Editorial. Unleashing embryonic stem cells for treatment of human spinal cord injury

Tobias PrasseDepartment of Neurological Surgery, University of Washington, Seattle, Washington

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Christoph P. HofstetterDepartment of Neurological Surgery, University of Washington, Seattle, Washington

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 MD, PhD
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Since their discovery, stem cells have fascinated laypersons, scientists, and physicians alike given the American dream–like capability of these cells for self-renewal and potency in giving rise to any cell type.1 Stem cells can be harvested from a variety of adult tissues; however, adult stem cells are difficult to expand in cell culture and their potential to differentiate is limited. Embryonic stem cells (ESCs), on the other hand, are derived during early development at the blastocyst stage, proliferate rapidly, and can give rise to cells of all three germ layers. ESCs represent an almost unlimited source for neurons, oligodendrocytes, and astrocytes. However, more widespread application has been hampered by ethical concerns and the risk of teratoma formation upon transplantation.2 The current study by Dr. Fessler’s group significantly advances the field as it demonstrates the feasibility and long-term safety of predifferentiated ESCs grafted to acute traumatic spinal cord injuries (tSCIs).3

Traumatic spinal cord injuries lead to acute and chronic loss of neural tissue4 with ensuing irreversible functional impairment in humans. While the mammalian central nervous system fails to repair itself following injury, successful regeneration of the severed spinal cord has been documented in some primitive species such as zebrafish and salamanders. In these animals, endogenous ependymal progenitor cells proliferate and migrate through the lesion to create a permissive environment for axon regeneration,5,6 resulting in successful spinal cord regeneration.7 A similar, albeit functionally inadequate, response of endogenous stem cells can be seen in mammals following tSCI.8 In these injuries, proliferating endogenous progenitor cells give rise to mainly reactive astrocytes which contribute to a dense glial scar acting as a major barrier for axonal regeneration.9 Experimental therapeutic approaches have targeted the insufficient endogenous repair mechanisms via two main strategies.

First, the endogenous progenitor cells may be stimulated and differentiation guided via local delivery of growth factors, such as epidermal growth factor (EGF) or brain-derived neurotrophic factor,10,11 or via small molecules.12,13 Intrathecal delivery of neuregulin has been shown to promote oligodendroglial differentiation of endogenous spinal progenitor cells following a rodent spinal cord contusion injury.13 In these experiments, promoting an oligodendroglial cell fate of endogenous progenitor promoted remyelination, protected axons, and resulted in enhanced functional recovery.

The second strategy entails cell-based therapeutic approaches for delivery of proregenerative spinal cord progenitor cells in order to facilitate functional recovery from tSCI. Transplantation of neural stem cells into a rodent spinal cord results in formation of mainly astrocytes14 and has been associated with sprouting of pain fibers and the possibility of causing hypersensitivity.1517 Therefore, various strategies have been applied to guide differentiation of engrafted cells. Engrafted cells may be transduced with transcription factors such as neurogenin-2 to counteract astroglial differentiation.15 More clinically applicable, the lineage of the cells can be determined prior to transplantation.

Experiments with oligodendrocyte precursors in rodent spinal cord injury models have demonstrated integration, remyelination of spared host axons, and possibly enhanced functional recovery.18,19 The limited ability to harvest and propagate these cells has been overcome by discovering human ESCs as an almost unlimited resource for generation of oligodendrocyte precursors.20 Transplantation of these ESC-derived cells led to doubling of remyelinated axons in a rodent contusion tSCI model.22 Treatment resulted in enhanced sparing of gray and white matter and attenuated cavitation in cervical spinal cord contusion injuries.21 Importantly, oligodendrocyte precursor cells derived from human ESCs grafted 7 days following a rodent tSCI resulted in significant improvement of locomotor function compared to untreated controls.22

