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Stem CellsCurrent Approach and Future Prospects in Spinal Cord Injury Repair.

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THE ANATOMICAL RECORD 293:519–530 (2010)
Stem Cells: Current Approach and
Future Prospects in Spinal Cord Injury
Department of Orthopaedics, 2nd Affiliated Hospital, School of Medicine,
Zhejiang University, Hangzhou, People’s Republic of China
Section for Orthopedics, Campus Luebeck, University Medical Center Schleswig-Holstein,
Luebeck, Germany
Spinal cord injury (SCI) invariably results in the loss of neurons and
axonal degeneration at the lesion site, leading to permanent paralysis
and loss of sensation. There has been no successful treatment for severe
spinal cord injuries to recover back to normal function yet. Studies have
shown that the transplantation of stem cells may provide an effective
treatment for SCI because of the self-renewing and multipotential nature
of these cells. Stem cells have the capability to repair injured nervous tissue through replacement of damaged cells, neuroprotection, or the creation of an environment conducive to regeneration by endogenous cells. Up
to today several types of stem cells have been transplanted into the
injured spinal cord. However, the question of which cell type is most beneficial for SCI treatment is still unresolved. There are still several limitations to the current data sets which require further investigation. Anat
C 2009 Wiley-Liss, Inc.
Rec, 293:519–530, 2010. V
Key words: stem cells; spinal cord injury; therapy; transplantation
Spinal cord injury (SCI) invariably results in the loss
of neurons and axonal degeneration at the lesion site,
leading to permanent paralysis and loss of sensation
below the site of the injury, because damaged nerve
fibers are incapable to regenerate. Unfortunately, there
has been no successful treatment for severe spinal cord
injuries to regain satisfactory function so far (Lim and
Tow, 2007). The transplantation of stem cells may provide an effective treatment for SCI because of the selfrenewing and multipotential nature of these cells
(Thuret et al., 2006). Stem cells are capable of repairing
injured nervous tissue by replacing damaged cells, neuroprotection or the creation of an environment conducive
to regeneration by endogenous cells. In addition, transplanted cells could offer a number of possible therapeutic
uses, including delivery of therapeutic factors to provide
trophic support or missing gene products, mobilization of
endogenous stem cells and replacement of lost or dysfunctional cells (McDonald et al., 2004).
Scientists are trying to use stem cells from a variety
of sources to help animals with spinal cord injuries
regain movement. Human embryonic and adult stem
cells have been coaxed into becoming types of cells that
repair damaged spinal cord insulation and replace damaged spinal cord nerve cells (Kerr et al., 2003; Li et al.,
2005; Deshpande et al., 2006). To date, several types of
stem cells have been transplanted into the injured spinal
cord, including foetal nervous tissue, embryonic stem
cells (ESCs), bone marrow mesenchymal stem cells
*Correspondence to: Wei-Shan Chen, Department of Orthopaedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang
University, #88 Jiefang Road, Hangzhou, People’s Republic of
China 310009. Fax: þ8657187022776.
Received 9 January 2009; Accepted 21 July 2009
DOI 10.1002/ar.21025
Published online 20 November 2009 in Wiley InterScience
(MSCs), Schwann cells, peripheral nervous tissue, collagen-based matrices containing cells, and neuroactive
substances. Meanwhile, the potency of these cells and
the relative ease of isolating and expanding them are
invaluable properties for clinical application. Some clinical trials have also been undertaken in SCI (Daley,
2004; Grunt, 2004).
There are two main types of stem cells which are embryonic and non-embryonic stem cells (Weissman, 2000).
ESCs are totipotent and can differentiate into all three
embryonic germ layers. On the other hand, non-embryonic stem cells are multipotent. Their potential to differentiate into a variety of cell types is limited to the kind
of tissue where they originated from (Geuna et al., 2001;
Lee and Hui, 2006).
Embryonic Stem Cells
As early as their derivation, ESCs have attracted a
great attention to clinicians (Chen et al., 2007). Derived
from early embryos, these cells remain pluripotent in
culture while they can be principally expanded without
any limits (Gokhan and Mehler, 2001). They give rise to
most progenies and differentiate to all major somatic lineages of potential use in regenerative medicine (McDonald et al., 2004).
Previous studies showed that ESCs, induced to differentiate into motor neuron and oligodendrocytes in culture, can be transplanted into damaged adult animal
spinal cords to remyelinate injured neurons (Liu et al.,
2000; Senior, 2000; Wichterle et al., 2002; Miles et al.,
2004; Song et al., 2007). It was shown that the transplant-derived cells survived, differentiated into astrocytes, oligodendrocytes, and neurons, promoting modest
functional recovery for the injured animal spinal cord.
Keirstead et al. found that the human ESC-derived
treatment they developed was successful in restoring the
insulation tissue for neurons in rats treated 7 days after
the initial SCI, which led to a recovery of motor skills.
