Using Stem Cells For Spinal Cord Injury Biology Essay

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It has been estimated that there are 2.5 million patients worldwide living with spinal cord injuries (101). Spinal cord injury (SCI) results in vast personal suffering due to its chronic disabling nature and has great cost implications on society (102). Currently there is no cure with the acute phase therapy being limited to high doses of methylprednisolone to reduce inflammation and prevent further damage. A high dose of metylprednisolone (30mg/kg) when administered in less than 8 hours after injury reduces the formation of cytotoxic oedema, inflammation and the release of glutamate and free radicals. However, this treatment is still fairly controversial since it may lead to a higher rate of complications, including wound infection (101). For chronic treatment the focus relies mainly on symptomatic relief of pain and infection, as well as physiotherapy (103).

SCI completely or partially removes the patients' mobility and sensory output as well as autonomic nervous system control below the injury, together known as incomplete injury (102). The initial impact causes the vertebral to fracture which causes local segmented limited damage to the spine (primary damage). As a consequence of the impact contusion of axons, haemorrhage, ischemia and oedema develops causing more damage (secondary damage). The secondary damage expands within the first few weeks due to further axonal destruction as well as glial cell loss (101). Figure 1 below shows schematically the process of a spinal cord injury in the acute and chronic phase.

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Figure 1 - Schematic presentation of the pathophysiological process of a spinal cord injury in the acute and the chronic stage with the different treatments options indicated (adapted from Ronsyn et al 2008) (109)

Most SCI are incomplete injuries, i.e. still neurological findings with partial loss of sensory and/or motor function below injury (105). Incomplete injuries leave some spared tissue connecting the spinal cord from areas above to areas below the lesion. The loss of neurons in the adult, which are unable to be regenerated, results in an impaired function of the affected segment. Demyelination usually compromises the remaining axonal function. Demyelination is recognised as a universal pathological alteration in SCI which involves the breakdown of myelin and the loss of myelin-forming cells, which are called olidendrocytes (107). Without the myelin insulating sheaths, the spared axons become less efficient in their ability to conduct electrical impulses (106). The adult spinal cord appears unable to replace the lost myelin or oligodendrocytes (117) resulting in further damage to the axons. The effects of axon transection, neuronal death, and demyelination on overall signal transmission are compounded by other tissue reactions to the injury such as inflammatory and immune responses, cyst formation, and vascular changes (108). Nashmi and Fehlings (2001) have demonstrated that axonal demyelination contributes to functional impairment of the neurons. This leads to an increased surface area of the exposed axonal membrane, increasing the resistive and capacitive load of the neurons affected. Thus, the current of the neuron's density decreases (116). Therefore, remyelinating the demyelinated axons may be a reasonable therapeutic target for recovery of neural function.

In 1858, Rudolph Virchow was one of the first scholars to describe that there were other cells than neuronal ones present in the nervous system. Since he thought former to be connective tissue, so he named them neuroglia (meaning 'neuron glue') (114). Later neuroglial (or glial) cells were subdivided into macroglial and microglial based on size. Oligodendrocytes form part of the macroglial cell family and are derived from stem cell precursors found in the subventricular zones of the developing central nervous system (CNS) (113). Oligodendrocytes are the cells that produce myelin (112), the fatty substance that provides the neuronal axon with insulation (104). They are able to myelinate up to 50 axonal segments, depending on the region of the CNS (112).

A vast number of patients suffer from SCI, severely affecting their lives as well as that of their families. It is therefore important to research alternative therapies that could limit the impact of the injury. Regaining control over their own bowel movements could significantly increase a patient's quality of life.


Figure 2 - Therapeutic strategies following spinal cord injury (adapted from Schwab et al 2006) (101)

The figure above highlights several theoretical options to repair the spinal cord are summarised in the figure below. An obvious possible treatment of SCI is to replace the perished neurons and/or glial cells (101). Using stem cells may enable the reconstruction of some of the perished oligodendrocytes, which in turn can promote remyelination. C. Lu, Q. Shen 2009 cite evidence for three functions that neural stem cells, found in the mammalian embryonic brain, fulfil. First, they are capable of self-replication, facilitating proliferation of the absent oligodendrocytes. Second, neural stem cells secrete various neurotrophic factors. Finally, they differentiate into neurons, astrocytes and oligodendrocytes (110).

