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.15–17 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.
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