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The adult central nervous system shows a very limited capacity to regenerate. However, recently new hopes have arisen as a result of the discovery of the endogenous precursors, or stem cells in adult brain, that could provide a potential source of new neurons. This topic will involve providing evidence in favour and against this hope.
Contrary to the long held belief that the adult mammalian central nervous system (CNS) lacked the ability to regenerate injured neurones (Cajal, 1928) it was later found that neurogenesis occurs in discrete regions of the mammalian brain under physiological conditions (Gage 2004, Song et al., 2005, Kempermann 1997, Eriksson et al., 1998). Neurogenesis is a well established phenomenon and can be defined as a process of generating functional neurones from progenitor cells (Song et al., 2005). New cells are continuously generated from immature proliferating cells and are added throughout adulthood in many
Figure 1. Shows the sub granular zone (SGZ) of the hippocampus of a rodent. DG represents the dentate gyrus. (Schnieder 2004)
organisms (Lie et al., 2004). Although the vast majority of cells in the CNS are added during the embryonic stage, cells are continuously added throughout the developmental stage in certain regions of the brain for example the hippocampus thus the concept of neurogenesis implies that the development of the brain is a continuous process. Neurons and glial cells derived from multi-potent neural stem cells are continuously added to the mammalian CNS during development. Various reports have suggested that neural stem cells exist within the entire CNS. Consequently if neurogenesis exists the CNS should have the ability to repair and regenerate itself after injury.
Neurogenesis was first reported to occur in the hippocampus of rodents (see figure.1) over forty years ago by Altman and Das in 1965. Furthermore, Altman and Das using [H] thymidine radiographic labelling reported that the new cells could divide, proliferate, migrate and differentiate and therefore the new neurones generated in the rat's hippocampus are capable of making functional synaptic connection. Altman's and Das findings were not immediately accepted by the scientific community; in fact it was met with great scepticism due to the inability of the CNS to repair itself. However, during the late 1990's several researchers including Eriksson et al., 1998, Kempermann, 1997 and Gross et al., 2000 reported the growth of new cells including neurones in the hippocampus and olfactory bulb can be observed in the mammalian brain. Bromodeoxuridine (BrdU) a marker for dividing cells was widely used as the main tool for the study of neurogenesis and neural stem cells throughout the 1990's.
Figure 1.2. Functional analysis of neurogenesis. (Kempermann et al., 2004)
It has been reported that neurogenesis occurs throughout life primarily in the forebrain sub ventricular zone and the sub granular zone of the dentate gyrus of the hippocampus (Gage et al., 1998, Kempermann et al., 1997 and 1998,). In the dentate gyrus, new cells in the sub granular zone migrate to the granular layer where they differentiate into granule like cells (Taupin, 2008), mature neuronal cell (Kempermann et al., 2004) and axonal projections to the CA3 area of the hippocampus. The sub-granular zone consists of three types of proliferative cells namely type 1 cells (glia-like stem cells), type 2 (progenitor cell) and type 3 cells (double cortin positive cells). New neuronal cells in the sub ventricular zone migrate to the olfactory bulb via the rostrimigratory stream (Kempermann 2003) where they differentiate into interneurones of the olfactory bulb (Song et al., 2005). The sub ventricular zone contains three cell types, namely type A, B and C (Caille et al., 1999). Type B cells are said to act as stem cells which gives rise to precursor cells. Kempermann and Gage, 1999 proposed that the fact that neurogenesis occurs in these discrete areas of the CNS is of some functional significance. Neurogenesis has also been reported to occur at lower levels in other areas of the brain such as the neocortex (Taupin, 2008). However studies reporting that neurogenesis occurs in regions outside hippocampus are often very contradicting and perhaps would benefit from further research.
Neurogenesis is a multi-step process that begins with division of precursor cell and ending with a new functioning neurone (Kempermann, 2004 and 2006). The new neurones must undergo proliferation, survival migration of newly generated neuronal cells, and differentiation (Gage and Kempermann, 1998) in order to form functional synaptic connections with the already existing neuronal network. The new cells have to proliferate and amplify into a progenitor cell, differentiate into immature neurones and then migrate to the final location (Song et al., 2004). Survival of the new cell is of upmost importance since many cells die very soon after generation. In addition, in order for new neurones to join and function in the already existing neuronal network they must extend dendrites and axons and form synapses (Kempermann et al, 2004).