In several clinical trials cells have been transplanted for the purpose of facilitating myelination of spared spinal cord nerve fiber tracts. Cell sources for these clinical trials included neural stem cells,23 Schwann cells,24,25 and olfactory ensheathing cells.26 These studies have provided proof of concept that exogenous oligodendrocyte precursor cells enhance myelination of spared host nerve fibers following tSCI. Utilizing ESC-derived oligodendrocyte precursors for the first time, McKenna’s landmark paper published in this edition of Journal of Neurosurgery: Spine3 is a significant contribution to this emerging field.27 In the current study, human ESC–derived oligodendrocyte progenitor cells were administered to 5 patients with acute complete thoracic tSCI. The study was carried out with the highest possible level of scientific rigor and demonstrates both the feasibility and safety of ESC-derived oligodendrocyte progenitor cell administration in acutely injured tSCI patients. Despite the use of only minimal immunosuppression, no rejection of engrafted allogeneic cells was observed. MRI performed periodically for the first 5 years demonstrated the lack of tumorigenicity. Imaging revealed T2 signal changes consistent with the formation of a tissue matrix at the injury site in 80% of the participants. Given the small number of infused cells (2 × 106) used for this safety and feasibility study, it is not surprising that the patient cohort did not show an improvement of neurological function. In summary, the current report by Dr. Fessler’s group demonstrates that transplantation of ESC-derived oligodendrocyte precursors after acute thoracic tSCI is clinically feasible and safe, and does not cause malignant neoplasms. While ESC-derived cellular replacement therapies remain in the experimental phase, the current study should be of interest to all practicing neurosurgeons as it provides a clinically applicable strategy utilizing an abundantly available cell source for transplantation into the central nervous system. The authors are planning to proceed with a dose escalation study which will further address the therapeutic efficacy of this approach.

The current study is also a reminder of the tedious pace of innovation and progress in the field of clinical stem cell research. While the current study serves as an example of scientific rigor, data quality, and patient safety, the readers of this editorial are certainly all too familiar with the desperate young tSCI victims who return to our clinics with complications from entirely uncontrolled experimental treatments overseas. A recent scoping review for cell-based therapies targeting human spinal cord injury found that only 1 out of 43 studies was carried out in the United States.27 Domestic risk adversity combined with the "export" of risks overseas is an all-too-common pattern seen in developed nations. The feasibility of accelerating approval processes has been shown during the current COVID-19 pandemic, whereby the FDA accelerated approval for some therapies. The current study will hopefully rejuvenate these efforts.

In summary, this study will have a tremendous impact as it proves the safety of ESC-derived progenitor cell grafting following acute tSCI. Going forward, the combination of stem cell treatment with other therapeutic strategies such as electrical spinal cord stimulation28,29 or neuroprotective strategies could greatly amplify the beneficial effects. The authors should be commended for this excellent, thorough work advancing neurosurgery into the field of neuroregeneration.

Disclosures

This work was supported with funds from the Raisbeck family foundation.

References

  • 1

    Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981;292(5819):154156.

  • 2

    Hentze H, Soong PL, Wang ST, Phillips BW, Putti TC, Dunn NR. Teratoma formation by human embryonic stem cells: evaluation of essential parameters for future safety studies. Stem Cell Res (Amst). 2009;2(3):198210.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3

    McKenna SL, Ehsanian R, Liu CY, et al. Ten-year safety of pluripotent stem cell transplantation in acute thoracic spinal cord injury. J Neurosurg Spine. Published online April 1, 2022. doi: 10.3171/2021.12.SPINE21622

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Crowe MJ, Bresnahan JC, Shuman SL, Masters JN, Beattie MS. Apoptosis and delayed degeneration after spinal cord injury in rats and monkeys. Nat Med. 1997;3(1):7376.

  • 5

    Sabin K, Santos-Ferreira T, Essig J, Rudasill S, Echeverri K. Dynamic membrane depolarization is an early regulator of ependymoglial cell response to spinal cord injury in axolotl. Dev Biol. 2015;408(1):1425.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Diaz Quiroz JF, Tsai E, Coyle M, Sehm T, Echeverri K. Precise control of miR-125b levels is required to create a regeneration-permissive environment after spinal cord injury: a cross-species comparison between salamander and rat. Dis Model Mech. 2014;7(6):601611.