The same treatment failed on rats which had been
injured for 10 months. The findings pointed to the potential of using stem cell-derived therapies for treatment of
spinal cord damage in humans during the early stages
of the injury (Keirstead et al., 2005). In addition, Keirstead et al. showed that transplantation of oligodendrocyte
progenitor cells (OPCs) derived from human ESCs into
adult rat spinal cord injuries enhanced remyelination
and promoted improvement of motor function (Keirstead
et al., 2005). Deshpande et al. (2006) explored the potential of motor neurons derived from ESCs to functionally
replace those cells destroyed in paralyzed adult rats,
demonstrating the potential of restoring functional
motor units by ESCs. Recently, Cui et al. used a rat sciatic nerve transection model to show that the transplanted ESCs differentiated into myelin-forming cells
and offered a potential therapy for severely injured peripheral nerves. These and other studies have clearly
established the potential of ESCs transplantation for
nerve repair in both the central and peripheral nervous
system. Furthermore, Xie et al. (2009) showed that a
combination of electrospun fiber scaffolds and ESCs-
derived neural progenitor cells could lead to the development of a better strategy for nerve injury repair.
Multiple studies have demonstrated remyelination
and motor improvement after stem cell transplantation
into injured spinal cords (Nishio et al., 2006; Dasari
et al., 2007b; Someya et al., 2008). However, no dramatic
increase in functional recovery has been reliably demonstrated. One hypothesis suggests that muted functional
recovery may be a result of improper localization, differentiation, or orientation of ESCs at the site of injection.
For this reason many researchers have turned to the
use of tissue scaffolds as means of structuring and
organizing ESCs populations in situ. To this end, studies
have investigated the optimization of fibrin scaffolds for
differentiation of murine ESCs into neural lineage cells
and the effects of soluble growth factors on ESC differentiation inside fibrin scaffolds, which could provide a new
platform for the treatment of SCI (Willerth et al., 2006,
2007). Also, nanotubes, nanodevices, and polymer hygrogels have been developed to promote outgrowth and
guidance of neuritis (Sykova et al., 2006b; Jan and
Kotov, 2007). Despite some promising results, most of
the work is still in an early stage (Xie et al., 2009).
Meanwhile, a possible rejection of human ESCs following transplantation into an organ is still a challenging
question. Although not yet reported, it is likely that
human ESCs will express their HLA upon differentiation. Indeed, human ESCs express a low level of HLA
Class I and II. The low level of HLA Class I was recently
attributed to a downregulation of the antigen processing
machinery (Cabrera et al., 2007). Such downregulation
is often associated with tumorigenesis in cancer cells
through mechanisms of immune evasion. It would allow
human ESCs to be tolerated upon grafting in adult incompatible organs while raising a safety issue in the
case of hyperproliferation (Puceat and Ballis, 2007). In
addition, studies showed that stem cells could express
low levels of MHC-I antigens and demonstrated some
degree of immunotolerance (Menendez et al., 2005;
Drukker et al., 2006).
Non-embryonic Stem Cells
Mesenchymal stem cells. Adult MSCs can be isolated from bone marrow or marrow aspirates and
expanded in culture while maintaining their multipotency. These cells have two important capacities (Young
et al., 2004). First, MSCs can differentiate into distinctive end-stage cell types, and have been shown by independent investigators to give rise to neural-like cells
(neurons and glia) both in vitro and in vivo (Song et al.,
2007). Hence, these cells can be used for reforming mesenchymal tissues through the principles and practices of
tissue engineering. Preclinical studies have been performed on rats with a SCI and have shown that transplanted MSCs in the injured spinal cord survive,
migrate into the host tissue and lead to axonal regeneration and motor function recovery. Dasari et al. showed
that expression of caspase-3 on both neurons and oligodendrocytes after SCI was significantly downregulated
by MSC. Animals treated with MSC had higher Basso,
Beattie, Bresnahan (BBB) locomotor scoring and better
recovery of hind limb sensitivity. It had a positive effect
on behavioral outcome and histopathological assessment
after SCI (Dasari et al., 2007a). Sheth et al. showed that
grafted human derived MSCs (hMSC) could survive for
6 weeks after transplantation, although they did not differentiate into neural or glial cells. Spinal cord injured
rats grafted with hMSCs had smaller contusion cavities,
which did not have a significant influence on functional
recovery (Sheth et al., 2008). Injured animals grafted
with MSCs had smaller lesions 35 days post-grafting
and higher scores in BBB testing than did control animals and showed a faster recovery of sensitivity in their
hind limbs using the plantar test (Sykova et al., 2006b).
Further clinical studies proved the safety of such an
approach and partial improvement of function in
patients with acute injuries (Park et al., 2005).
In addition, MSCs are attractive targets for ex vivo
cell and gene therapy. Ronsyn et al. investigated the feasibility of a plasmid-based strategy for genetic modification of human hMSCs with enhanced green fluorescent
protein and neurotrophin (NT). They demonstrated that
genetically modified hMSC lines could survive in healthy
rat spinal cords over at least 3 weeks by using adequate
immune suppression and can serve as vehicles for transgene expression (Ronsyn et al., 2007). Some studies have
tested the feasibility of novel minimally invasive methods for transplanting MSCs into a clinically relevant spinal cord contusion model. Bakshi et al. found that MSCs
delivered by lumbar puncture reached the contused spinal cord tissues and exerted a significant beneficial
effect by reducing cyst and injury size. Transplantation
within 14 days of injury provided significantly greater
grafting efficiency than a delayed delivery. An increased
dosage of MSCs improved cell engraftment (Bakshi
et al., 2006).
