury facts and figures at a glance. The Journal of Spinal Cord Medicine, 37(1), 117–118.

  3. Ackery, A., Tator, C., & Krassioukov, A. (2004). A global perspective on spinal cord injury epidemiology. Journal of Neurotrauma, 21(10), 1355–1370.

    Article  PubMed  Google Scholar 

  4. Silva, N. A., Sousa, N., Reis, R. L., & Salgado, A. J. (2014). From basics to clinical: A comprehensive review on spinal cord injury. Progress in Neurobiology, 114, 25–57.

    Article  PubMed  Google Scholar 

  5. Yip, P. K., & Malaspina, A. (2012). Spinal cord trauma and the molecular point of no return. Molecular Neurodegeneration, 7, 6.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Ulndreaj, A., Chio, J. C., Ahuja, C. S., & Fehlings, M. G. (2016). Modulating the immune response in spinal cord injury. Expert Review of Neurotherapeutics, 16(10), 1127–1129.

    Article  CAS  PubMed  Google Scholar 

  7. Schwab, M. E., & Strittmatter, S. M. (2014). Nogo limits neural plasticity and recovery from injury. Current Opinion in Neurobiology, 27, 53–60.

    Article  CAS  PubMed  Google Scholar 

  8. Bartlett, R. D., Burley, S., Ip, M., Phillips, J. B., & Choi, D. (2020). Cell therapies for spinal cord injury: Trends and challenges of current clinical trials. Neurosurgery., 87(4), E456–EE72.

    Article  PubMed  Google Scholar 

  9. Tetzlaff, W., Okon, E. B., Karimi-Abdolrezaee, S., Hill, C. E., Sparling, J. S., Plemel, J. R., et al. (2011). A systematic review of cellular transplantation therapies for spinal cord injury. Journal of Neurotrauma, 28(8), 1611–1682.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Assinck, P., Duncan, G. J., Hilton, B. J., Plemel, J. R., & Tetzlaff, W. (2017). Cell transplantation therapy for spinal cord injury. Nature Neuroscience, 20(5), 637–647.

    Article  CAS  PubMed  Google Scholar 

  11. Teng, Y. D., Lavik, E. B., Qu, X., Park, K. I., Ourednik, J., Zurakowski, D., 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(5), 3024–3029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Franz, S., Weidner, N., & Blesch, A. (2012). Gene therapy approaches to enhancing plasticity and regeneration after spinal cord injury. Experimental Neurology, 235(1), 62–69.

    Article  CAS  PubMed  Google Scholar 

  13. Wyse, R. D., Dunbar, G. L., & Rossignol, J. (2014). Use of genetically modified mesenchymal stem cells to treat neurodegenerative diseases. International Journal of Molecular Sciences, 15(2), 1719–1745.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Lee, H. J., Lim, I. J., Park, S. W., Kim, Y. B., Ko, Y., & Kim, S. U. (2012). Human neural stem cells genetically modified to express human nerve growth factor (NGF) gene restore cognition in the mouse with ibotenic acid-induced cognitive dysfunction. Cell Transplantation, 21(11), 2487–2496.

    Article  PubMed  Google Scholar 

  15. Park, D., Lee, H. J., Joo, S. S., Bae, D. K., Yang, G., Yang, Y. H., et al. (2012). Human neural stem cells over-expressing choline acetyltransferase restore cognition in rat model of cognitive dysfunction. Experimental Neurology, 234(2), 521–526.

    Article  CAS  PubMed  Google Scholar 

  16. Salehi, M. S., Safari, A., Pandamooz, S., Jurek, B., Hooshmandi, E., Owjfard, M., et al. (2021). The beneficial potential of genetically modified stem cells in the treatment of stroke: A review. Stem Cell Reviews and Reports, 18(2), 412–440.

  17. Cofano, F., Boido, M., Monticelli, M., Zenga, F., Ducati, A., Vercelli, A., et al. (2019). Mesenchymal stem cells for spinal cord injury: Current options, limitations, and future of cell therapy. International Journal of Molecular Sciences, 20(11), 2698.

  18. Thomson, J. A., Itskovitz-Eldor, J., Shapiro, S. S., Waknitz, M. A., Swiergiel, J. J., Marshall, V. S., et al. (1998). Embryonic stem cell lines derived from human blastocysts. Science., 282(5391), 1145–1147.

    Article  CAS  PubMed  Google Scholar 

  19. Shamblott, M. J., Axelman, J., Wang, S., Bugg, E. M., Littlefield, J. W., Donovan, P. J., et al. (1998). Derivation of pluripotent stem cells from cultured human primordial germ cells. Proceedings of the National Academy of Sciences of the United States of America, 95(23), 13726–13731.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Jin, M. C., Medress, Z. A., Azad, T. D., Doulames, V. M., & Veeravagu, A. (2019). Stem cell therapies for acute spinal cord injury in humans: A review. Neurosurgical Focus, 46(3), E10.

    Article  PubMed  Google Scholar 

  21. Gerrard, L., Rodgers, L., & Cui, W. (2005). Differentiation of human embryonic stem cells to neural lineages in adherent culture by blocking bone morphogenetic protein signaling. Stem Cells, 23(9), 1234–1241.