The discovery of differentiating stem cells found in the brain has revolutionised the idea of treating SCI for several reasons. There may now be the possibility of partial or full recovery from paralysis using these stem cells. Stem cells are defined as self-renewing cells capable of differentiating into a cell lineage (111). Treating SCI with adult stem cells can be more advantageous than treatment with embryonic stem cells, as these cells may be more similar to the cell types that require regeneration. Furthermore, adult stem cells bear greater oncogenic potential than embryonic stem cells. Most importantly, neural stem cells do not normally produce cells of nonneural lineage. Thus, Parr et al. consider neural stem cells to be more reliable as a source for neural cell regeneration (115).

Two different theoretical strategies to employ stem cells for the repair of SCI. The first approach involves the transplantation of stem cells, or cells derived from stem cells, to the injured spinal cord. Second, endogenous neural stem cells resident in the adult spinal cord could be recruited or modulated to promote recovery (102).

In this paper, I will therefore examine how the transplantation of stem cells promotes remyelination. I will then continue by examining whether the activation of endogenous stem cells promote remyelination. Finally, I will elaborate on the potential of stem cell-based therapies in the clinic to determine the most effective one.

Transplantation of Stem cells to Promote Remyelination

Several approaches to transplant stem cells to improve the recovery after a SCI have been taken into clinical trials reviewed in Tator (118). A large number (citation, citation, citation!!!) of studies have evaluated the effects of transplanting a variety of different stem cells in SCI models, mainly rodents, and a surprisingly large amount of the studies have indicated some level of benefit. However, there is difficulty in comparing the different studies due to the varying degree of the characterisation of the cells. In addition, they tend to use different injury models and examine transplantations occurring at different intervals after injury. Definitive conclusions on the effects have been further complicated by the dissimilar conduct of studies (102).

Studies have shown (citation, citation, citation!!!) that cell replacement is able to facilitate axonal remyelination as well as restore axonal conductive function (120). Despite the many studies that have indicated a beneficial role of transplanted cells, the mechanistic insight is still very limited (119). The simplest explanation for recovery is the transplantion of cells to replace the lost cells, thereby reconstructing the local circuitry. The figure below shows the mechanism proposed which includes creation of a permissive substance for axonal growth, remyelination and supplying trophic support to reduce further damage (102).

Figure 3 - Mechanisms by which transplanted stem cells may facilitate regeneration (adapted from Barnabe-Heider) (102).

Glial cells have been widely used for transplantation into the brain and spinal cord of various animals. They are necessary for the correct neuronal development and the functions of mature neurones. The ability of glial cells to respond to the changes in the cellular and extracellular environment is essential to the function of the nervous system (114). Many studies are concerned with the environment provided by glial cells and the suspected trophic factors expressed. These experiments have shown that glial cells play an important role in the development, regenerative capacity and function of the spinal cord. Some of the recent investigations revealed several important features of glial cells, namely their excessive capability to migrate and remyelinate axons (121). Stem cells for transplantation include but not limited to Schwann cells, oligodendrocytes and embryonic or neural cells (107). A discussion of Schwann cells, oligodendrocytes and macrophages will give an overview of the potential of this method.

Schwann Cells

Schwann cells have been shown to be a very potent cell population of the peripheral nervous system (PNS). They are part of the microglia (114) and are capable of rapid and effective repair of demyelinated areas when transplanted into the CNS. Schwann cells have the ability to migrate towards the stripped axons and compete with less potent host oligodendrocytes for remyelination. This ability results from adult olidogendrocytes that have a limited migratory and myelinating capacity. In comparison, mature Schwann cells are able to proliferate and remyelinate more aggressively.

Mature Schwann cells' aggressive capacity to remyelinate the axons in the CNS may be disadvantageous to a certain extent. The forceful penetration of the host tissue may result in deteriorating changes of the microenvironment at the lesion site, as they may displace both host astrocyte and oligodendrocyte cells. This uncontrolled myelinating capability may therefore limit their potential use in the CNS of SCI patients (121).


Oligodendrocytes are macroglial cells responsible for providing and maintaining the CNS axons with insulating myelin sheaths. This enables the rapid conduction of action potentials by the axons. Any harmful influence or effects on the oligodendrocytes may result in an incomplete or imperfect myelination, or gradual loss of existing myelin layers. It has become evident (citation, citation, citation!!!) that SCI induces considerable oligodendrocyte apoptosis and therefore reduces the number of glial cells capable of remyelinating the lesion site (122). There has been evidence (citation, citation, citation!!!) to show that oligodendrocytes are able to myelinate naked axons, both in vivo (123) and in vitro (124). It was shown (citation, citation, citation!!!) that in vivo normal oligodendrocytes transplanted into a hypomeylinated brain of shiverer mice, overcame the defective shiverer oligodendrocytes and remyelinated the axons (125). It was also discovered (citation, citation, citation!!!) through electron microscopy that the host and transplanted oligodendrocytes were competing for the unmeylinated axons (126).