Unanticipated is the realization that the MSCs secrete
a large spectrum of bioactive molecules. It has also been
reported that MSCs stimulate glial cells to produce colony stimulating factor (CSF), interleukins, stem cell factor, nerve growth factor (NGF), brain derived
neurotrophic factor (BDNF), hepatocyte growth factor,
vascular endothelial cell growth factor, neurotrophic factors such as NGF, and BDNF among others (Sykova
et al., 2006b). These molecules are immunosuppressive,
especially for T-cells, thus allogeneic MSCs can be considered for therapeutic use. The secreted bioactive molecules provide a regenerative microenvironment for a
variety of injured adult tissues limiting the area of damage and mounting a self-regulated regenerative
response. This regenerative microenvironment is
referred to as trophic activity and, therefore, MSCs
appear to be valuable mediators for tissue repair and
regeneration. The natural titers of MSCs drawn to sites
of tissue injury can be augmented by allogeneic MSCs
delivered via the bloodstream (Caplan, 2007). Meanwhile, MSCs can promote axonal regeneration by guiding nerve fibers (Hofstetter et al., 2002). Wu et al. (2003)
showed that transplanted MSCs promote compensatory
mechanisms to reorganize neural networks and activate
endogenous stem cells. It was also shown that MSCs
improve neurologic deficits by generating either neural
cells or myelin-producing cells (Sasaki et al., 2001).
However, understanding the actual differentiation spectrum of stromal cells requires further investigation.
Clinical studies are necessary for transferring preclinical findings from animal experiments to humans. Some
studies have investigated the transplantation of unmanipulated autologous bone marrow in patients with
transversal SCI with respect to safety, therapeutic time
window, implantation strategy, method of administration
and functional improvement (Park et al., 2005; Deda
et al., 2009; Vaquero and Zurita, 2009). Data has been
report from 20 patients with complete SCI who received
stem cell transplantation (Sykova et al., 2006a). The
study showed no adverse effect that might be caused by
the administration of MSCs into CSF. Although the findings of MRI after the injury suggest a poor prognosis of
neural functional recovery, definite improvements were
shown in motor and sensory functions up to 6 months
(Saito et al., 2008). Chernykh et al. showed that transplantation of MSCs into the cyst cavity and intravenously was well tolerated, did not cause allergic or
inflammatory reactions in the early and delayed periods
after surgery, and did not induce the formation of ossification foci in the nervous tissue. Transplantation of autologous bone marrow cells has the potential to be a
novel and safe strategy for the treatment of patients in
the late period after spinal trauma (Chernykh et al.,
2007). In addition, Park et al. (2005) showed that autologous bone marrow cell transplantation and GM-CSF
administration represent a safe protocol to efficiently
manage SCI patients, especially those with acute complete injury. A phase I/II open-label and nonrandomized
study was conducted on 35 complete SCI patients. The
American Spinal Injury Association Impairment Scale
(AIS) grade increased in 30.4% of the acute and subacute treated patients (AIS A–B or C), whereas no significant improvement was observed in the chronic
treatment group. Increasing neuropathic pain during
the treatment and tumor formation at the site of transplantation are still remaining to be investigated (Yoon
et al., 2007). More clinical trials of stem cell transplantation as treatment option for SCI are under study (Pandya, 2008).
Human umbilical cord blood stem cells. Human
umbilical cord blood contains a mixture of different types
of stem cells in large numbers not seen in any other tissue. It is believed that human umbilical cord blood stem
cells (UCBSCs) present the best alternative to ESCs as
these stem cells can be used to derive tissues from the
mesodermal, endodermal, and ectodermal germ lineages.
In addition to being readily available, UCBSCs have
more mesenchymal progenitor cells per volume, a higher
pluripotent capacity and are genetically more flexible
than bone marrow-derived MSCs (Gang et al., 2004).
Meanwhile, it has been suggested that they are not as
mature as other adult stem cells so that they may not
elicit alloreactive responses that modulate the immune
system (Di Nicola et al., 2002; Le Blanc et al., 2003;
Kang et al., 2005; Watt and Contreras, 2005). Besides
these properties, UCBSCs have other distinct advantages for transplantation, including greater tolerance for
HLA-mismatches between donor and recipient and a
decreased risk of graft-versus-host disease (Harris,
As UCBSCs have the ability to differentiate into various types of nervous cells, it may be possible to extend
their application to SCI. In fact, spinal cord injured rats
infused with UCBSCs showed significant improvements
5 days post-treatment compared with untreated animals.
After transplantation UCBSCs were observed at the site
of injured nervous tissue but not at uninjured regions of
the spinal cord (Zhao et al., 2004). Studies examined the
effects of UCBSC transplantation after complete spinal
cord transection in rats. Transplanted UCBSCs survived
for 16 weeks and produced large amounts of human neutrophil-activating protein-2, NT-3, basic fibroblast
growth factor, glucocorticoid induced tumor necrosis factor receptor, and vascular endothelial growth factor
receptor 3 within the host spinal cord, which may support the repair of spinal cord injuries (Yang et al., 2008).