    • Search Google Scholar
    • Export Citation
  • 7

    Gilbert EAB, Vickaryous MK. Neural stem/progenitor cells are activated during tail regeneration in the leopard gecko (Eublepharis macularius). J Comp Neurol. 2018;526(2):285309.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Ke Y, Chi L, Xu R, Luo C, Gozal D, Liu R. Early response of endogenous adult neural progenitor cells to acute spinal cord injury in mice. Stem Cells. 2006;24(4):10111019.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Sellers DL, Maris DO, Horner PJ. Postinjury niches induce temporal shifts in progenitor fates to direct lesion repair after spinal cord injury. J Neurosci. 2009;29(20):67226733.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Hachem LD, Mothe AJ, Tator CH. Effect of BDNF and other potential survival factors in models of in vitro oxidative stress on adult spinal cord-derived neural stem/progenitor cells. Biores Open Access. 2015;4(1):146159.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Kojima A, Tator CH. Epidermal growth factor and fibroblast growth factor 2 cause proliferation of ependymal precursor cells in the adult rat spinal cord in vivo. J Neuropathol Exp Neurol. 2000;59(8):687697.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Karimi-Abdolrezaee S, Schut D, Wang J, Fehlings MG. Chondroitinase and growth factors enhance activation and oligodendrocyte differentiation of endogenous neural precursor cells after spinal cord injury. PLoS One. 2012;7(5):e37589.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Ding Z, Dai C, Zhong L, et al. Neuregulin-1 converts reactive astrocytes toward oligodendrocyte lineage cells via upregulating the PI3K-AKT-mTOR pathway to repair spinal cord injury. Biomed Pharmacother. 2021;134:111168.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Johansson CB, Momma S, Clarke DL, Risling M, Lendahl U, Frisén J. Identification of a neural stem cell in the adult mammalian central nervous system. Cell. 1999;96(1):2534.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Hofstetter CP, Holmström NA, Lilja JA, et al. Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome. Nat Neurosci. 2005;8(3):346353.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Macias MY, Syring MB, Pizzi MA, Crowe MJ, Alexanian AR, Kurpad SN. Pain with no gain: allodynia following neural stem cell transplantation in spinal cord injury. Exp Neurol. 2006;201(2):335348.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Tsuda M, Kohro Y, Yano T, et al. JAK-STAT3 pathway regulates spinal astrocyte proliferation and neuropathic pain maintenance in rats. Brain. 2011;134(Pt 4):11271139.

  • 18

    Rosenbluth J, Schiff R, Liang WL, Menna G, Young W. Xenotransplantation of transgenic oligodendrocyte-lineage cells into spinal cord-injured adult rats. Exp Neurol. 1997;147(1):172182.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Bambakidis NC, Miller RH. Transplantation of oligodendrocyte precursors and sonic hedgehog results in improved function and white matter sparing in the spinal cords of adult rats after contusion. Spine J. 2004;4(1):1626.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Nistor GI, Totoiu MO, Haque N, Carpenter MK, Keirstead HS. Human embryonic stem cells differentiate into oligodendrocytes in high purity and myelinate after spinal cord transplantation. Glia. 2005;49(3):385396.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Sharp J, Frame J, Siegenthaler M, Nistor G, Keirstead HS. Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants improve recovery after cervical spinal cord injury. Stem Cells. 2010;28(1):152163.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    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):46944705.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Levi AD, Anderson KD, Okonkwo DO, et al. Clinical outcomes from a multi-center study of human neural stem cell transplantation in chronic cervical spinal cord injury. J Neurotrauma. 2019;36(6):891902.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Saberi H, Moshayedi P, Aghayan HR, et al. Treatment of chronic thoracic spinal cord injury patients with autologous Schwann cell transplantation: an interim report on safety considerations and possible outcomes. Neurosci Lett. 2008;443(1):4650.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Saberi H, Firouzi M, Habibi Z, et al. Safety of intramedullary Schwann cell transplantation for postrehabilitation spinal cord injuries: 2-year follow-up of 33 cases. J Neurosurg Spine. 2011;15(5):515525.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Nakhjavan-Shahraki B, Yousefifard M, Rahimi-Movaghar V, et al. Transplantation of olfactory ensheathing cells on functional recovery and neuropathic pain after spinal cord injury; systematic review and meta-analysis. Sci Rep. 2018;8(1):325.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Willison AG, Smith S, Davies BM, Kotter MRN, Barnett SC. A scoping review of trials for cell-based therapies in human spinal cord injury. Spinal Cord. 2020;58(8):844856.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Inanici F, Samejima S, Gad P, Edgerton VR, Hofstetter CP, Moritz CT. Transcutaneous electrical spinal stimulation promotes long-term recovery of upper extremity function in chronic tetraplegia. IEEE Trans Neural Syst Rehabil Eng. 2018;26(6):12721278.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Inanici F, Brighton LN, Samejima S, Hofstetter CP, Moritz CT. Transcutaneous spinal cord stimulation restores hand and arm function after spinal cord injury. IEEE Trans Neural Syst Rehabil Eng. 2021;29:310319.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
Richard G. FesslerDepartment of Neurosurgery, Rush University Medical Center, Chicago, Illinois;