Historically, the CNS has been regarded as a site of the body where little immunological actions occur. However, more recently this view has changed suggesting that under specific circumstances such as infection, the immune system becomes involved in the response to these processes (122). Macrophages are the most important components of the immunological response in the brain. They are known to remove debris after injury and to secrete cytokines that regulate mitogenic and chemotatic activities within the tissue (127). The potential renewing abilities of the macrophages in combination with the limited inflammatory response of the CNS following an injury suggest that grafting of these cells into a lesioned spine may have beneficial effects. When macrophages, exposed ex vivo to regenerating peripheral nerves, were grafted into the lesion site, some recovery in paralysed rates occurred as well as improved electrophysiological activity (128). The mechanism here appears to be indirect. For instance, it provides trophic support, modulates the inflammatory response or provides substrate for axonal growth (115).

The scientific literature has to date not reached a consensus on the in vivo union of the exogenous transplanted adult stem cells and the endogenous differentiated neural cells. It has been suggested (citation, citation, citation!!!) that the transplanted cells may even fuse with the endogenous stem cells of the spinal cord. This concept should be further researched in the framework of SCI (111).

Activation of Endogenous Stem cells to Promote Remeylination

The presence of neural stem cells in the adult's central nervous system has raised several exciting possibilities in treating SCI. This includes the potential modulation of the pre-existing endogenous stem cells. Modulation of endogenous stem cells may be an attractive alternative to transplantation as it is a non-invasive autologous therapy that would circumvent many of the limitations and risks associated with transplantation (102). Transplantation may cause injury and also require immunosuppressant therapy (129). The endogenous stem cells can be modulated by pharmaceuticals and react in response to different types of stressors (131). A pharmaceutical formulated into a tablet would have a greater appeal than injection into the spine, used to transplant the cells. It is however difficult to predict today whether this is a viable option.

Resident cells are activated in SCI and produce a response, but the lack of functional recovery after a lesion suggests that this activation and response is insufficient to promote recovery (102). It is necessary to better understand the properties and functional role of cells derived from endogenous stem cells in order to consider optimal strategies to modulate their response. As mentioned before, the main descendants of the endogenous stem cells after SCI are oligodendrocytes and astrocytes. Astrocytes are heterogenous and it is currently unclear to what degree the subtypes play a role after injury. The glial scar formed after injury is comprised of both locally present astrocytes, which become hypertrophic in response, and new astrocytes, derived from endogenous stem cells that invade the lesion (102). It is unknown whether these different astrocyte populations have different roles or functions in spinal regeneration.

As discussed above, the mortality of oligodendrocytes has a significant impact on axonal death. The idea of promoting endogenous stem cells to differentiate into oligodendroctytes, and therefore increase the number of such cells at the site of injury, seems like a reasonable treatment option. However, endogenous stem cell population responds to injury primarily by proliferating and maturing into astrocytes (133). A much smaller number differentiate into neurons and oligodendrocytes. The microenviromental cues play an important role in the development and maturation of these cells. The modification of these microenviromental cues is therefore significant in order to control the differentiation of these stem cells (134). Several researchers (citation, citation, citation!!!) have experimented with manipulating of the spinal cord environment to instruct stem cells in order to adopt a neuronal or glial fate.

In broad terms, the type of modulating agents used experimentally can be divided into three categories; cytokines, growth factors and transcription factors (132). This article will only be able to touch on some of the modulating agents that have been investigated to date. Figure 4 shows some of the published experimental manipulations that have had an influence on endogenous stem cells.

Figure 4 - Schematic drawing showing a SCI and published experimental manipulations influencing endogenous spinal cord stem cells (Taken from Obermair et al 2008) (132)


After a SCI, the immune system responds with up-regulation of pro-inflammatory cytokines such as tumour necrosis factor (TNF-α), IL-6, IL-1β and IL-4. TNF-α has immune effects as well as a promoting consequence on survival and proliferation of oligodendrocytes (135).