These findings were supported by studies showing that
UCBSCs transplanted into spinal cord injured animals
differentiated into various neural cells, thereby improving axonal regeneration and motor function (Kuh et al.,
Furthermore, studies showed that systemic UCBSCs
infusion significantly attenuated SCI-induced hind limb
dysfunction in rats. Serum IL-10 levels were increased
while TNF-a levels were decreased after UCBSCs infusion. Both VEGF and GDNF could be detected in the
injured spinal cord after transplantation of UCBSCs
(Chen et al., 2008). Kao et al. reported that systemic
administration of 95% pure CD34þ progenitor cells
derived from UCBSCs attenuates spinal cord infarction
and apoptosis as well as behavioral deficits in a standard
rat compression SCI model. In addition, current investigation provides new evidence suggesting that CD34þ
cell therapy may cause restoration of spinal cord function during SCI by stimulating both GDNF and VEGF
production in injured spinal cords (Kao et al., 2008). In
previous reported clinical use of UCBSC to treat a
patients with a SCI (Kang et al., 2005), it was stated
that transplantation of UCBSCs improved sensory perception and mobility in hip and thigh regions. Both CT
and MRI studies revealed regeneration of the spinal
cord at the injury site. Dasari et al. confirmed that the
involves activation of the Akt signaling pathway. The
neuroprotective potential of UCBSCs against glutamateinduced apoptosis of cultured cortical neurons was suggested (Dasari et al., 2008b). In addition, it was indicated that human umbilical cord blood-mediated
downregulation of Fas receptors and caspases leads to
functional recovery of hind limbs of rats after SCI
(Dasari et al., 2008a).
Neural stem cells. Neural stem cells (NPCs) are
potential grafts for treatment of traumatic CNS injury
and neurodegenerative disorders because of their potential to differentiate into neurons and glial cells (Shihabuddin et al., 2004). Following transplantation into the
injured adult rat spinal cord they survive for at least 6
weeks, migrate and maintain the ability to differentiate
into the three main CNS cell lineages. Studies indicated
that adult rat spinal cord ependymal NPCs differentiate
preferentially into oligodendrocytes and radial glia (RG),
which may support axonal regeneration in future trials
of transplant therapy for SCI (Kulbatski et al., 2007).
However, no robust recovery in behavioral function was
observed (Webber et al., 2007).
Studies stated that NPCs have a distinct advantage
over fetal tissue because of their greater ability to circumvent the restrictions of the blood–brain barrier and
integrate throughout the central nervous system. Addi-
tionally, a disease of a particular organ system is probably most efficiently treated with stem cells from the
same organ (Daley, 2004; Snyder et al., 2004).
Studies have proved that NPCs were capable of repairing damaged spinal tissue and helping to restore function in rats with spinal cord injuries (McDonald et al.,
1999; Ogawa et al., 2002; Cloutier et al., 2006; Kelsch
et al., 2007; Yan et al., 2007). More than one-third of the
transplanted cells traveled along the spinal cord, were
incorporated into damaged tissue, developed into the
type of cells destroyed at the injured site and produced
myelin. An injured spinal cord loses its ability to regenerate myelin-forming cells, leading to paralysis. Fehlings
et al. showed that where stem cells restored myelin in
the injured spine, rats showed some recovery and
walked with more coordination (Karimi-Abdolrezaee
et al., 2006). In an animal study, Alcon et al. grafted
NPCs into the lumbar spinal cord of a mouse mutant
that has a specific loss of motoneurons (progressive
motor neuronopathy/pmn). A small number of grafted
cells (B3000) increased the life span of the mice by 56%.
The improved survival was accompanied by a rescue of
host motoneurons, stabilization of weight and an
increase in the size of the muscle fibers. The grafted
NPCs were small and round and exhibited no neural
markers, suggesting that they remained in an undifferentiated state (Pan et al., 2008). Magnetically labeled
NPCs were suspended with activated magnetic beads
and individual NPCs, were transplanted to the co-cultures. There were few toxic effects of magnetically
labeled NPCs. The differentiation potential was not
changed whether NPCs were localized or scattered
in vitro. Corticospinal axon growth was promoted in accordance with the transplanted NPC numbers around
the organotypic co-culture. Magnetically labeled NPCs,
which were directed toward the preferred site using a
magnet, promoted more axon growth than scattered
magnetically labeled NPCs. Overall magnetically localized labeled NPCs expressed higher potential in axon
growth (Hamasaki et al., 2007). Moreover, OPCs have
shown to migrate into the injured site, promoted remyelination, increased production of neurotrophic factors
and improved locomotor activity, and kinematic scores in
spinal cord injured rats. The study demonstrated that
xenografted cells from porcine neural precursor cells
might be able to recreate the damaged circuitry in CNS
disease. It also showed the reliable long-term survival of
grafts derived from porcine expanded neural precursors
in a rat model, with maturation and integration into the
host brain (El-Badri et al., 2006; Harrower et al., 2006).