    Article  CAS  PubMed  Google Scholar 

  22. Keirstead, H. S., Nistor, G., Bernal, G., Totoiu, M., Cloutier, F., Sharp, K., 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(19), 4694–4705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. US National Library of Medicine. 2018 [Available from: https://clinicaltrials.gov/ct2/show/study/NCT02302157. Accessed 20 Jul 2021.]

  24. White, S. V., Czisch, C. E., Han, M. H., Plant, C. D., Harvey, A. R., & Plant, G. W. (2016). Intravenous transplantation of mesenchymal progenitors distribute solely to the lungs and improve outcomes in cervical spinal cord injury. Stem Cells, 34(7), 1812–1825.

    Article  CAS  PubMed  Google Scholar 

  25. Chopp, M., Zhang, X. H., Li, Y., Wang, L., Chen, J., Lu, D., et al. (2000). Spinal cord injury in rat: Treatment with bone marrow stromal cell transplantation. Neuroreport., 11(13), 3001–3005.

    Article  CAS  PubMed  Google Scholar 

  26. Reynolds, B. A., & Weiss, S. (1992). Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science., 255(5052), 1707–1710.

    Article  CAS  PubMed  Google Scholar 

  27. Rosenzweig, E. S., Brock, J. H., Lu, P., Kumamaru, H., Salegio, E. A., Kadoya, K., et al. (2018). Restorative effects of human neural stem cell grafts on the primate spinal cord. Nature Medicine, 24(4), 484–490.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mandai, M., Watanabe, A., Kurimoto, Y., Hirami, Y., Morinaga, C., Daimon, T., et al. (2017). Autologous induced stem-cell-derived retinal cells for macular degeneration. The New England Journal of Medicine, 376(11), 1038–1046.

    Article  CAS  PubMed  Google Scholar 

  29. Kawabata, S., Takano, M., Numasawa-Kuroiwa, Y., Itakura, G., Kobayashi, Y., Nishiyama, Y., et al. (2016). Grafted human iPS cell-derived oligodendrocyte precursor cells contribute to robust Remyelination of demyelinated axons after spinal cord injury. Stem Cell Reports, 6(1), 1–8.

    Article  CAS  PubMed  Google Scholar 

  30. Sieber-Blum, M. (2010). Epidermal neural crest stem cells and their use in mouse models of spinal cord injury. Brain Research Bulletin, 83(5), 189–193.

    Article  CAS  PubMed  Google Scholar 

  31. Pandamooz, S., Salehi, M. S., Nabiuni, M., Dargahi, L., & Pourghasem, M. (2016). Evaluation of epidermal neural crest stem cells in Organotypic spinal cord slice culture platform. Folia Biologica (Praha), 62(6), 263–267.

    CAS  Google Scholar 

  32. Kim, Y., Jo, S. H., Kim, W. H., & Kweon, O. K. (2015). Antioxidant and anti-inflammatory effects of intravenously injected adipose derived mesenchymal stem cells in dogs with acute spinal cord injury. Stem Cell Research & Therapy, 6, 229.

    Article  Google Scholar 

  33. Chua, S. J., Bielecki, R., Yamanaka, N., Fehlings, M. G., Rogers, I. M., & Casper, R. F. (2010). The effect of umbilical cord blood cells on outcomes after experimental traumatic spinal cord injury. Spine (Phila Pa 1976), 35(16), 1520–1526.

    Article  Google Scholar 

  34. Kao, C. H., Chen, S. H., Chio, C. C., & Lin, M. T. (2008). Human umbilical cord blood-derived CD34+ cells may attenuate spinal cord injury by stimulating vascular endothelial and neurotrophic factors. Shock., 29(1), 49–55.

    Article  PubMed  Google Scholar 

  35. Uchida, K., Nakajima, H., Guerrero, A. R., Johnson, W. E., Masri, W. E., & Baba, H. (2014). Gene therapy strategies for the treatment of spinal cord injury. Therapeutic Delivery, 5(5), 591–607.

    Article  CAS  PubMed  Google Scholar 

  36. Sykova, E., Jendelova, P., Urdzikova, L., Lesny, P., & Hejcl, A. (2006). Bone marrow stem cells and polymer hydrogels--two strategies for spinal cord injury repair. Cellular and Molecular Neurobiology, 26(7–8), 1113–1129.

    CAS  PubMed  Google Scholar 

  37. Kadoya, K., Lu, P., Nguyen, K., Lee-Kubli, C., Kumamaru, H., Yao, L., et al. (2016). Spinal cord reconstitution with homologous neural grafts enables robust corticospinal regeneration. Nature Medicine, 22(5), 479–487.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Pandamooz, S., Salehi, M. S., Zibaii, M. I., Ahmadiani, A., Nabiuni, M., & Dargahi, L. (2018). Epidermal neural crest stem cell-derived glia enhance neurotrophic elements in an ex vivo model of spinal cord injury. Journal of Cellular Biochemistry, 119(4), 3486–3496.

    Article  CAS  PubMed  Google Scholar 

  39. Vismara, I., Papa, S., Rossi, F., Forloni, G., & Veglianese, P. (2017). Current options for cell therapy in spinal cord injury. Trends in Molecular Medicine, 23(9), 831–849.

