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Stem Cell Therapies in Spinal Cord Injuries
Individual Neurowiki by Salwa Hasan (996769796)
As part of the “Stem Cell Therapies in Neuroscience” Group
Spinal cord injury (SCI) refers to injuries to the spinal cord that resulted from trauma rather
than disease. Symptoms of SCI can range from pain to paralysis to incontinence. SCI results in
loss of neuronal tissue which could lead to additional tissue loss, ultimately impairing of sensory
and motor functions. Secondary tissue damage that follows SCI involves an inflammatory
cascade that includes the infiltration of neutrophils and macrophages into the site of lesion, in
concert with resident microglia, stimulation of glial cells and increased expression of proinflammatory cytokines (Taoka et al., 1997; Popovich et al., 2002). These inflammatory
responses create a hostile environment for axonal regrowth (Ramer et al., 2000) and therefore,
often lead to the formation of a cyst at the site of injury, promoting neurological dysfunction
(Carlson et al., 1998).
Research using a mouse model of contusive injury has shown that pathology to white matter
caused by the injury determines the extent of functional recovery1. In particular, SCI is
associated with a chronic and progressive loss of myelination of spared axons2, which is caused
by apoptosis of oligodendrocytes. Previous studies have attempted to obtain functional
recovery through the antagonism of growth inhibitors, application of growth factors, cell
transplantation, and vaccination strategies. But none of these approaches have provided full
recovery in either animal models or humans. Thus, there is currently no therapeutic treatment
for full functional recovery after SCI. Stem cell therapy has the potential to provide an
alternative source of cells that could ameliorate the symptoms associated with spinal cord
injury, either directly or indirectly through secondary mechanisms, such as reducing
inflammation that prevents the growth of spared axons after contusion. Stem cells, either
embryonic or adult (from human bone marrow, neural progenitor population, adipose-derived
cells, etc.) can be transplanted into the site of injury and they can proliferate there or recruit
other cells such as glial cells that provide support in the damaged area.
1.1 Human embryonic stem cells used in rat models of SCI
Previous studies have implicated both mouse and human embryonic stem cells (ESCs), which
are derived from the inner cell mass of an embryo, of having therapeutic effects on animal
models of spinal cord injury (cite intro). In particular, these studies have shown that neural
precursor populations from ESCs, such as oligodendrocyte progenitor cells (OPCs) enable partial
recovery of SCI by protecting host neurons and promoting remyelination of damaged cells in rat
models of SCI, leading to recovery of motor skills. However, these studies showed recovery
when the stem cell transplantation took place within 7 days of injury and the same effects were
1
Noble LJ, Wrathall JR (1989) Correlative analyses of lesion development and functional status after graded spinal
cord contusive injuries in the rat. Exp Neurol 103: 34-40.
2
Bunge RP, Puckett WR, Becerra JL, Marcillo A, Quencer RM (1993) Observations on the pathology of human spinal cord injury.
A review and classification of 22 new cases with details from a case of chronic cord compression with extensive focal
demyelination. Adv Neurol 59: 75-89.
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not replicated when the animals were treated after 10 months of injury. This suggested that
stem cell therapy in humans would be most efficient if done at an early time point following
injury.
In a study by Kerr et al., human ESCs have been shown to differentiate efficiently into
oligodendrocyte cells, which corresponded with increased neurological responses. In particular,
the study used a rat model of SCI, which was transplanted with OPCs derived from human ESCs
at the two critical time-points when extensive damage to surrounding tissue takes place, that is,
3 and 24 hours post-injury. The transplanted stem cells were analyzed for migration and
survivability after 8 days, post-mortem. In-vitro immunoflourescence studies detected
oligodendrocyte markers within the transplanted cells, suggesting that efficient differentiation
had taken place. Furthermore, OPCs were found to survive at the site of injury and migrate
outwards from the site of injection after one week. Histological analyses also confirmed that
ESC-derived OPCs integrated with host cells in the spinal cord without disrupting the
parenchyma, which is an important consideration in these transplants. In addition, tumour or
cyst formation was not observed, which is important in the transplantation of undifferentiated
stem cells. Finally, behavioural and electrophysiological assessments revealed enhanced
neurological responses in contused rats that received the cell transplant versus controls.