Several researchers including Kempermann and Gage, 1999 have reported that cells in the nervous system can be induced to undergo proliferation. The proliferation and differentiation of adult neural stem cells is dependent upon many environmental and molecular factors (Gage et al., 2000). Specific growth factors can enhance the growth of neural stem cells in vitro. Differentiation of neural stem cells can be amplified using growth factors e.g. fibroblast growth factors. Factors controlling survival and migration of neural stem cells are currently unknown.
Interestingly it has been reported that neurogenesis occurs after injury to areas of the brain thought to be non neurogenic. Ischemic brain insults and seizures stimulate neurogenesis in the sub ventricular and sub granular zones of the hippocampus (Song et al., 2004). Furthermore epilepsy increases proliferation in the dentate gyrus (Song et al., 2005). It would be a very one sided view to conclude that new neurones replace injured or old neurones and furthermore there is no evidence to suggest that the new neurones becomes function. Neurogenesis may offer hope for regeneration of injured neurones of the CNS but more research is needed before a definitive conclusion can be reached. Newly generated neurones are said to originate from neural stem cells.
Neural Stem cells
Neural stem cells (NSCs) are somatic stem cells found in various regions of the central nervous system of mammals including humans (Gage, 2000). Neural stem cells can be defined as self renewing, multi-potential cells that can generate all major cell types of the adult mammalian system (Williams et al., 2001, Taupin and Gage, 2002). NSCs are subtypes of progenitor cells that give rise to neurones, astrocytes and oligodendrocytes. They can be derived from embryonic stem cells or isolated from the hippocampus. Through the use of [H] thymidine and BrdU labelling, it is widely accepted that stem cells exist in the adult mammalian; however the fact that a cell can be labelled with [H] thymidine and BrdU doesn't mean that it is a stem cell!
Figure 2. Location of neural stem cells in the adult hippocampus. (Temple 2001)
Neural stem cells are highly ubiquitous since they can be isolated from various regions of the central nervous system including the spinal cord (Gage and Praag, 2004), however the vast majority is found in the hippocampus, the sub ventricular and sub-granular zones to be precise (see figure 2). A neural stem cell must be able to generate astrocytes, neurones and oligodendrocytes and also be able to renew these cells when damaged. Thus the idea that the CNS lacks the potential to regenerate itself after injury can be challenged by taking advantage of the multi-lineage and self renewal characteristics of neural stem cells. The multi-lineage properties of a stem cell are correlated with its plasticity. An important characteristic of neural stem cells is that they are highly plastic. Plasticity refers to the brains ability to change its structure and function during maturation, learning, environmental challenges or pathology (Grubb et al 2006). It is through this plasticity that neural stem cells are able to differentiate into any cell. Thus, neural stem cells have great potential as a therapeutic tool for a number of CNS disorders. The extent of the plasticity of adult neural stem cell is controversial, however it has been reported that plasticity allows neural stem cells to make the appropriate replacement cells after injury as and when they are required.
In vitro, self renewing multipotential neural stem cells have been isolated and characterised from various regions of the adult CNS, including the spinal cord. This supports the fact that neural stem cells are present in the CNS. The question is, if neural stem cells are present in the CNS, why is the CNS unable to recover from injury. It would seem that stem cells are not able to spontaneously regenerate injured neurones. The confirmation that neurogenesis occurs in the adult brain of several species, including humans, and the isolation and characterisation in vitro of self renewing multi-potential NSCs from the adult CNS opens new possibility for cell therapy.
3. The role of neurogenesis in regeneration of the injured CNS
It is self evident that the brain and spinal has limited ability to regenerate injured neurone thus injury of the CNS is devastating since it can lead to permanent disability. The CNS reacts to injury by triggering a series of events over several days. These events are a combination of cellular and molecular reactions and incorporate various cell types including oligodendrocytes and astrocytes (Fawcett et al., 1999). Although there are several reasons for the inability of the CNS to effectively repair itself, it can be concluded that the formation of glial scar is the most important reason for ineffective repair. When the CNS is injured, it triggers a glial reaction which recruits a number of cells including astrocytes and oligodendrocytes. Ultimately glial reaction leads to the formation of glial scars. Glial scars can be described as an evolving structure integrating different cell at different times (Fawcett et al., 1999). Glial scars hinder regeneration of axons as well as remyelination. Injury to the CNS also results in myelin debris which further hinders self- repair of the CNS.