    Article  CAS  PubMed  Google Scholar 

  40. Teng, Y. D., Yu, D., Ropper, A. E., Li, J., Kabatas, S., Wakeman, D. R., et al. (2011). Functional multipotency of stem cells: A conceptual review of neurotrophic factor-based evidence and its role in translational research. Current Neuropharmacology, 9(4), 574–585.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Teng, Y. D. (2019). Functional multipotency of stem cells: Biological traits gleaned from neural progeny studies. Seminars in Cell & Developmental Biology, 95, 74–83.

    Article  Google Scholar 

  42. Widenfalk, J., Lundstromer, K., Jubran, M., Brene, S., & Olson, L. (2001). Neurotrophic factors and receptors in the immature and adult spinal cord after mechanical injury or kainic acid. The Journal of Neuroscience, 21(10), 3457–3475.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Arvanian, V. L., & Mendell, L. M. (2001). Acute modulation of synaptic transmission to motoneurons by BDNF in the neonatal rat spinal cord. The European Journal of Neuroscience, 14(11), 1800–1808.

    Article  CAS  PubMed  Google Scholar 

  44. Ji, W. C., Zhang, X. W., & Qiu, Y. S. (2016). Selected suitable seed cell, scaffold and growth factor could maximize the repair effect using tissue engineering method in spinal cord injury. World Journal of Experimental Medicine, 6(3), 58–62.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Feng, S. Q., Kong, X. H., Liu, Y., Ban, D. X., Ning, G. Z., Chen, J. T., et al. (2009). Regeneration of spinal cord with cell and gene therapy. Orthopaedic Surgery, 1(2), 153–163.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Wang, J. M., Zeng, Y. S., Liu, R. Y., Huang, W. L., Xiong, Y., Wang, Y. H., et al. (2007). Recombinant adenovirus vector-mediated functional expression of neurotropin-3 receptor (TrkC) in neural stem cells. Experimental Neurology, 203(1), 123–127.

    Article  CAS  PubMed  Google Scholar 

  47. Mortazavi, M. M., Verma, K., Harmon, O. A., Griessenauer, C. J., Adeeb, N., Theodore, N., et al. (2015). The microanatomy of spinal cord injury: A review. Clinical Anatomy, 28(1), 27–36.

    Article  PubMed  Google Scholar 

  48. Liu, N. K., & Xu, X. M. (2012). Neuroprotection and its molecular mechanism following spinal cord injury. Neural Regeneration Research, 7(26), 2051–2062.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Guerrero, A. R., Uchida, K., Nakajima, H., Watanabe, S., Nakamura, M., Johnson, W. E., et al. (2012). Blockade of interleukin-6 signaling inhibits the classic pathway and promotes an alternative pathway of macrophage activation after spinal cord injury in mice. Journal of Neuroinflammation, 9, 40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Leibinger, M., Zeitler, C., Gobrecht, P., Andreadaki, A., Gisselmann, G., & Fischer, D. (2021). Transneuronal delivery of hyper-interleukin-6 enables functional recovery after severe spinal cord injury in mice. Nature Communications, 12(1), 391.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Wang, L., Wei, F. X., Cen, J. S., Ping, S. N., Li, Z. Q., Chen, N. N., et al. (2014). Early administration of tumor necrosis factor-alpha antagonist promotes survival of transplanted neural stem cells and axon myelination after spinal cord injury in rats. Brain Research, 1575, 87–100.

    Article  CAS  PubMed  Google Scholar 

  52. Silver, J., & Miller, J. H. (2004). Regeneration beyond the glial scar. Nature Reviews. Neuroscience, 5(2), 146–156.

    Article  CAS  PubMed  Google Scholar 

  53. Rosenzweig, E. S., Salegio, E. A., Liang, J. J., Weber, J. L., Weinholtz, C. A., Brock, J. H., et al. (2019). Chondroitinase improves anatomical and functional outcomes after primate spinal cord injury. Nature Neuroscience, 22(8), 1269–1275.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kanno, H., Pressman, Y., Moody, A., Berg, R., Muir, E. M., Rogers, J. H., et al. (2014). Combination of engineered Schwann cell grafts to secrete neurotrophin and chondroitinase promotes axonal regeneration and locomotion after spinal cord injury. The Journal of Neuroscience, 34(5), 1838–1855.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Griffin, J. M., Fackelmeier, B., Clemett, C. A., Fong, D. M., Mouravlev, A., Young, D., et al. (2020). Astrocyte-selective AAV-ADAMTS4 gene therapy combined with hindlimb rehabilitation promotes functional recovery after spinal cord injury. Experimental Neurology, 327, 113232.

    Article  CAS  PubMed  Google Scholar 

  56. Domeniconi, M., & Filbin, M. T. (2005). Overcoming inhibitors in myelin to promote axonal regeneration. Journal of the Neurological Sciences, 233(1–2), 43–47.

    Article  CAS  PubMed  Google Scholar 

  57. Wang, D., Liang, J., Zhang, J., Liu, S., & Sun, W. (2014). Mild hypothermia combined with a scaffold of NgR-silenced neural stem cells/Schwann cells to treat spinal cord injury. Neural Regeneration Research, 9(24), 2189–2196.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Zorner, B., & Schwab, M. E. (2010). Anti-Nogo on the go: From animal models to a clinical trial. Annals of the New York Academy of Sciences, 1198(Suppl 1), E22–E34.