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Reza EhsanianDivision of Physical Medicine and Rehabilitation, Department of Orthopedics & Rehabilitation, University of New Mexico School of Medicine, Albuquerque, New Mexico;

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Charles Y. LiuUSC Neurorestoration Center, Los Angeles, California;
Department of Neurological Surgery, USC Keck School of Medicine, Los Angeles, California;
Rancho Los Amigos National Rehabilitation Center, Downey, California;

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Gary K. SteinbergDepartment of Neurosurgery, Stanford University School of Medicine, Stanford, California;

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Linda JonesThomas Jefferson University, Philadelphia, Pennsylvania;

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Jane S. LebkowskiAsterias Biotherapeutics, now Lineage Cell Therapeutics, Carlsbad, California;
Regenerative Patch Technologies, LLC, Menlo Park, California;

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Edward Wirth IIIAsterias Biotherapeutics, now Lineage Cell Therapeutics, Carlsbad, California;
Aspen Neuroscience, San Diego, California; and

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Stephen L. McKennaDepartment of Neurosurgery, Stanford University School of Medicine, Stanford, California;
Department of Physical Medicine and Rehabilitation, Santa Clara Valley Medical Center, San Jose, California

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Response

We thank Drs. Prasse and Hofstetter for their thoughtful commentary on our article. Among the many maladies affecting humans, spinal cord injury (SCI) is one for which the means to progress in successful treatment has remained an enigma for ages. From the initial description of SCI in the Edwin Smith Papyrus (where it was deemed an illness not to be treated) to the near universal mortality rate during the American Civil War, literally thousands of years have passed with essentially no progress in SCI treatment, and no improvement in prognosis! The invention of antibiotics to treat infection and progress in physical therapy to prevent bedsores and contractures of the extremities have increased the lifespan of individuals living with SCI. However, there have been inadequate improvements in the debilitating loss of motion, sensation, and bowel and bladder control.

Over the past several decades, stem cell technology has had significant impacts on multiple areas of medicine. It is not surprising, then, that the potential efficacy of this technology in treating SCI would be the subject of exploration. When the use of stem cell technology is explored responsibly, numerous preclinical evaluations must be performed before human trials can be considered. This trial (NCT01217008) was based on years of research examining safety in animal models, including clinical chemistry, hematology, immunology, teratology, histology, multiorgan distribution, and surgical technique, as well as clinical benefit. Only then, after safety in each of these areas was demonstrated, was a limited human trial initiated. The trial itself was designed to maximize patient safety. Extensive pretreatment examinations ensured that the patients who were entered into the trial had no clinical or psychological contraindications to receiving the treatment. Sterility and viability of the cells was assured. The lowest potentially clinically effective number of cells (2 × 106) was selected, and the cells were given in a single injection using a syringe-positioning device which could precisely deliver the cells to the intended location within the spinal cord. The midthoracic spinal cord level was chosen to minimize potential neurologic deterioration resulting from the treatment. Finally, appropriate informed consent and the lack of coercion were assured through the use of independent trial observers.