Figure 3. Normal functional recovery in the CNS. (Horner and Gage. 2000)
Regeneration of the CNS includes replacing injured neurones as well as recovery of function. The previous dogma in terms of regeneration of CNS was that most adult neurons are said to be post-mitotic thus no replacement or regeneration occurs due to sprouting of axons terminals and formation of glial scars amongst other things. Neurogenesis challenges the previous dogma and gives hope for the recovery of the CNS from injury. Successful regeneration is dependent upon a number of factors including the ability of injured axon to re-grow and survive as well joining and functioning with the already existing neuronal network. Currently regeneration of injured neurons cannot be readily observed after lesion in the adult spinal cord; however Hasan et al., 1993 reported that spinal cord lesions in chicken embryos leads to renervation of spinal cord and growth of fibers. Most parts of the adult CNS are non neurogenic under physiological conditions (Okano, 2006).
Although there is sufficient evidence for the existence of neurogenesis in the adult hippocampus, it is not known whether the new neurones generated are transient or leads to new functional neurones (Kempermann, 2003). The new cells formed have a transient existence and the number of cells generated ultimately depends on two things; the proliferation rate and the survival rate (Gould et al., 2001) Furthermore Okano et al., 2008 stated that regeneration of the CNS fails because neurones produced from neurogenesis are often in low numbers and short lived as they are unable to form synaptic connections. These problems can be overcome which gives hope for cell transplantation and other methods of repairing the injured CNS.
According to Shaoyu et al., 2006 the new neurones formed are said to have unique properties during their maturation stages which suggests that they may be involved replacing dying cells to maintain brain function. The basis of many neurodegenerative diseases is that most cells die in the brain so replacing those dying cells may be a way to maintain brain function. The 'neurogenic reserve' hypothesis by G Kempermann 2008 proposes that 'neurogenesis in the adult hippocampus might contribute to the maintenance and promotion of hippocampus function in health and disease across the lifespan. According to Kempermann the 'neurogenic reserve' is the brains compensatory potential in the face of neurodegeneration a common sign in brain diseases such as Parkinson's disease and Alzheimer's. The hippocampus is amongst the brain regions affected in degenerative disease. Several researchers including Murphy et al 1993 and Csernansky et al 2000 have concluded that degeneration in the hippocampus and particularly in the CA1 region is one of the earlier signs implicated in Alzheimer's disease. Hence any regeneration of neurone could potentially be a replacement mechanism and therefore may be implicated in the cure and study of such diseases. All the factors such as age, depression and stress that are believed to be causative factors of decreased neurogenesis are implicated in Alzheimer's disease (Gould et al 1998) and to some extent Parkinson's. This also implies that decreased neurogenesis may be a causative factor for Alzheimer's disease. Several researchers including Gage et al and others have concluded that the potential of the adult brain to generate new neurons may potentially be utilized to develop therapies in for neurodegenerative diseases; the rate of neurogenesis makes it unfeasible that the role of new neurones in the hippocampus is to replace dying cells. This is because more cells die than are being formed.
Furthermore injured cells in the CNS can also be induced to self repair themselves after injury via the secretion of growth factors (Tai and Svendsen, 2004).
4. Cell replacement therapies for injuries of the CNS
It has already be shown that neurogenesis respond to areas of injury in the neurogenic regions of the CNS. What are the options for non neurogenic region? Can stem cells be used to repair lesion in the non neurogenic regions of the CNS? So far reports of neurogenesis in non neurogenic areas are encouraging. One way of repairing damage CNS is via cell replacement therapies incorporating neural stem cells. However for stem cells to be suitable for therapeutic transplantation, they must meet several criteria including the ability to differentiate and migrate appropriately. Additionally any cell used should not be rejected by recipient and should be harvested in sufficient numbers. Research has shown that cell transplantation using neural stem cells is the most promising treatment for central nervous system injuries; however replacement of dying or lost neurones requires survival and even more importantly the need to integrate into the adult host brain and function effectively (Kempermann et al., 2004).