    Article  PubMed  Google Scholar 

  59. Kucher, K., Johns, D., Maier, D., Abel, R., Badke, A., Baron, H., et al. (2018). First-in-man intrathecal application of neurite growth-promoting anti-Nogo-a antibodies in acute spinal cord injury. Neurorehabilitation and Neural Repair, 32(6–7), 578–589.

    Article  PubMed  Google Scholar 

  60. Wakeman, D. R., Redmond Jr., D. E., Dodiya, H. B., Sladek Jr., J. R., Leranth, C., Teng, Y. D., et al. (2014). Human neural stem cells survive long term in the midbrain of dopamine-depleted monkeys after GDNF overexpression and project neurites toward an appropriate target. Stem Cells Translational Medicine, 3(6), 692–701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Dergham, P., Ellezam, B., Essagian, C., Avedissian, H., Lubell, W. D., & McKerracher, L. (2002). Rho signaling pathway targeted to promote spinal cord repair. The Journal of Neuroscience, 22(15), 6570–6577.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Liu, K., Lu, Y., Lee, J. K., Samara, R., Willenberg, R., Sears-Kraxberger, I., et al. (2010). PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nature Neuroscience, 13(9), 1075–1081.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Jin, D., Liu, Y., Sun, F., Wang, X., Liu, X., & He, Z. (2015). Restoration of skilled locomotion by sprouting corticospinal axons induced by co-deletion of PTEN and SOCS3. Nature Communications, 6, 8074.

    Article  CAS  PubMed  Google Scholar 

  64. Liu, Y., Wang, X., Li, W., Zhang, Q., Li, Y., Zhang, Z., et al. (2017). A sensitized IGF1 treatment restores corticospinal axon-dependent functions. Neuron., 95(4), 817–33 e4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Kolevzon, A., Bush, L., Wang, A. T., Halpern, D., Frank, Y., Grodberg, D., et al. (2014). A pilot controlled trial of insulin-like growth factor-1 in children with Phelan-McDermid syndrome. Molecular Autism, 5(1), 54.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Kabu, S., Gao, Y., Kwon, B. K., & Labhasetwar, V. (2015). Drug delivery, cell-based therapies, and tissue engineering approaches for spinal cord injury. Journal of Controlled Release, 219, 141–154.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Sakamoto, K., Karelina, K., & Obrietan, K. (2011). CREB: A multifaceted regulator of neuronal plasticity and protection. Journal of Neurochemistry, 116(1), 1–9.

    Article  CAS  PubMed  Google Scholar 

  68. Bo, X., Wu, D., Yeh, J., & Zhang, Y. (2011). Gene therapy approaches for neuroprotection and axonal regeneration after spinal cord and spinal root injury. Current Gene Therapy, 11(2), 101–115.

    Article  CAS  PubMed  Google Scholar 

  69. Li, C., Li, X., Zhao, B., & Wang, C. (2020). Exosomes derived from miR-544-modified mesenchymal stem cells promote recovery after spinal cord injury. Archives of Physiology and Biochemistry, 126(4), 369–375.

    Article  CAS  PubMed  Google Scholar 

  70. Tebas, P., Stein, D., Tang, W. W., Frank, I., Wang, S. Q., Lee, G., et al. (2014). Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. The New England Journal of Medicine, 370(10), 901–910.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Hotta, A., & Yamanaka, S. (2015). From genomics to gene therapy: Induced pluripotent stem cells meet genome editing. Annual Review of Genetics, 49, 47–70.

    Article  CAS  PubMed  Google Scholar 

  72. Capecchi, M. R. (1989). Altering the genome by homologous recombination. Science., 244(4910), 1288–1292.

    Article  CAS  PubMed  Google Scholar 

  73. Zhang, H. X., Zhang, Y., & Yin, H. (2019). Genome editing with mRNA encoding ZFN, TALEN, and Cas9. Molecular Therapy, 27(4), 735–746.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Guo, J., Gaj, T., & Barbas 3rd., C. F. (2010). Directed evolution of an enhanced and highly efficient FokI cleavage domain for zinc finger nucleases. Journal of Molecular Biology, 400(1), 96–107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Joung, J. K., & Sander, J. D. (2013). TALENs: A widely applicable technology for targeted genome editing. Nature Reviews. Molecular Cell Biology, 14(1), 49–55.

    Article  CAS  PubMed  Google Scholar 

  76. Mohanraju, P., Makarova, K. S., Zetsche, B., Zhang, F., Koonin, E. V., & van der Oost, J. (2016). Diverse evolutionary roots and mechanistic variations of the CRISPR-Cas systems. Science., 353(6299), aad5147.

    Article  PubMed  Google Scholar 

  77. Cohen, J. (2019). Prime editing promises to be a cut above CRISPR. Science., 366(6464), 406.

    Article  CAS  PubMed  Google Scholar 

  78. Moses, C., Hodgetts, S. I., Nugent, F., Ben-Ary, G., Park, K. K., Blancafort, P., et al. (2020). Transcriptional repression of PTEN in neural cells using CRISPR/dCas9 epigenetic editing. Scientific Reports, 10(1), 11393.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Klatt Shaw, D., Saraswathy, V. M., Zhou, L., McAdow, A. R., Burris, B., Butka, E., et al. (2021). Localized EMT reprograms glial progenitors to promote spinal cord repair. Developmental Cell, 56(5), 613–26 e7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Yin, H., Kauffman, K. J., & Anderson, D. G. (2017). Delivery technologies for genome editing. Nature Reviews. Drug Discovery, 16(6), 387–399.