This study clearly demonstrated the safety of intraparenchymal injection of this oligodendrocyte progenitor cell line. As pointed out by Drs. Prasse and Hofstetter, T2-weighted MRI scans also suggested the presence of a tissue matrix (and possible incorporation) of the injected tissue into the host spinal cord. Although sensory improvement was observed in several patients, the dose of only 2 × 106 cells and the midthoracic location of injection also reduced the likelihood of observing significant motor improvement in this safety trial. In the subsequent dose escalation trial in patients with cervical SCI (NCT02302157), which is currently under peer review, in addition to safety, more impressive clinical results are being observed. While not randomized, the results of the second trial do strongly argue for the continued exploration of stem cell transplantation as a potential treatment for acute SCI. We heartily agree with the suggestion of Drs. Prasse and Hofstetter that the ultimate "cure" for SCI will likely be a multifactorial treatment potentially including stem cell transplantation, scaffold implantation, neurohormonal/neuroprotective agent administration, and electrical spinal cord stimulation, to name only a few of the most obvious. Moreover, we also agree that in light of the demonstrated safety, the feasibility of accelerated approval for future research and possibly therapy should certainly be entertained.

Once again, we thank Drs. Prasse and Hofstetter (also renowned for their work in SCI) for their thorough and thoughtful commentary, as well as their kind words.

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Illustration from Dibble et al. (pp 384–394). © Washington University Department of Neurosurgery, published with permission.

  • 1

    Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981;292(5819):154156.

  • 2

    Hentze H, Soong PL, Wang ST, Phillips BW, Putti TC, Dunn NR. Teratoma formation by human embryonic stem cells: evaluation of essential parameters for future safety studies. Stem Cell Res (Amst). 2009;2(3):198210.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3

    McKenna SL, Ehsanian R, Liu CY, et al. Ten-year safety of pluripotent stem cell transplantation in acute thoracic spinal cord injury. J Neurosurg Spine. Published online April 1, 2022. doi: 10.3171/2021.12.SPINE21622

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Crowe MJ, Bresnahan JC, Shuman SL, Masters JN, Beattie MS. Apoptosis and delayed degeneration after spinal cord injury in rats and monkeys. Nat Med. 1997;3(1):7376.

  • 5

    Sabin K, Santos-Ferreira T, Essig J, Rudasill S, Echeverri K. Dynamic membrane depolarization is an early regulator of ependymoglial cell response to spinal cord injury in axolotl. Dev Biol. 2015;408(1):1425.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Diaz Quiroz JF, Tsai E, Coyle M, Sehm T, Echeverri K. Precise control of miR-125b levels is required to create a regeneration-permissive environment after spinal cord injury: a cross-species comparison between salamander and rat. Dis Model Mech. 2014;7(6):601611.

