SE M I N SP I N E S U R G 27 (2015) 90–92

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Current concepts in the use of stem cells for the

article info abstract

Following spinal cord injury, significant losses in the neural and stromal structures occur.
This event contributes to the development of scar tissue that may hinder or prevent the
regeneration and formation of functional neural tissue. The regenerative potential of stem
cells to reverse or prevent the progression of neural injury has driven substantial interest
in their clinical application. The aim of this article is to review the current understanding
regarding the promise of stem cell therapy in the setting of spinal cord injuries.
& 2015 Elsevier Inc. All rights reserved.

1. Introduction treatments that have been researched, the use of stem cells
to bridge the area of cavitation and to mitigate the inhibitory
Spinal cord injuries (SCIs) represent severely traumatic con- effects of the glial scar tissue may hold the greatest potential
ditions with little effective medical and surgical interventions for effective treatment.4
currently available. The incidence of spinal cord injury in the
United States is approximately 13,000 events per year.1 Tradi-
tionally, the most common mechanism of injury has been
motor vehicle accidents. However, with the aging of the United 2. Pathology of Injury
States population, the leading cause of SCIs in this country is
now falls.1 The mortality in the first year from SCIs ranges from The initial traumatic event results in a baseline zone of injury
5% to 12% for thoracolumbar and cervical injuries, respectively.2 followed by secondary insult that increases the size of the
Cavitation at the site of injury with loss of neural elements lesion.5 A combination of necrosis and apoptosis contributes to
and stromal tissues is observed in all SCIs. The physical gap the loss of oligodendrocytes and demyelination. Studies have
does not reconstitute with functional spinal cord tissue, as demonstrated that apoptosis continues for weeks after the
such the remodeling results in glial scar formation without initial traumatic event.5 The mechanisms of continued injury
neuronal elements. Scar hypertrophy and production of exist along a spectrum from necrosis to apoptosis. For exam-
inhibitory molecules result in an environment not conducive ple, initiation of apoptosis results in exhaustion of intracellular
to axon formation or regeneration.3 Thus, among the many energy stores leading to mitochondrial dysfunction and

Disclosure: No funds were received in support of this work. No benefits in any form have been or will be received from any commercial
party related directly or indirectly to the subject of this article.
n
Corresponding author.
E-mail address: Kern.singh@rushortho.com (K. Singh).
1
Subject to change March 2015.

http://dx.doi.org/10.1053/j.semss.2015.03.005
1040-7383/& 2015 Elsevier Inc. All rights reserved.
 S E M I N SP I N E SU R G 27 (2015) 90–92 91

ultimately necrosis.5 Such mechanisms are responsible for different types of stem cells and progenitor cells offer prom-
high rates of oligodendrocyte cell death in the lesion center.6 ise for the reconstitution of neural elements in SCI.
The inflammatory response contributes to both early and Embryonic stem cells have received the most media atten-
late injury progression. Neutrophil recruitment and activity tion since their original culture in mouse embryos in 1981.11
at the lesion site peaks in the first 24 hours.6 The initial injury Embryonic stem cells have unlimited differentiation poten-
mechanism results in immediate cell death at the site of tial, and as such have significant potential to bridge neural
injury compounded by late cell death as apoptosis, necrosis, tissue defects. Additionally, embryonic cells have the poten-
and inflammatory processes continue. Additional neuronal tial to form teratomas.10 The specific ability to regenerate
loss occurs over a period of weeks circumferentially from the neurons and oligodendrocytes is of particular interest for SCI.
zone of injury.7 Phagocytosis and microglial activity gives rise Investigators have demonstrated in vitro the ability to direct
to cavitary formation at 1 week.6 At 2 weeks post-injury, the differentiation of embryonic stem cells into neuronal
macrophage and microglial activity continues as neutrophil progenitors while inhibiting the formation of other mesoder-
activity diminishes. Some studies demonstrate remyelination mal or endodermal cells.12 Treatment with retinoic acid and
at the periphery of the lesion, which may contribute to the recombinant fibroblast growth factor has been demonstrated
preservation of neural function. The inflammatory and to direct differentiation into spinal motor neurons.12
remodeling process continues and expands radially from In vitro studies to direct differentiation of embryonic cells are
the site of injury.6 As the remodeling progresses, the resul- ongoing. Presently, the in vivo potential of embryonic stem
tant defect and scar form an insurmountable barrier to the cells has been demonstrated in animals only. In Sprague Daw-
intrinsic regeneration of neural elements (Fig. 1).3 ley rats, transplantation of retinoic acid treated embryonic cells
into the post-traumatic cavitary spinal cord defect at 9 days
after injury resulted in locomotor improvements compared
with controls. Histologic analysis revealed that the trans-
3. Embryonic Stem Cells and Spinal Cord planted cells differentiated into neuronal and oligodendrocyte
Injury lineages migrating radially from the zone of injury.13
The feasibility of human embryonic stem cell transplants to
In 1986, Bregman et al. transplanted fetal spinal cord tissue restore motor function and to re-myelinate injured segments
into midthoracic spinal cord lesions in newborn rats. Breg- has been recently demonstrated. Keirstead et al. induced stem
man et al.8 demonstrated inhibition of post-injury neuronal cells into the oligodendrocyte pathway and transplanted the
cell loss via treatment with fetal stem cells. Subsequent precursor cells into rats with SCI. Both remyelination and
studies have produced convincing evidence of preservation improvements in motor function were noted.14
and restoration of neuronal function with stem cell treat- In vitro and in vivo studies with animals using human-
ment. None of these promising treatments have yet trans- derived embryonic stem cells have cleared the path for
lated into results in human clinical trials.9 human trials.14,15 In 2009, the Geron Corporation (Menlo Park,
Stem cells and progenitor cells exist in a continuum CA) announced FDA approval for Phase I human clinical trials
demonstrating varying levels of self-renewal and differentia- of oligodendrocyte precursor-directed embryonic stem cells
tion capacity. By definition, stem cells have an unlimited for the treatment of thoracic level ASIA (American Spinal
capacity to replicate whereas progenitor cells can divide only Injury Association) A SCI.16 The Geron trial protocol was used
over a limited number of cycles. Progenitor cells also have to treat patients in the subacute phase of injury of 7 14 days.
less capacity to differentiate into other cell types.10 Many Previous animal studies had suggested that this was the

Fig. 1 – Cascade demonstrating the progression from initial spinal cord insult to secondary injury with subsequent glial scar
formation. (Adapted with permission from, Ruff CA, Fehlings MG. Neural stem cells in regenerative medicine: bridging the
gap. Panminerva Med. 2010;52(2):125–47.)
92 SE M I N SP I N E SU R G 27 (2015) 90–92

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cells.14,15 The Geron trial was heavily criticized for recruiting evidence for apoptosis after spinal cord injury. J Neurotrauma.
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