    Article  CAS  PubMed  Google Scholar 

  81. Xu, X., Wan, T., Xin, H., Li, D., Pan, H., Wu, J., et al. (2019). Delivery of CRISPR/Cas9 for therapeutic genome editing. The Journal of Gene Medicine, 21(7), e3107.

    Article  PubMed  Google Scholar 

  82. Leonhardt, C., Schwake, G., Stogbauer, T. R., Rappl, S., Kuhr, J. T., Ligon, T. S., et al. (2014). Single-cell mRNA transfection studies: Delivery, kinetics and statistics by numbers. Nanomedicine., 10(4), 679–688.

    Article  CAS  PubMed  Google Scholar 

  83. Liu, J., Gaj, T., Yang, Y., Wang, N., Shui, S., Kim, S., et al. (2015). Efficient delivery of nuclease proteins for genome editing in human stem cells and primary cells. Nature Protocols, 10(11), 1842–1859.

    Article  CAS  PubMed  Google Scholar 

  84. Chew, W. L. (2018). Immunity to CRISPR Cas9 and Cas12a therapeutics. Wiley Interdisciplinary Reviews. Systems Biology and Medicine, 10(1), e1408.

  85. Bevan, A. K., Duque, S., Foust, K. D., Morales, P. R., Braun, L., Schmelzer, L., et al. (2011). Systemic gene delivery in large species for targeting spinal cord, brain, and peripheral tissues for pediatric disorders. Molecular Therapy, 19(11), 1971–1980.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Zhang, Y., Zheng, Y., Zhang, Y. P., Shields, L. B., Hu, X., Yu, P., et al. (2010). Enhanced adenoviral gene delivery to motor and dorsal root ganglion neurons following injection into demyelinated peripheral nerves. Journal of Neuroscience Research, 88(11), 2374–2384.

    CAS  PubMed  Google Scholar 

  87. Ruitenberg, M. J., Plant, G. W., Hamers, F. P., Wortel, J., Blits, B., Dijkhuizen, P. A., et al. (2003). Ex vivo adenoviral vector-mediated neurotrophin gene transfer to olfactory ensheathing glia: Effects on rubrospinal tract regeneration, lesion size, and functional recovery after implantation in the injured rat spinal cord. The Journal of Neuroscience, 23(18), 7045–7058.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Liu, Y., Himes, B. T., Moul, J., Huang, W., Chow, S. Y., Tessler, A., et al. (1997). Application of recombinant adenovirus for in vivo gene delivery to spinal cord. Brain Research, 768(1–2), 19–29.

    Article  CAS  PubMed  Google Scholar 

  89. Nakajima, H., Uchida, K., Yayama, T., Kobayashi, S., Guerrero, A. R., Furukawa, S., et al. (2010). Targeted retrograde gene delivery of brain-derived neurotrophic factor suppresses apoptosis of neurons and oligodendroglia after spinal cord injury in rats. Spine (Phila Pa 1976), 35(5), 497–504.

    Article  Google Scholar 

  90. Uchida, K., Nakajima, H., Hirai, T., Yayama, T., Chen, K., Guerrero, A. R., et al. (2012). The retrograde delivery of adenovirus vector carrying the gene for brain-derived neurotrophic factor protects neurons and oligodendrocytes from apoptosis in the chronically compressed spinal cord of twy/twy mice. Spine (Phila Pa 1976), 37(26), 2125–2135.

    Article  Google Scholar 

  91. Liu, Y., Himes, B. T., Tryon, B., Moul, J., Chow, S. Y., Jin, H., et al. (1998). Intraspinal grafting of fibroblasts genetically modified by recombinant adenoviruses. Neuroreport., 9(6), 1075–1079.

    Article  CAS  PubMed  Google Scholar 

  92. Robbins, P. D., & Ghivizzani, S. C. (1998). Viral vectors for gene therapy. Pharmacology & Therapeutics, 80(1), 35–47.

    Article  CAS  Google Scholar 

  93. Murray, M., & Fischer, I. (2001). Transplantation and gene therapy: Combined approaches for repair of spinal cord injury. Neuroscientist., 7(1), 28–41.

    Article  CAS  PubMed  Google Scholar 

  94. Blessing, D., & Deglon, N. (2016). Adeno-associated virus and lentivirus vectors: A refined toolkit for the central nervous system. Current Opinion in Virology, 21, 61–66.

    Article  CAS  PubMed  Google Scholar 

  95. Tom, V. J., Sandrow-Feinberg, H. R., Miller, K., Domitrovich, C., Bouyer, J., Zhukareva, V., et al. (2013). Exogenous BDNF enhances the integration of chronically injured axons that regenerate through a peripheral nerve grafted into a chondroitinase-treated spinal cord injury site. Experimental Neurology, 239, 91–100.