In addition to directly replacing damaged neurons and
oligodendrocytes, stem cell therapies could also support
endogenous stem cells (Thuret et al., 2006). The capacity
of endogenous stem cells present in the spinal cord for
regeneration is poor, and it is likely that many of the
same factors that prevent axonal regeneration also inhibit the function of endogenous NPCs, including the formation of the glial scar, the lack of neurotrophic factors,
inhibitory sulfated proteoglycans, and inhibitory myelinassociated molecules (Divani et al., 2007; Fitch and Silver, 2008). Nevertheless, therapies using endogenous
stem cells would require no exogenous stem cell sources
and would therefore circumvent the obstacle of immune
rejection, as well as the ethical and moral considerations
associated with their use (Bajada et al., 2008).
Several mechanisms of central nervous system regeneration after transplantation of NPCs have been proposed (Pfeifer et al., 2006). However, the precise
mechanism has not been clarified. A number of studies
have demonstrated that transplanted NPCs promote anatomical plasticity and modest behavioral recovery in
contusive and surgical lesion models of SCI (McDonald
et al., 1999; Ogawa et al., 2002). Transplanted cells may
remyelinate denuded axons, decrease glial scar formation, prevent secondary cell loss, promote regeneration,
form bridges and relays and replace neural cells (Lepore
et al., 2005). Kamei et al. demonstrated that transplanted NPCs secreted humoral factors which in turn
promoted corticospinal axon growth using the unique
organotypic co-culture system involving brain cortex and
spinal cord from neonatal rats (Kamei et al., 2007). The
neurotrophic factors, BDNF, NT-3, and NGF, secreted by
transplanted NPCs, were involved in the promotion of
corticospinal axon growth after transplantation of NPCs.
Axonal regeneration is inhibited by scar formation and
growth-inhibitory factors associated with myelin and
astrocytes (Schwab, 2004; Fawcett, 2006). Modulating
the responsiveness to axonal growth-inhibitory factors
and glial scar formation are attractive strategies to
improve functional recovery after central nervous system
injuries (Kwon et al., 2005; Freund et al., 2006; Kaneko
et al., 2006; Okada et al., 2006). The majority of ependyma-derived cells differentiates into astrocyte-like cells
after injury and is found in the core of the scar tissue.
However, these cells are found in complementary nonoverlapping domains, which areas are immunoreactive
to Chondroitin Sulfate Proteoglycans, the most important axonal growth inhibitor associated with glial scars
(Busch and Silver, 2007). Moreover, axons in the scar tissue, most likely sprouts from severed axons growing into
the scar tissue, were frequently found in direct proximity to ependyma-derived cells. This suggests that ependyma-derived cells in the scar tissue do not constitute a
major impediment to axonal growth, but may even support some local sprouting (Meletis et al., 2008).
Fetal neural progenitors present less risk of tumor formation than ESCs but inefficiently differentiate into
motor neurons, in line with their low expression of
motor neuron-specific transcription factors and poor
response to soluble external factors. Bohl et al. suggested genetic engineering could drive the differentiation
of fetal neural precursors into motor neurons that efficiently engraft in the spinal cord. To overcome this limitation, they genetically engineered fetal rat spinal cord
neurospheres to express the transcription factors HB9,
Nkx6.1, and Neurogenin. When transplanted in the
injured adult rat spinal cord, a model of acute motor
neuron degeneration, the engineered precursors transiently proliferated, colonized the ventral horn, expressed
motor neuron-specific differentiation markers and projected cholinergic axons into the ventral root (Bohl et al.,
Some findings suggest that co-grafts supporting NPCs
may have benefits for SCI. These results suggest that
amniotic epithelial cells modified with the Basic Fibroblast Growth factor (bFGF) gene could enhance NPCs
survival and neural differentiation in vivo and promote
repair of the injured spinal cord (Meng et al., 2008).
Thonhoff et al. suggested that a peptide hydrogel (PuraMatrixTM, 3DM, Cambridge, Massachusetts) was most
suitable for human NPC (hNPC) transplantation,
because of the low toxicity, suitable gelling capability at
a low concentration, gelling upon salt incorporation and
permission of hNPC migration (Nisbet et al., 2008;
Thonhoff et al., 2008). Atalay et al. (2007, 2008) showed
that Nogo-A monoclonal antibodies (NEP1-40) promote
functional recoveries in injured rat spinal cords. Pan
et al. (2008) showed that synergy between Granulocate
CSF (G-CSF) and neuronal stem cells may be because of
the increased proliferation of progenitor cells in the
injured area and increased expression of neuronal stem
cell markers extrinsically or intrinsically in the distal
end of injured cord. The study provided evidence that
lithium may have therapeutic potential in cell replacement strategies for CNS injury because of its ability to
promote proliferation and neuronal generation of grafted
NPCs and reduce the host immune reaction (Su et al.,
2007). In addition, there are some studies showing that
Schwann cells within NPC grafts could contribute to
remyelination. The NPCs present inherent plasticity to
differentiate into oligodendrocytes or Schwann-like cells,
depending on the host environment. Mothe and Tator
(2008) stated that both cell types are capable of in the
demyelinated and dysmyelinated adult spinal cord. However Schwann cells fail as a supporting platform to
maintain NPCs within the graft and impair CNS axon
regeneration, which makes them an unfavorable candidate for NPC graft support following SCI (Vroemen
et al., 2007).