1.2 Neural precursor cells reduce secondary tissue damage
Various studies have shown that transplanted neural stem/precursor cell populations impart
therapeutic benefits via multiple neuroprotective and immune modulatory mechanisms rather
than simply cell replacement. In a study by Cusimano et al. to characterize the molecular and
cellular mechanisms responsible for such therapeutic plasticity, syngeneic neural
stem/precursor cells were injected in a severely contused mouse spinal cord. Subsequently, the
researchers studied the motor functions and secondary pathology in the animals, the fate of
the transplanted cells, and level of inflammation at the site of injury. Neural stem/precursor cell
injections were made at two time-points, which were subacute (7 days after injury) or early
chronic (21 days after injury). Benefits to motor function were observed in the mice treated
sub-acutely only. In terms of cell fate, the transplanted cells survived in an undifferentiated
state around the lesion and communicated with host phagocytes via cellular-junctional
coupling. These interactions correlated with enhanced expression of significant inflammatory
cell transcripts. In particular, the transplanted cells reduced the ratio of ‘classically-activated’
M1-like macrophages, which promoted healing of the injury. Therefore, in this study, the
results suggest that neural stem/precursor cells can alter the local inflammatory cell
microenvironment into a less hostile one, promoting the healing of the injury and regeneration
past the lesion.
1.3 Olfactory ensheathing cell transplantation
Olfactory ensheathing cells (OECs) are particular glial cells found only in the olfactory system
that have special properties which make them conducive to use for cell-mediated repair
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following SCI. In particular, OECs, which play an important role in olfactory neuron turnover,
retain exceptional plasticity and promote olfactory neurogenesis. OECs have been used in
various models of rodent SCI and have shown varying degrees of effectiveness at functional
recovery. OECs promote tissue sparing and neuroprotection, stimulate outgrowth of damaged
axons and enhance angiogenesis and remyelination of damaged axons, among other beneficial
effects that they impart.
In particular, a clinical study by Huang et al. tested the efficacy of intraspinal OEC
transplantations in SCI patients of varying ages. After the transplantation surgery, various
behavioural tests were used to show motor improvement, such as light touch and pin prick
tests. The study concluded that OEC transplantation improved neurological function in patients
with SCI over varying age groups.
1.4 Bone marrow derived MSCs promotes functional recovery
Adult bone marrow derived mesenchymal stem cells (BM-MSC) have been shown to enhance
anatomical and functional recovery in SCI animal models by promoting tissue sparing (Himes et
al., 2006; Sheth et al., 2008) and axonal regeneration (Wu et al., 2003). It is thought that BMMSCs impart their therapeutic effects through the secretion of soluble factors and providing an
extracellular matrix that enhances neuroprotection. Additionally, these stem cells play a role in
remyelination and neural differentiation (Akiyama et al., 2002a, b) (Ankeny et al., 2004; Zurita
et al., 2008).
A recent study by Nakajima et al. used BM-MSCs to investigate the mechanism via which these
cells mediate the hostile inflammatory responses created after SCI. The group used a rat model
of SCI and intraspinally injected the animals with BM-MSCs, which were then showed to
migrate within the spinal cord without differentiating into glial or neuronal cell types. The
transplanted cells resulted in changed ratios of interleukins and cytokines, as well as increased
numbers of alternatively activated macrophages and decreased numbers of classically activated
macrophages, all of which corresponded with preservation of damaged axons, reduced scar
tissue formation and increased sparing of myelination. These changes lead to functional motor
recovery in the transplanted group compared to control. Therefore, Nakajima et al. concluded
that acute transplantation of MSCs causes a change in the inflammatory environment at the
site of lesion, which ultimately provides a permissive environment for locomotor recovery in
the subacute or chronic phase after SCI.
1.5 Therapeutic potential of induced pluripotent stem cells in SCI
Although neural stem/progenitor cells derived from human embryonic stem cells are a
promising source for cell replacement therapy in SCI models, the use of ES cells is associated
with various ethical and immunological concerns, which may be overcome by using induced
pluripotent stem cells (iPSCs). These are created by taking somatic cells and introducing the
expression of four particular transcription factors (Oct4, Sox2, Klf4 and Nanog) to induce
pluripotency.
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A recent study by Tsuji et al. investigated the therapeutic potential of murine iPSCs
differentiated into neurons in a mouse model of SCI. iPS-derived neurospheres were first
evaluated as non-tumouigenic by transplanting them into NOD/SCID mice, to ensure the
production of functional neurons, astrocytes and oligodendrocytes. When these iPS-derived
neurospheres were transplanted into the spinal cord within 9 days after injury, they were
shown to differentiate into these three lineages without teratoma formation. In addition, they
played a role in remyelination of damaged axons, and induced outgrowth of axons in host
serotonergic fibres, enhancing motor function recovery. The findings of this study suggest that
iPS-derived neurospheres may be a promising source of stem cells for transplantation therapy
in cases of SCI. However, these cells must be ascertained to be ‘safe’ prior to the initiation of
clinical applications. In particular, their differentiation potentials and the possibility for
tumourogenicity in the context of the host cells, must be investigated to establish their safety
and efficacy as transplantation therapies.