    • Search Google Scholar
    • Export Citation
  • 7

    Gilbert EAB, Vickaryous MK. Neural stem/progenitor cells are activated during tail regeneration in the leopard gecko (Eublepharis macularius). J Comp Neurol. 2018;526(2):285309.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Ke Y, Chi L, Xu R, Luo C, Gozal D, Liu R. Early response of endogenous adult neural progenitor cells to acute spinal cord injury in mice. Stem Cells. 2006;24(4):10111019.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Sellers DL, Maris DO, Horner PJ. Postinjury niches induce temporal shifts in progenitor fates to direct lesion repair after spinal cord injury. J Neurosci. 2009;29(20):67226733.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Hachem LD, Mothe AJ, Tator CH. Effect of BDNF and other potential survival factors in models of in vitro oxidative stress on adult spinal cord-derived neural stem/progenitor cells. Biores Open Access. 2015;4(1):146159.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Kojima A, Tator CH. Epidermal growth factor and fibroblast growth factor 2 cause proliferation of ependymal precursor cells in the adult rat spinal cord in vivo. J Neuropathol Exp Neurol. 2000;59(8):687697.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Karimi-Abdolrezaee S, Schut D, Wang J, Fehlings MG. Chondroitinase and growth factors enhance activation and oligodendrocyte differentiation of endogenous neural precursor cells after spinal cord injury. PLoS One. 2012;7(5):e37589.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Ding Z, Dai C, Zhong L, et al. Neuregulin-1 converts reactive astrocytes toward oligodendrocyte lineage cells via upregulating the PI3K-AKT-mTOR pathway to repair spinal cord injury. Biomed Pharmacother. 2021;134:111168.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Johansson CB, Momma S, Clarke DL, Risling M, Lendahl U, Frisén J. Identification of a neural stem cell in the adult mammalian central nervous system. Cell. 1999;96(1):2534.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Hofstetter CP, Holmström NA, Lilja JA, et al. Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome. Nat Neurosci. 2005;8(3):346353.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Macias MY, Syring MB, Pizzi MA, Crowe MJ, Alexanian AR, Kurpad SN. Pain with no gain: allodynia following neural stem cell transplantation in spinal cord injury. Exp Neurol. 2006;201(2):335348.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Tsuda M, Kohro Y, Yano T, et al. JAK-STAT3 pathway regulates spinal astrocyte proliferation and neuropathic pain maintenance in rats. Brain. 2011;134(Pt 4):11271139.

  • 18

    Rosenbluth J, Schiff R, Liang WL, Menna G, Young W. Xenotransplantation of transgenic oligodendrocyte-lineage cells into spinal cord-injured adult rats. Exp Neurol. 1997;147(1):172182.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Bambakidis NC, Miller RH. Transplantation of oligodendrocyte precursors and sonic hedgehog results in improved function and white matter sparing in the spinal cords of adult rats after contusion. Spine J. 2004;4(1):1626.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Nistor GI, Totoiu MO, Haque N, Carpenter MK, Keirstead HS. Human embryonic stem cells differentiate into oligodendrocytes in high purity and myelinate after spinal cord transplantation. Glia. 2005;49(3):385396.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Sharp J, Frame J, Siegenthaler M, Nistor G, Keirstead HS. Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants improve recovery after cervical spinal cord injury. Stem Cells. 2010;28(1):152163.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    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):46944705.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Levi AD, Anderson KD, Okonkwo DO, et al. Clinical outcomes from a multi-center study of human neural stem cell transplantation in chronic cervical spinal cord injury. J Neurotrauma. 2019;36(6):891902.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Saberi H, Moshayedi P, Aghayan HR, et al. Treatment of chronic thoracic spinal cord injury patients with autologous Schwann cell transplantation: an interim report on safety considerations and possible outcomes. Neurosci Lett. 2008;443(1):4650.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Saberi H, Firouzi M, Habibi Z, et al. Safety of intramedullary Schwann cell transplantation for postrehabilitation spinal cord injuries: 2-year follow-up of 33 cases. J Neurosurg Spine. 2011;15(5):515525.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Nakhjavan-Shahraki B, Yousefifard M, Rahimi-Movaghar V, et al. Transplantation of olfactory ensheathing cells on functional recovery and neuropathic pain after spinal cord injury; systematic review and meta-analysis. Sci Rep. 2018;8(1):325.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Willison AG, Smith S, Davies BM, Kotter MRN, Barnett SC. A scoping review of trials for cell-based therapies in human spinal cord injury. Spinal Cord. 2020;58(8):844856.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Inanici F, Samejima S, Gad P, Edgerton VR, Hofstetter CP, Moritz CT. Transcutaneous electrical spinal stimulation promotes long-term recovery of upper extremity function in chronic tetraplegia. IEEE Trans Neural Syst Rehabil Eng. 2018;26(6):12721278.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Inanici F, Brighton LN, Samejima S, Hofstetter CP, Moritz CT. Transcutaneous spinal cord stimulation restores hand and arm function after spinal cord injury. IEEE Trans Neural Syst Rehabil Eng. 2021;29:310319.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

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