Although SCI could specifically benefit from the
engraftment of stem cells, there are some challenges facing the use of stem cells for clinical cell therapy (Baker,
2005). The first is to develop cell-culture protocols that
generate relatively defined and large numbers of transplantable cells, and to obtain adequate cell survival and
functionality of grafted cells after intracerebral transplantation. Secondly, potential adverse effects of transplanted stem cells, such as tumor formation, must be
avoided. Grafted ESCs may generate teratocarcinomas
(Erdo et al., 2003; Asano et al., 2006) and teratomas
(Denker, 2006). Although differentiated progeny of ESCs
are not tumorigenic, there is an absolute need to assess
the tumorigenic potential of a pre-differentiated ESC
culture in immune-compromised pre-clinical models
before they can be considered as clinically safe (Chen
et al., 2007). Finally, the risk for immune rejection of the
grafted cells must be eliminated (Li et al., 2008a).
Appropriate Processes
One fundamental challenge facing all forms of stem
cell-based therapy is that large quantities of a specific
cell type must be generated, preferably without contamination of other cells that could be detrimental. Defining
conditions, under which a small proportion of stem cells
differentiates into a desired cell type is relatively easy. It
is more difficult to devise strategies leading to a development of the majority of cells into a desired cell type.
Phinney et al. first demonstrated that MSCs injected
into the central nervous systems of newborn mice
migrate throughout the brain and adopt morphological
and phenotypic characteristics of astrocytes and
neurons. Studies indicated that the methods used to promote neural cell differentiation and assess the biology of
the differentiated cells are fragmented and inconsistent.
Furthermore, they showed that ascribing a neural fate
to MSCs is further confounded by the lack of specificity
of neural markers employed, the heterogeneous nature
of the MSC populations under examination, and artifacts
associated with methods used to culture-expand cells in
vitro (Phinney, 2007; Phinney and Prockop, 2007). The
most preferable differentiation protocol for stem cells to
date is the combination of the three methods: feeder
cells, growth factors, and genetic engineering (Kim
et al., 2006). Culture protocols based on growing stem
cells together with specific feeder cells have been widely
used and similar proportions of tyrosine hydroxylase
(TH)-positive neurons have been obtained from mouse
and human ESCs (Kawasaki et al., 2000; Barberi et al.,
2003; Perrier et al., 2004; Takagi et al., 2005; Brederlau
et al., 2006). Approximately 16% of murine ESCs
(mESC) became TH positive when co-cultured with stromal cell feeder cells (Li et al., 2008a). Lowry et al.
showed a method using a co-culture system with endothelial cells, which could improve NPC survival and preserves their multipotency, including their ability to
make motor neurons. Transplantation of endothelialexpanded NPCs that were treated with sonic hedgehog
(SHH) and retinoic acid (RA) during the expansion
phase, into an adult mouse SCI model could result in
significant recovery of sensory and motor function
(Lowry et al., 2008). Genetic manipulation is an additional strategy to improve the rate of differentiation of
dopaminergic neurons from ESCs that has been tested
extensively (Li et al., 2008a). For human studies, it is
also important to document the karyotype of the cultured cells, although to date, cytogenetic abnormalities
among passaged human MSCs are admittedly rare.
Another issue that remains to be addressed is the importance of cell dosage in the transplanted inoculum and
if there is a safe upper limit. Some data suggest that
better functional outcomes are dose dependent. One
study showed the benefit of multiple injections. This
may help to explain some of the varied results of different studies, but needs to be explored more extensively
(Parr et al., 2007). Moreover, some studies showed that
stem cells injected either intrathecally or intravenously
reach the injured site at smaller concentrations and
have a lower beneficial effect compared with direct intraparenchymal injection (Xiao et al., 2005; Habisch et al.,
2007; Niranjan et al., 2007).
Timing of transplantation is also a key issue, as evidence suggests that cell survival and functional outcome
may be improved if cells are transplanted at least 1
week, but no more than 14 days, after injury. The extent
of cellular division after transplantation is not known.
Although it has generally been suggested to be very low,
this finding is not supported by all studies. At present,
studies showed that the intralesional administration of
bone marrow stromal cells is useful in chronic phases after SCI, in situations of established paraplegia (Zurita
and Vaquero, 2004, 2006). In addition, in a study which
compared the effect of systemic and local administration
of MSC in adult Wistar rats suffering chronic paraplegia
as consequence of severe SCI, the results showed that
intravenous administration of MSC achieves some
degree of functional recovery when compared with con-
trol groups. Nevertheless, administration of MSC into
postraumatic spinal cord cavity promotes a clear and
progressive functional recovery, which is significantly
superior to the recovery obtained by means of the intravenous administration (Vaquero et al., 2006). Further
studies showed that signs of functional recovery were
seen 4 weeks after transplantation increasing during the
following weeks (Zurita et al., 2008a,b; Vaquero and Zurita, 2009). The best method of administering MSCs is
being explored. Although direct administration of MSCs
results in the highest number of cells in the injury site
it is an invasive procedure. Thus, intra-lesional injection
may result in further local damage. Of note, cells appear
to have improved survival when injected next to the
lesion rather than directly into the injured area (Parr
et al., 2007).
