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Treating Traumatic Spinal Cord Injuries with Embryonic-Derived Stem Cells or iPSCs: The Question of Translatability

   Traumatic spinal cord injuries (SCIs) are significant causes of mortality and neurological morbidity that impose extensive psychological and economic strain on patients and health care systems. According to the most recent statistical report of the National Spinal Cord Injury Statistical Centre (NSCISC) there are about 17,500 new cases of spinal cord injury each year in the United States alone (1). Furthermore, it is estimated that approximately 285,000 people are living with spinal cord injuries in the United States (1). The average age at injury ranges from 29-42 years, with motor vehicle accidents being the leading cause of injury (1). Less than 1% of persons with SCI experience complete neurological recovery by the time of hospital discharge (1).

   Curing paralysis and the neurological damage caused by SCIs has always been both a goal of regenerative medicine and an expectation of it. However, the complex and time-sensitive pathophysiology of SCI poses challenges for tissue-repair (2). The injury is immediately followed by substantial structural disturbance and vascular damage, leading to a secondary inflammatory response (2). While inflammation expands the injury site, an inhibitory milieu is created within and surrounding the injured area, resulting in scar tissue formation and preventing tissue regeneration (2).

   Despite the abysmal picture painted above, there have been significant improvements in research on stem cell therapies for SCI, showing potential promise for regenerative treatments (2). Numerous studies have shown that the endogenous population of neural progenitor cells, especially widely distributed oligodendrocyte progenitors, play an important role in axonal regeneration and remyelination after injury (2). Recent studies have also demonstrated that post-injury transplantation of human embryonic stem cell (hESC)-derived oligodendrocyte progenitor cells (OPCs) into rodent models of cervical and thoracic spinal cord injuries improved locomotor performance (3). These studies have led to the initiation of a phase I/IIa clinical trial, testing the dosage, efficacy, and side effects of the therapy across multiple centers in the United States (4).

   In the field of regenerative medicine, translatability of the preclinical studies that test the efficacy and safety of novel therapies, such as those mentioned above, is of utmost importance. A translatable model or treatment is one that can be effectively and successfully applied to a human population in a clinical trial. Successful translatability requires that the models used in the preclinical studies resemble the human population the treatment is meant for as much as possible. Although this may not be as easily achieved as talked about, there are ways to improve the translatability of preclinical studies to a great extent. There are various factors limiting the translatability of spinal cord research into clinical trials. One of these limitations is the immunodeficient state of the animal models used in research. Immunodeficiency is required in the mice so that they can accept the allogenic human cells injected into their spinal cord so that researchers can accurately determine whether the cells play a role in spinal cord regeneration or not. Most human SCI patients are not immunodeficient and human embryonic stem cells, by virtue of their source, are allogenic grafts to humans as well. Therefore, the chance of immune rejection of hESC derived cells used in transplant exists, limiting the translatability of the research on hESC derived progenitor cells and SCI therapy.

   This limitation can be potentially addressed by the use of induced pluripotent stem cell (iPSC) derived progenitor cells.  In 2015 Salewski et al., differentiated OPCs from murine fibroblast-derived iPSCs using neurosphere expansion methods (5). Transplantation of iPSC-derived OPCs into athymic rodent models of thoracic SCI lead to functional improvements and myelinated axon regeneration (6). The use of iPSC derived OPCs primarily addresses the issue of cell rejection because the iPSCs can be made from patients’ own fibroblasts, leading to an autologous cell source and drastic decrease in rejection potential (5-6).  However, two limitations of iPSC use exist: first the increased potential of tumorigenicity caused by the induction methods used to create iPSCs, and second the preference iPSCs show for differentiating into parental cell lines due to their epigenetic memory (8, 10). To address the first problem, cells with common ectodermal origin, like keratinocytes, that are more likely to have similar epigenetic layouts as neural cells can be used as parent cells in the reprogramming process (6). Keratinocyte-derived iPSCs have been shown to efficiently differentiate into neural progenitor cells via reprogramming methods (6). Keratinocytes are easily accessible and can be reprogrammed at a higher frequency due to their greater basal levels of Klf4 and cMyc, important reprogramming transcription factors, providing a nearly unlimited source of autologous iPSCs (6). To address the second problem, the potential for increased tumorigenicity caused by viral induction methods can be decreased by using other reprogramming methods such as the PiggyBac transposon/transposase system, which catalyzes insertion and exertion events to introduce the required reprogramming factors (4-8).

   Successful preclinical studies on the transplantation of stem cell derived OPCs provide a promising potential for future treatments of SCIs and hope for functional recovery. This overview only provides a snapshot of a segment of this field of research. Even though hESC derived OPC transplantation is currently being tested in clinical trials (3-4). the possibility of immune rejection of allogenic cells might hinder the successful translation of this model. iPSC derived OPCs have been shown to be successful in improving outcome and axonal remyelination post SCI (5). Even though iPSC generation may require longer processing times with the extra reprogramming steps involved, the results in human clinical trials might prove to be better because of the autologous nature of the cells and the reduction in rejection potential, making iPSC-derived OPC transplantation a more translatable model for treatment of SCI. Nevertheless, the limitations of deriving differentiated cells from iPSCs also exist, which highlights the fact that much more research is required in this field before novel treatments can be successfully introduced into clinics.

(1)National Spinal Cord Injury Statistical Center. Facts and Figures at a Glance. Birmingham, AL: University of Alabama at Birmingham. (2017). (Accessed Nov. 23rd 2017)From: https://www.nscisc.uab.edu/Public/Facts%202016.pdf

(2) Badner, A., Sidddiqui, A. M., & Fehlings, M. G. Spinal cord injuries: how could cell therapy help? Expert Opin Biol Ther. 17, 529-541 (2017).

(3) Manley, N. C., Priest, C. A., Denham, J., Wirth III, E. D., & Lebkowski, J. S. Human embryonic stem cell-derived oligodendrocyte progenitor cells: preclinical efficacy and safety in cervical spinal cord injury. Stem Cells Transl Med. 6, 1917-1929 (2017).

(4) NIH, U.S National Library of Medicine. Dose escalation study of AST-OPC1 in Spinal Cord Injury. (Accessed October 16th 2017).  https://clinicaltrials.gov/ct2/show/NCT02302157?term=oligodendrocyte+progenitor+cell+transplant&cond=Spinal+Cord+Injuries&rank=1

(5) Salewski, R. et al. Transplantation of induced pluripotent stem cell-derived neural stem cells mediate functional recovery following thoracic spinal cord injury through remyelination of axons. Stem Cells Transl Med. 4, 743-754 (2015).

(6) Khazaei, M., Ahuja, C. S., & Fehlings, M. G. Induced Pluripotent stem cells for traumatic spinal cord injury. Front Cell Dev. 4, 152 (2017).

(7) Sachewsky, N. Stem cell: the building blocks of regenerative medicine.  Translational medicine. University of Toronto, Lecture. (September 19th 2017).

(8) Woltjen et al. PiggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature. 458, 766-771 (2009).

Kimia Ghannad-Zadeh is a senior at the University of Toronto, completing a specialist degree in Human Biology: Health and Disease alongside a minor in Psychology. She is currently the co-president of the UofT SSSCR chapter, and has previously worked with the chapter as community outreach co-chair and conference planning co-chair. Aside from her passion for stem cells, Kimia enjoys painting and illustrating.

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