    Article  CAS  PubMed  Google Scholar 

  96. Lin, W. P., Chen, X. W., Zhang, L. Q., Wu, C. Y., Huang, Z. D., & Lin, J. H. (2013). Effect of neuroglobin genetically modified bone marrow mesenchymal stem cells transplantation on spinal cord injury in rabbits. PLoS ONE, 8(5), e63444.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Bedbrook, C. N., Deverman, B. E., & Gradinaru, V. (2018). Viral strategies for targeting the central and peripheral nervous systems. Annual Review of Neuroscience, 41, 323–348.

    Article  CAS  PubMed  Google Scholar 

  98. Grosse, S., Penaud-Budloo, M., Herrmann, A. K., Borner, K., Fakhiri, J., Laketa, V., et al. (2017). Relevance of assembly-activating protein for adeno-associated virus vector production and capsid protein stability in mammalian and insect cells. Journal of Virology, 91(20), e01198–17.

  99. Rolling, F., & Samulski, R. J. (1995). AAV as a viral vector for human gene therapy. Generation of recombinant virus. Molecular Biotechnology, 3(1), 9–15.

    Article  CAS  PubMed  Google Scholar 

  100. Samulski, R. J., & Muzyczka, N. (2014). AAV-mediated gene therapy for research and therapeutic purposes. The Annual Review of Virology, 1(1), 427–451.

    Article  PubMed  Google Scholar 

  101. Kaeppel, C., Beattie, S. G., Fronza, R., van Logtenstein, R., Salmon, F., Schmidt, S., et al. (2013). A largely random AAV integration profile after LPLD gene therapy. Nature Medicine, 19(7), 889–891.

    Article  CAS  PubMed  Google Scholar 

  102. Blits, B., Oudega, M., Boer, G. J., Bartlett Bunge, M., & Verhaagen, J. (2003). Adeno-associated viral vector-mediated neurotrophin gene transfer in the injured adult rat spinal cord improves hind-limb function. Neuroscience., 118(1), 271–281.

    Article  CAS  PubMed  Google Scholar 

  103. Nassi, J. J., Cepko, C. L., Born, R. T., & Beier, K. T. (2015). Neuroanatomy goes viral! Frontiers in Neuroanatomy, 9, 80.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Hutson, T. H., Verhaagen, J., Yanez-Munoz, R. J., & Moon, L. D. (2012). Corticospinal tract transduction: A comparison of seven adeno-associated viral vector serotypes and a non-integrating lentiviral vector. Gene Therapy, 19(1), 49–60.

    Article  CAS  PubMed  Google Scholar 

  105. Buchholz, C. J., Friedel, T., & Buning, H. (2015). Surface-engineered viral vectors for selective and cell type-specific gene delivery. Trends in Biotechnology, 33(12), 777–790.

    Article  CAS  PubMed  Google Scholar 

  106. Yin, H., Kanasty, R. L., Eltoukhy, A. A., Vegas, A. J., Dorkin, J. R., & Anderson, D. G. (2014). Non-viral vectors for gene-based therapy. Nature Reviews. Genetics, 15(8), 541–555.

    Article  CAS  PubMed  Google Scholar 

  107. Wells, D. J. (2004). Gene therapy progress and prospects: Electroporation and other physical methods. Gene Therapy, 11(18), 1363–1369.

    Article  CAS  PubMed  Google Scholar 

  108. De Vry, J., Martinez-Martinez, P., Losen, M., Temel, Y., Steckler, T., Steinbusch, H. W., et al. (2010). In vivo electroporation of the central nervous system: A non-viral approach for targeted gene delivery. Progress in Neurobiology, 92(3), 227–244.

    Article  PubMed  Google Scholar 

  109. De Ravin, S. S., Reik, A., Liu, P. Q., Li, L., Wu, X., Su, L., et al. (2016). Targeted gene addition in human CD34(+) hematopoietic cells for correction of X-linked chronic granulomatous disease. Nature Biotechnology, 34(4), 424–429.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Mock, U., Machowicz, R., Hauber, I., Horn, S., Abramowski, P., Berdien, B., et al. (2015). mRNA transfection of a novel TAL effector nuclease (TALEN) facilitates efficient knockout of HIV co-receptor CCR5. Nucleic Acids Research, 43(11), 5560–5571.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Shimamura, M., Sato, N., Taniyama, Y., Kurinami, H., Tanaka, H., Takami, T., et al. (2005). Gene transfer into adult rat spinal cord using naked plasmid DNA and ultrasound microbubbles. The Journal of Gene Medicine, 7(11), 1468–1474.

    Article  CAS  PubMed  Google Scholar 

  112. Ando, T., Sato, S., Toyooka, T., Kobayashi, H., Nawashiro, H., Ashida, H., et al. (2012). Photomechanical wave-driven delivery of siRNAs targeting intermediate filament proteins promotes functional recovery after spinal cord injury in rats. PLoS ONE, 7(12), e51744.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Guan, S., & Rosenecker, J. (2017). Nanotechnologies in delivery of mRNA therapeutics using nonviral vector-based delivery systems. Gene Therapy, 24(3), 133–143.

    Article  CAS  PubMed  Google Scholar 

  114. Felgner, P. L., Gadek, T. R., Holm, M., Roman, R., Chan, H. W., Wenz, M., et al. (1987). Lipofection: A highly efficient, lipid-mediated DNA-transfection procedure. Proceedings of the National Academy of Sciences of the United States of America, 84(21), 7413–7417.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Kauffman, K. J., Dorkin, J. R., Yang, J. H., Heartlein, M. W., DeRosa, F., Mir, F. F., et al. (2015). Optimization of lipid nanoparticle formulations for mRNA delivery in vivo with fractional factorial and definitive screening designs. Nano Letters, 15(11), 7300–7306.