Neural stem cells are potential therapeutic source for cellular transplantation because they are stable in vitro and can maintain their multipotentiality (Cao et al., 2002). Transplanted cells could potentially repair injuries CNS for example myelination, cell replacement as well as maintaining synapses and axons. On the other hand diseases of the brain and spinal cord may pose problems for cell replacement therapies given the diversity of cell types within the adult mammalian CNS as well as the number of cells lost in degenerative diseases. Research has shown that diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), disorders of myelination such as multiple sclerosis (MS) as well as injuries of the spinal cord may potentially benefit from cell replacement therapies. Research on the use of neural stem cell transplantation as a replacement mechanism for neurodegenerative disorders such AD, Huntington's disease (HD) and PD has significantly increased in recent years.
Parkinson's is a neurodegenerative disease characterised by progressive degeneration of neurones in the substantia nigra dopaminergic system of the midbrain. It is the second commonest neurodegenerative disease thus neuron transplantation as a means of replacing the loss neurones is presumably of utmost important. The cells used for transplantation in PD are taken from the midbrain during foetal development i.e. the time where the dopaminergic neurons are undergoing differentiation. They are then incorporated into the striatum giving them the opportunity to establish functional synaptic connections. Studies have shown that neural stem cells are able to differentiate into dopamine neurons. Yang et al., 2002 that stem cells can differentiate to express traits of dopamine neurones.
Figure 4. Application of NSCs for transplantation. (Lindavall and Kokaii 2006
PD more than any other neurodegenerative disease presents itself more as a target for cell transplantation due to the neurodegeneration is highly specific to the substantia nigra thus primary neural transplant therapies are focused on replacing lost striatum dopamine which in theory should provide some functional recovery, replacement of neurones via therapy should at least eliminate some of the symptoms of PD. Bjorklund et al., 2001 reported that dopaminergic neurons grafted into the dopamine deficient striatum should at least reverse the major symptoms of the disease. Bjorklund and Lindvall, 2000 reported that donor dopaminergic neurones are able to significantly improve many of the symptoms of PD, however only when sufficient number of the donor neurones survive. Here in lies the first problem with neural stem cell transplantation. Although there has been some success, cell transplantation for PD difficult to carry out clinically because to treat one PD patient requires 4-8 foetuses, not only does this raise ethical concerns but it also complicates matters. According to Windrem and Goldman 2006 the preparation of engraftable quantities of dopaminergic progenitors from foetal tissue is difficult die to the small number of NSCs and the controversial large number of abortuses required.
Akerud et al., 2001 reported that neural stem cells are able to delivering transgenes with therapeutic values by integrating into the adult host brain and differentiating into multiple phenotypes and also release high levels of GDNF for at least 4 months preventing further degeneration of dopaminergic neurons and motor alterations in a mouse model of PD which is consistent with other reports. Bjorklund et al., 2001 reported newly transplanted dopaminergic cell can restore 10-40% of normal function. Lindvall et al., 1990 reported that neural transplantation can restore striatal dopamine neurotransmission in animal models of animals and thus improve motor impairment symptoms observed in PD. Most of these reports are based on findings from animal studies so one has to be careful in extrapolating these findings to humans. . It would appear that transplantation is far more successful in animal models of PD compared to foetal cell graft However according to Lindvall et al., 1990 mesencephalic dopamine neurons obtained from humans foetuses are able to survive in the human brain and provide immediate and sustained relieve of symptoms in people suffering from idiopathic PD. Although the stem cell therapy is successful in the early stages of PD, it is far less successful in the later stages when multiple dopamine system degenerates. Lindvall et al., 2004 reported that clinical trials have shown that cell replacement incorporating human foetal dopaminergic neurones can result in long lasting improvement in humans. Additionally it has been shown that foetal cells for transplanatation taken at the developmental stage are far more successful in terms of long term survival and function in the striatum. Neural stem cell transplantation incorporating mouse models has paved the way for exploring NSCs for cell replacement therapies.
Huntington's disease is an autosomal dominant neurodegenerative disorder characterised by abnormal movement and cognitive impairment. It results from the repeat of IT15 locus on chromosome 4. Clinical features of HD include neuronal loss in the striatum and cerebral cortex. HD like PD is characterised by loss of discrete neuronal population thus is ideal for cell replacement therapy. The ideal the engrafment for HD IS γ-aminobutyric acid (GABA)-ergic phenotype (Cao et al., 2005). Studies have shown functional recovery in animal models of HD after cell replacement using grafts of striatal neurones.