As research struggles forward in the absence of federal funding, the number of stem cell lines will continue
to grow, creating ever more valuable tools that are out of
reach for scientists (Daley, 2004). Biomedical scientists
are inherently innovators, drawn to new technologies,
and these missed opportunities are difficult to accept.
Cell Differentiation
Specification of distinct cell types from stem cells is
the key to the potential application of these naive pluripotent cells in regenerative medicine. Potential use of
stem cells in biotechnology and regenerative medicine
depends upon the development of strategies for directed
differentiation into functional cell types. With the exception of neuroepithelial cells, which can be differentiated
from hESCs with more than 95% efficiency (Pankratz
et al., 2007), most differentiation protocols yield a mixed
cell population. Differentiation to more specialized subtypes of neurons, such as midbrain dopamine neurons
(Perrier et al., 2004; Yan et al., 2005; Roy et al., 2006;
Sonntag et al., 2007) and spinal motor neurons (Singh
Roy et al., 2005; Lee et al., 2007) becomes less efficient.
Consequently, it is not known what the non-target cells
in the mixture are. These non-target cells are often the
source of aberrant tissue formation in transplants (Brederlau et al., 2006). There is therefore a critical need to
develop strategies for directed differentiation of stem
cells into specialized functional cell types, such as subtypes of neural progenitors and functional motor
Stem cell differentiation is amenable to manipulation
by exogenous factors such as growth factors and by
changes of in vitro environmental conditions (Kulbatski
and Tator, 2009). In the ventral neural tube, there are
five different progenitor domains (p0, p1, p2, p3, and
pMN), which give rise to motoneurons and inter-neuron
subtypes of the ventral spinal cord (Watt and Contreras,
2005). These progenitor domains are established mainly
by interaction of Class I and Class II homeodomain proteins, which are inhibited or induced by the graded
secreted inductive factors, such as SHH (Kuh et al.,
2005). Previous studies showed that human stem cells
can differentiate to spinal motor neurons in an adherent
culture by applying retinoid acid (RA) and SHH with
20% efficiency (Shin et al., 2007; Soundararajan et al.,
2007), similar to that from mouse ESCs. However, this
efficiency is not ideal for a variety of analyses, and the
identity of nearly 80% of the differentiated cells in the
culture remains unknown. Present studies have developed a simple chemically defined suspension culture for
a near-complete restriction of hESCs to a ventral spinal
progenitor fate, with highly efficient generation of motor
neurons. This process can also be achieved by using the
small molecule purmorphamine, instead of SHH (Li
et al., 2008b).
To avoid debates over the point of time when a fertilized egg becomes a person, the field has aggressively
explored ethically neutral alternative sources including
multipotent adult stem cells. After birth sources like the
umbilical cord, placenta or amniotic fluid (De Coppi
et al., 2007) may provide patient-specific stem cells
which could be banked at birth for autologous grafting.
A promising alternative to trans-differentiation is the
reprogramming of somatic cells by nuclear transfer
(Hochedlinger and Jaenisch, 2002) or gene conversion
(Takahashi and Yamanaka, 2006) to generate induced
stem cells with properties similar to pluripotential ESCs
(Okita et al., 2007; Wernig et al., 2007). Thereafter the
challenge to program the differentiation of stem cells to
efficiently generate tissue-specific cells for repair will
remain (Chen et al., 2007). Though promising, such
speculative cellular-engineering research does not obviate the need for expanded access to new human ESCs.
Adult stem cells are not equivalent to ESCs and cannot
satisfy all scientific and medical needs (Grunt, 2004).
The safety of stem cell derived therapy is a major
issue. If, the logic goes, stem cells can regenerate the hematopoietic system of a cancer patient, then stem cells
hold the promise and potential to regenerate any organ
system curing various kinds of disease (Chen et al.,
2007). Undifferentiated and injected in immune
depressed mice, ESCs generate teratomas, a tumor
made up of elements of different types of tissue. It has
thus been predicted that any non-differentiated stem
cell that could have escaped from a commitment or differentiation protocol may trigger a teratoma. Focused on
teratomas derived from pluripotent cells, one had forgotten the possibility of tumors deriving from a progenitor
cell, which could stop its differentiation and proliferate
in vivo. Studies showed differences between using ESCs
and adult stem cells regarding the risk of originating
tumors. The clinical experience with cell therapy using
adult MSCs allows clearly excluding this risk, which,
however, is present when ESCs are used. Furthermore,
human UCBSCs have been shown to have lower carcinogenic potential than ESCs (Kuh et al., 2005; Lim et al.,
Such a scenario was recently reported from neuronal
progenitors grafted in rat brain (Roy et al., 2006). Of
note, Puce et al. showed their experience with mice and
hESCs. Committed to the cardiac lineage and engrafted
in mice, sheep, and rats hESC transplantation did not
reveal any kind of tumors several months after cell
transplantation in infarcted myocardium (Tomescot
et al., 2007). The environment that releases various
soluble factors might be of importance to promote or to
prevent tumor formation from hESCs. Among factors
that strengthen the tumorigenic property of hESCs, several epigenetic and genetic issues must be considered
(Puceat and Ballis, 2007). Chernykh et al. found that
transplantation of MSCs into cyst cavities and intravenously was well tolerated, did not cause any allergic or
inflammatory reactions, and did not induce the formation of ossification foci in the nervous tissue. Analysis of
the neurological status by ASIA, Bartel, and Ashworth
scales showed that in the main group the positive clinical dynamics was more often observed than in the control. The decrease in neurological deficit included
improvement of sensory and motor activity and conducting sensory function (Chernykh et al., 2007).