    Article  CAS  PubMed  Google Scholar 

  116. Immordino, M. L., Dosio, F., & Cattel, L. (2006). Stealth liposomes: Review of the basic science, rationale, and clinical applications, existing and potential. International Journal of Nanomedicine, 1(3), 297–315.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Ajmani, P. S., Tang, F., Krishnaswami, S., Meyer, E. M., Sumners, C., & Hughes, J. A. (1999). Enhanced transgene expression in rat brain cell cultures with a disulfide-containing cationic lipid. Neuroscience Letters, 277(3), 141–144.

    Article  CAS  PubMed  Google Scholar 

  118. Ohki, E. C., Tilkins, M. L., Ciccarone, V. C., & Price, P. J. (2001). Improving the transfection efficiency of post-mitotic neurons. Journal of Neuroscience Methods, 112(2), 95–99.

    Article  CAS  PubMed  Google Scholar 

  119. Obata, Y., Ciofani, G., Raffa, V., Cuschieri, A., Menciassi, A., Dario, P., et al. (2010). Evaluation of cationic liposomes composed of an amino acid-based lipid for neuronal transfection. Nanomedicine., 6(1), 70–77.

    Article  CAS  PubMed  Google Scholar 

  120. Samal, S. K., Dash, M., Van Vlierberghe, S., Kaplan, D. L., Chiellini, E., van Blitterswijk, C., et al. (2012). Cationic polymers and their therapeutic potential. Chemical Society Reviews, 41(21), 7147–7194.

    Article  CAS  PubMed  Google Scholar 

  121. Bus, T., Traeger, A., & Schubert, U. S. (2018). The great escape: How cationic polyplexes overcome the endosomal barrier. Journal of Materials Chemistry B, 6(43), 6904–6918.

    Article  CAS  PubMed  Google Scholar 

  122. Zhang, C., Yadava, P., & Hughes, J. (2004). Polyethylenimine strategies for plasmid delivery to brain-derived cells. Methods., 33(2), 144–150.

    Article  CAS  PubMed  Google Scholar 

  123. Kwon, E. J., Bergen, J. M., Park, I. K., & Pun, S. H. (2008). Peptide-modified vectors for nucleic acid delivery to neurons. Journal of Controlled Release, 132(3), 230–235.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Edgar, J. M., Robinson, M., & Willerth, S. M. (2017). Fibrin hydrogels induce mixed dorsal/ventral spinal neuron identities during differentiation of human induced pluripotent stem cells. Acta Biomaterialia, 51, 237–245.

    Article  CAS  PubMed  Google Scholar 

  125. Whittlesey, K. J., & Shea, L. D. (2006). Nerve growth factor expression by PLG-mediated lipofection. Biomaterials., 27(11), 2477–2486.

    Article  CAS  PubMed  Google Scholar 

  126. Kotterman, M. A., Chalberg, T. W., & Schaffer, D. V. (2015). Viral vectors for gene therapy: Translational and clinical outlook. Annual Review of Biomedical Engineering, 17, 63–89.

    Article  CAS  PubMed  Google Scholar 

  127. Yao, L., Yao, S., Daly, W., Hendry, W., Windebank, A., & Pandit, A. (2012). Non-viral gene therapy for spinal cord regeneration. Drug Discovery Today, 17(17–18), 998–1005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Burnside, E. R., De Winter, F., Didangelos, A., James, N. D., Andreica, E. C., Layard-Horsfall, H., et al. (2018). Immune-evasive gene switch enables regulated delivery of chondroitinase after spinal cord injury. Brain., 141(8), 2362–2381.

    Article  PubMed  PubMed Central  Google Scholar 

  129. Wang, L. J., Zhang, R. P., & Li, J. D. (2014). Transplantation of neurotrophin-3-expressing bone mesenchymal stem cells improves recovery in a rat model of spinal cord injury. Acta Neurochirurgica, 156(7), 1409–1418.

    Article  PubMed  Google Scholar 

  130. Sasaki, M., Radtke, C., Tan, A. M., Zhao, P., Hamada, H., Houkin, K., et al. (2009). BDNF-hypersecreting human mesenchymal stem cells promote functional recovery, axonal sprouting, and protection of corticospinal neurons after spinal cord injury. The Journal of Neuroscience, 29(47), 14932–14941.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Galieva, L. R., Mukhamedshina, Y. O., Akhmetzyanova, E. R., Gilazieva, Z. E., Arkhipova, S. S., Garanina, E. E., et al. (2018). Influence of genetically modified human umbilical cord blood mononuclear cells on the expression of Schwann cell molecular determinants in spinal cord injury. Stem Cells International, 2018, 4695275.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Muir, E., De Winter, F., Verhaagen, J., & Fawcett, J. (2019). Recent advances in the therapeutic uses of chondroitinase ABC. Experimental Neurology, 321, 113032.

    Article  CAS  PubMed  Google Scholar 

  133. Li, X., Peng, Z., Long, L., Tuo, Y., Wang, L., Zhao, X., et al. (2020). Wnt4-modified NSC transplantation promotes functional recovery after spinal cord injury. The FASEB Journal, 34(1), 82–94.