In a study by (citation, citation, citation!!!) where stem cells were incubated with IL-6, in vitro astrocytes were the preferential phenotype produced. They then blocked the function of IL-6 with MR16-1 and showed that the differentiation towards astrocytes was inhibited (136). Inhibition of astrocyte differentiation may be beneficial to the remyelination process, because astrocytes can produce inhibitory molecules such as Jagged1. Molecules like this inhibit oligodendrocytes differentiation and growth (143).

L-1β is remarkably unregulated in the adult spinal cord immediately after injury. It is one of the first factors to initiates an immune response and therefore causes secondary neuro-damage. It was shown by Vela et al. (Very well done, Mader! You deserve a sticker for this! :-P) that IL-1β inhibits the proliferation of oligodendrocytes, but promotes their differentiation from stem cells (137).

Growth Factors

Different growth factors have been tested experimentally to influence the differentiation of endogenous stem cells. Insulin-like Growth Factor (IGF-1) was shown (citation, citation, citation!!!) to have in vivo and in vitro effects on the proliferative activity of stem cells in the hippocampal region of the brain (138). IGF-1 stimulates oligodendroglial differentiation by inhibition of bone morphogenic protein (BMP), by the upregulation of BMP antagonists such as Smad6, Smad7 and Noggin (139).

Endothelial growth factor (EGF) was shown (citation, citation, citation!!!) to enhance the migration and dispersion of cells in the surrounding parenchyma while Fibroblast growth factor 2 (FGF-2) enhances cell proliferation (133). The infusion of these growth factors induces a 50-fold increase in neurogenesis from the stem cells in response to ischemia (144).

Transcription Factors

Retroviral-mediated overexpression of neurogenin-2 (Ngn2) and Mash-1 as well as the mixture of growth factors (FGF-2 and EGF) increased the production of neurons and oligodendrocytes after SCI (140). It resulted in enhanced oligodendrocyte differentiation and maturation at the expense of astrocyte production, however the newly generated oligodendrocytes were no longer observed one month after injury (130).

A transcription factor called YY-1 regulates the early stages of oligodendrocyte differentiation after the immature cell exits the cell cycle. It was shown that YY-1 only mediates these events for olidogendrocyte differentiation and not for astrocytes (141). This may be an attractive target for the manipulation of the endogenous stem cells as differentiation can be promoted cell specifically.


Recent findings indicate the methylprednisolone not only affects the activation and proliferation of macrophages and microglia, but also impact endogenous stem cells in the spinal cord. Glucocorticoid and the mineralcorticoid receptors are found on the surface of adult spinal cord stem cells, suggesting a direct effect of metlyprednisolone on these cells. However, on the whole, the observed reduction in NG2-postive precursor cells after a SCI with methylprednisolone treatment may lead to a reduced oligodensdrocyte repair (134). These finding begs the question to what extent treatment with methylprednisolone limiting the regeneration capacity of the endogenous stem cells.

A majority of SCI patients also suffer from chronic neuropathic pain, which greatly decreases the quality of life (145). The transplantation of adult spinal cord neural stem cells promotes the functional recovery of the spine, but it can also increase neuropathic pain as shown in rats (146). The rats showed signs of allodynia, where a non noxious stimulus is perceived as painful. This sensation is probably due to the stem cell-derived astrocytes promoting the sprouting of sensory axons (102). This correlation should be established in clinical trials and methods to reduce the incidence of increased neuropathic pain should be considered and researched. Other complications and risks must be evaluated before a stem cell-based therapy can be applied in the clinic. These risks include tumorigenesis, immunological complications or other risks associated with an unexpected change in the phenotype of the transplanted cells (142).

A pharmaceutical therapy modulating endogenous stem cells to promote recovery would be advantageous over transplantation strategies since it is much less invasive. Transplantation of donor stem cells may require immunosuppression which has serious side effects associated. Immuno-incompatability may result in rejection of transplanted cells and can either lead to their loss or an inflammatory reaction furthering the secondary damage. However, there is still no evidence to suggest that recruitment of endogenous stem cells is beneficial at all. It may affect the outcome negatively, for example by contributing to scar formation (102).

Possibly, the normal response to the injury and scar formation is optimal. In terms of regaining tissue integrity, it prevents any further damage and containing the inflammatory cells. It is possible to modulate the response of endogenous stem cells to generate oligodendrocytes at the expense of astrocytes. However, this bears the risk of decreasing the recovery of tissue integrity.

For many years the prognosis for recovery after an injury to the spine was bleak, and this field of research was seen as a lost cause. This has changed significantly, at least from a researcher's perspective. Some of the new strategies to repair offer the possibility of clinically effective therapies in the not too distant future.