Several adverse events might occur when transplanting stem cells into the spinal cord. For example, residual
undifferentiated hESCs or dividing precursors might
continue to proliferate in vivo and generate tumors
(Draper et al., 2004). Chromosomal instability might
contribute to chromosomal aberrations during long-term
culturing of hESCs. This has unpredictable repercussions that obviously depend on the specific chromosomal
changes. Once the cells are grafted, rapidly dividing
hESCs with chromosomal changes might outgrow other
cells in the transplant and promote tumor formation.
Finally, hESC-derived grafts could stimulate an immune
reaction in the CNS, and this might adversely affect surrounding circuitry. Vroemen et al. (2005) showed that in
vivo gene expression in genetically engineered neural
progenitor cells is temporally limited and mostly
restricted to undifferentiated NPCs using the viral vectors tested.
Removal of undifferentiated stem cells and proliferating cells before grafting is a potentially powerful
approach to reduce the risk of tumor growth. Undifferentiated stem cells express unique cell-surface molecules. Upon differentiation, expression of these
molecules is downregulated. Therefore, these undesired
cells can be depleted by using antibodies against specific
cell-surface molecules conjugated with either a fiuorophore or a magnetic bead in combination with fiuorescent activated cell sorting or magnetic activated cell
sorting, respectively (Chung et al., 2006; Pruszak et al.,
Immunologic Barrier
Li et al. (2008a) reported that cells differentiated from
hESCs feature an immune privilege. In vitro immunological studies suggest that hESC-derived OPCs are poor
targets for both the innate and the adaptive human
immune effector cells as well as resistant to lysis by
anti-Neu5Gc antibodies. These results indicate that
hESC-derived OPCs retain some of the unique immunological properties of the parental cell line from which
they were differentiated. However, other authors showed
that OPCs derived from hESCs showed no immunoreactivity (Okamura et al., 2007).
With regard to the yet controversial immunological
status of stem cells, it is important to predict strategies
to overcome the potential immunoincompatibility. To
reach this aim, two main possibilities can be foreseen.
Banking of hESCs including 150 donors with unique
blood groups could provide a beneficial HLA matching
for most potential patients. If confirmed, such a bank
could be generated under Good manufacturing practice
(GMP) conditions and would avoid the need of somatic
cell nuclear transfer to customize hESCs, a yet not successful approach in human beings. However, 150 cell
lines may be too few to match a multiracial population
of patients. The approach suggests that the differentiation potential of each cell line is the same, a concept far
from being reality. Although chimerism between ESCs
and recipients has been reported, another strategy to
confer some immune tolerance to hESCs would be to
generate tolerogenic hematopoietic cells derived from
them. Together, these strategies demonstrate the possibilities to overcome the immunologic barrier (Li et al.,
In the developing nervous system, netrin-1 acts as a
repulsive or attractive signal, guiding nerve cells to their
proper targets. In the adult spinal cord, researchers
found that netrin-1 specifically repels stem cells away
from the injury site, thereby preventing stem cells from
replenishing nerve cells (Petit et al., 2007). In studies,
HUCB cells can survive long-term in vitro and undergo
neuron-like differentiation. In mice, these cells could
survive no more than a month. This may relate to the
differentiated state of the cells transplanted into the
unlesioned striatum, rather than T cell-mediated immunological rejection (Walczak et al., 2007).
Currently, immunosuppressive treatments have been
widely used to inhibit immune rejection resulting from
the histoincompatibility of transplanted cells. Unfortunately, they do not fully prevent chronic rejection and
increase the risk of opportunistic infections (Li et al.,
This review has discussed the major issues associated
with stem cell therapy for SCI by transplantation. Stem
cells from a variety of sources have shown effectiveness
in improving motor function after SCI in animal experiments and clinical trails. Differentiation and processes
protocols are improving, yielding cells of higher purity
and better function. Owing to their trophic and immunomodulatory properties, combining stem cell transplantation with therapies that block the activity of growth
inhibitory molecules, or other conventional approaches,
have the potential to be highly efficacious in the
Nevertheless, work remains to be done to ascertain
whether these therapies can safely improve outcome after human SCI. Significant research is still required to
answer the multitude of questions that remain before
these cells can proceed to further clinical trials, including the most appropriate and efficacious sources of these
cells, the optimal strategy and time for transplantation,
and the strategy for promoting stem cell transdifferentiation and function after transplantation. Individual
therapies are unlikely to emerge as a cure for SCI. Furthermore, we predict that tailored combinations of strategies will lead to cumulative improvements in outcome
after different types of SCI.
Clinicians, scientists, and regulatory agencies must
also consider longer-term safety issues of stem cell
therapies, including the likelihood of life-long immunosuppressive regimes. Meanwhile, long-term and largescale multicenter clinical studies are required to determine further the precise therapeutic effect of stem cell
Thanks must be given to Sheng-Jie Xu PhD for critical
review of the original manuscript.
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