    Article  PubMed  Google Scholar 

  134. Song, J. L., Zheng, W., Chen, W., Qian, Y., Ouyang, Y. M., & Fan, C. Y. (2017). Lentivirus-mediated microRNA-124 gene-modified bone marrow mesenchymal stem cell transplantation promotes the repair of spinal cord injury in rats. Experimental & Molecular Medicine, 49(5), e332.

    Article  CAS  Google Scholar 

  135. Huang, F., Gao, T., Wang, W., Wang, L., Xie, Y., Tai, C., et al. (2021). Engineered basic fibroblast growth factor-overexpressing human umbilical cord-derived mesenchymal stem cells improve the proliferation and neuronal differentiation of endogenous neural stem cells and functional recovery of spinal cord injury by activating the PI3K-Akt-GSK-3beta signaling pathway. Stem Cell Research & Therapy, 12(1), 468.

    Article  CAS  Google Scholar 

  136. Li, X., & Dai, J. (2018). Bridging the gap with functional collagen scaffolds: Tuning endogenous neural stem cells for severe spinal cord injury repair. Biomaterials Science, 6(2), 265–271.

    Article  CAS  PubMed  Google Scholar 

  137. Liu, W., Xu, B., Xue, W., Yang, B., Fan, Y., Chen, B., et al. (2020). A functional scaffold to promote the migration and neuronal differentiation of neural stem/progenitor cells for spinal cord injury repair. Biomaterials., 243, 119941.

    Article  CAS  PubMed  Google Scholar 

  138. Li, G., Zhang, B., Sun, J. H., Shi, L. Y., Huang, M. Y., Huang, L. J., et al. (2021). An NT-3-releasing bioscaffold supports the formation of TrkC-modified neural stem cell-derived neural network tissue with efficacy in repairing spinal cord injury. Biomedical Materials, 6(11), 3766–3781.

    CAS  Google Scholar 

  139. Ropper, A. E., Thakor, D. K., Han, I., Yu, D., Zeng, X., Anderson, J. E., et al. (2017). Defining recovery neurobiology of injured spinal cord by synthetic matrix-assisted hMSC implantation. Proceedings of the National Academy of Sciences of the United States of America, 114(5), E820–E8E9.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Cheriyan, T., Ryan, D. J., Weinreb, J. H., Cheriyan, J., Paul, J. C., Lafage, V., et al. (2014). Spinal cord injury models: A review. Spinal Cord, 52(8), 588–595.

    Article  CAS  PubMed  Google Scholar 

  141. Pandamooz, S., Salehi, M. S., Zibaii, M. I., Safari, A., Nabiuni, M., Ahmadiani, A., et al. (2019). Modeling traumatic injury in organotypic spinal cord slice culture obtained from adult rat. Tissue & Cell, 56, 90–97.

    Article  Google Scholar 

  142. Reier, P. J., Lane, M. A., Hall, E. D., Teng, Y. D., & Howland, D. R. (2012). Translational spinal cord injury research: Preclinical guidelines and challenges. Handbook of Clinical Neurology, 109, 411–433.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Thanks to the support of BioRender (https://app.biorender.com), all figures of the review were completed via the website.

Funding

This study was supported by the National Key Research and Development Program of China (2017YFA0104304), National Natural Science Foundation of China (NSFC) [81571213 and 82070459 (Bin Wang)], Key Project of Jiangsu Province (Grant No. BE2020765) (Bin Wang), Nanjing Medical Science and Technique Development Foundation (QRX17006, QRX17057, and ZKX20016) (Bin Wang), Jiangsu Provincial Plan for Mass Entrepreneurship and Innovation (2019) (Bin Wang), and Project of Modern Hospital Management and Development Institute, Nanjing University/Aid project of Nanjing Drum Tower Hospital Health, Education & Research Foundation (NDYG2020030) (Bin Wang).

Author information

Authors and Affiliations

  1. Clinical Stem Cell Center, the Affiliated Drum Tower Hospital of Nanjing University Medical School, School of Life Science, Nanjing University, Nanjing, Jiangsu Province, China

    Yirui Feng & Yu Li

  2. State Key Laboratory of Pharmaceutical Biotechnology and the Comprehensive Cancer Center, the Affiliated Drum Tower Hospital of Nanjing University Medical School, School of Life Science, Nanjing University, Nanjing, Jiangsu Province, China

    Ping-Ping Shen

  3. Clinical Stem Cell Center, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China

    Bin Wang

Authors
  1. Yirui Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yu Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ping-Ping Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

BW and PpS designed the study. YrF and YL performed the literature reviewing and writing. YrF wrote the first draft of the manuscript and all authors read, edited, and approved the final manuscript.

Corresponding authors

Correspondence to Ping-Ping Shen or Bin Wang.

Ethics declarations

Ethics Approval and Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Competing Interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Feng, Y., Li, Y., Shen, PP. et al. Gene-Modified Stem Cells for Spinal Cord Injury: a Promising Better Alternative Therapy. Stem Cell Rev and Rep 18, 2662–2682 (2022). https://doi.org/10.1007/s12015-022-10387-z

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12015-022-10387-z

Keywords

Search

Navigation