Unlike PD and HD the challenge for treating stroke with the use of neural stem cell is much greater due to the fact that stroke can affect several entities of the brain thus many types of neurones are lost as well as oligodendrocytes and astrocytes. Stroke is caused by lack of blood to the brain due to blockage of the cerebral artery. A stroke often results in loss of neuron and glial cells as well as neurological impairments (Lindvall et al., 2006). Bliss et el., 1998 shown that when neural stem cells are transplanted in stroke damaged rat brain they will migrate the injured region. Furthermore improved motor function can be observed stroke induced rats after transplantation using neural stem cells.
Another neurodegenerative disease that may benefit from therapy is AD. AD is a progressive disease characterised by senile plaques, neurofibrillary tangles and loss of nerve cells in areas of the brain concerned with memory. Research has shown that there is increased neurogenesis in the affected areas of the brain in patients with AD which would make it a possible target for cell replacement therapy, however due to the extent of which neurones are lost in AD and the fact that the loss of neurones cover a wide range of systems, a barrier is created for the use neural stem cell as a possible therapy for AD. Scientists at the University of California were able to report for the first time that neural stem cell offer potential treatment for AD in that NSC's can rescue memory in rodents with advanced AD.
Amyotrophic lateral sclerosis not only affects the brain but also affects the spinal cord. Degeneration of motor neurones can be observed in the spinal cord and in the cerebral cortex and brainstem thus stem cells can be used to replace neurones as well as regeneration of axons in the spinal cord. Porter et al., 2002 showed that cultured stem cells from rats can differentiate into motor neurones and these motor neurones can make appropriate synaptic connections to muscle cells.
Demyelination is the main hallmark for multiple sclerosis. Demyelination can also be observed in many spinal cord disorders as well as stroke. Multiple sclerosis is an autoimmune inflammatory disease of the CNS. Research into possible therapeutic treatment of MS focuses on remyelination. Remyelination plays a vital role in restoring conduction properties as well as protecting neurones. Oligodendrocytes regulated by several factors such as platelet derived growth factors, play an important role in remyelination. There are several hypotheses as to why remyelination fail in the CNS including the role of inflammation and unreceptive axons (Charles et al., 2002). MS is suitable for cell replacement therapy because it consists of solely replacing myelin. The major problem with using neural stem cell to treat multiple sclerosis has been the limited ability of donor cells to reach multiple demyelinating sites in the CNS as well as making functional recovery (Tai et al., 2004). Cao et al., 2004 reported that when cells in adult rats are labelled with BrdU, approximately three quarters of cells found in the spinal cord express NG2. NG2 is a marker for precursor of oligodendrocytes; oligodendrocytes have the capability to producing myelin following cell transplantation. Although there is limited evidence to suggest that these cells actually aid remyelination it may be significant in terms of developing a NSCs based therapy for demyelinating diseases such as MS. In fact Chang et al., 2000 reported that the presence of oligodendrocytes in lesion of MS did not replace or produce myelin.
Before any of the above can be carried out on a clinical level various factors including the number of cells to transplant, the developmental stage of transplantation, the type of cells to transplants, an in-depth molecular understanding of stem cells are all issues that need to be addressed with further research before treating neurological disorders with NSCs can be attempted.
The spinal cord
Injury to the spinal cord causes primary insults followed by inflammation, ultimately this results in loss of nervous tissue. Astrocytes often act as scavengers at the site of injury in the spinal cord which lead to formation of glial scar. It is these glial scars which hinder regeneration of axons in the spinal cord (Okano et al., 2003).Neural stem cells could potentially replace neurones after injury to the spinal cord by promoting axonal regeneration. Injuries of the spinal cord can result in various complications and severe damage for example paraplegia and tetraplegia amongst others. Most research into spinal cord injury focuses on axon growth and reducing neuronal degeneration. Spontaneous recovery of the spinal cord is limited due to the fact that the central nervous system has limited ability to regenerate, replace lost cells and establish functional connections.
Compared to injuries of the brain, injuries of the spinal cord may be more suitable for neural stem cell transplantation. According to Ogawo et al., 2002 transplanted neural stem cells give rise to a larger percentage of astrocytes than oligodendrocytes and neurones.
Transplantation of NSC's in the spinal cord has yielded many contradicting reports with some reporting success. Chow et al reported that transplanted cells only differentiated into astrocytes whereas McDonald et al reported that NSC's differentiated into neurones. However several studies have reported functional improvement after transplantation of neural stem cells into injured spinal cord. Namiki et al., 1999, Horner et al., 2000 and Johansson et al., 1999 reported that neural stem cells in the spinal cord of rats have the ability to proliferate and differentiate into neurons and astrocytes. Hoffstetter et al., 2005 reported that grafting of adult neural stem cells into a rat's spinal cord improves motor recovery but also cause aberrant axonal sprouting. It has also been reported that grafting of neural stem cells improves functional recovery. In a 2006 study by Fehlings et al. it was reported that stem cells can repair damaged spinal cord tissues and restore function in rats suffering from spinal cord injuries (Science Daily, 2006). However therapeutic benefits of NSC's can be attributed to trophic factors such as NGFs. Trophic factors can be described as molecules released by target that induces biochemical changes in neurones that promotes survival and growth of axons. Also the timing of transplantation seems to be correlated to the success of the transplantation. It has been reported that only a small number of cells survive from early transplantation and late transplantation leads to formation of glial scars which hinders progress. According to Okano et al., 2003 7-14 days after injury is more suited to cell transplantation.
In order to develop a therapy to replace neuronal loss as seen in diseases such as PD, AD stroke amongst other, the lineage potential of stem cells in vitro has to be considered. The importance of survival, migration and differentiation of NSCs graft has been reported in several studies. Much of the data shows that grafted NSCs are highly plastic and can respond appropriately to injuries of the developing brain.
Ethical and political concerns
Although there has been successful improved in clinical trials of NSCs, ethical issues have called for alternative approaches, most notably is the use of stem cell replacement therapies. Ethical consideration has possibly hindered application of neural transplant studies in humans which is potentially preventing progress. Although many researchers would debate the potential end results would lead to significant advancements in medicine, there are as many people who would argue that the use of neural stem cells is unethical. The use of neural stem cells is under strict regulation which limits the research that can be done and thus hinders possible progress. Before proceeding further with clinical research into stem cell replacement therapy, ethical considerations needs to be taken into account to ensure that any possible benefit outweighs the risks. Risks include rejection and transplantation of infecting cell amongst other things. There are also great ethical concerns in regards to the number of foetuses used and also the number of aborted foetuses. As a result of ethical considerations, limits the availability of donor tissues thus further hindering progress.
The differentiation potential of NSCs and their potential use as therapeutic agents has dominated the research community for the last 20 years, however it is my belief that the full therapeutic benefits of NSCs are far from being fully explored. It was believed that after birth no new neurones are added to the adult brain. This belief was held for years. Not only does this show the necessity for new research, techniques and ideas in neurobiology, it also shows that we have come a long way in our understanding of the mammalian CNS. It is now accepted that there is neurogenesis at least in the dentate gyrus of the hippocampus. Thus research is now focused on regulatory mechanisms involved in neurogenesis especially the survival of new cells. The study of neurogenesis has given us an insight into the structure, function and plasticity of the brain and more specifically a better understanding of the hippocampus. The fact that neurogenesis occurs in the CNS is very important in terms of curing injuries of the CNS. At present the investigation of neurogenesis is limited to fixed tissues, therefore the research method is limited. Also at present the majority of what is known about NSCs and neurogenesis is obtained from animal models such as rodents. Although the use of animal models can be very useful in genetic and experimental studies it may be limited when generalising results to humans. The role of neurogenesis in the adult hippocampus remains unknown at present therefore further research and ideas are needed in order for the function of neurogenesis to be concluded, perhaps knowing the function will aid understanding of how to better utilise stem cells to cure diseases and injuries of the CNS.
Given the excitement of the possibly potential of neural stem cells, it is impossible to predict what may be revealed in the future about stem cells. Although the research has come a long way, there are several unanswered questions. To improve the success of more research is needed into the regulation of survival of new cells. It is evident that an understanding of the factors regulating neurogenesis will build the foundations for cell replacement therapy using neural stem cells. The diversity of neural cell types within the CNs poses significant challenges for repair, however preclinical testing is required before the full potential of neural stem cells can be realized. The task ahead would appear to be challenging, if efforts being made by scientific researchers at present continues to improve our understanding, it would be safe to say that the best is yet to come!