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Neurodegenerative disease is a condition characterized by the loss if neurons and glial cells within the spinal cord and the brain, and accumulation of intracellular fibrillary inclusions. These specialized neuronal and glial cells have maintained numerous functions in different physiological activities ranging from movement through to memory. Disruptions in cells of the nervous system do not regenerate successfully leading to irreversible changes and characteristic neurological disorder. Numerous diseases are distinguished as neurodegenerative diseases; examples include Alzheimer's Disease (AD), Amytotrophic lateral Scelerosis, Parkinson's disease (PD) and Huntington's disease (HD). Stem cells are cells found in most, if not all, multi-cellular organisms. They are characterized by the ability to renew themselves through mitotic cell division and differentiating into a diverse range of specialized cell types. The establishment of stem cells was discovered by a Russian scientist in the early 20th century but only introduced into medical research in the 1960s by two Canadian scientists named Ernest A. McCulloch and James E.Till, who demonstrated the presence of self-renewing cells in mouse bone marrow. In recent years, 'neuron and glia have been generated successfully from stem cells in culture; fuelling efforts have been extended to stimulating the formation and preventing the death of neurons and glial cells'.1
Medical researchers believe that stem cell therapy has the potential to dramatically change the treatment of human disease, specifically by replacing irreversibly disrupted cells. A number of adult stem cell therapies already exist such as bone marrow transplants that are used to treat leukemia. In the future scientist would like to use stem cell research to treat a wider variety of diseases including cancer, cardiovascular diseases and neurodegenerative diseases.
Stem cell treatment and technology are of eminent interest in research studies to treat neurodegenerative diseases. There are two types of stem: embryonic stem (ES) cells and adult stem cells, derived from either embryonic development stages or mature humans, respectively. The study of stem cells had a scientific breakthrough researchers successfully isolated a single cell from a 'teratocarcinoma', a form of cancer, that was able to replicated and grow in cell culture as a stem cell.
Embryonic stem cells are derived from the inner mass of blastocyst, an early-stage embryo. They are pluripotent stem cells which mean that they are able to differentiate into various cells types. The pluripotency distinguishes the embryonic stem cells from the adult stem cells. The ES cells have the ability to regenerate to all cell types in the body unlike the adult stem cell, which provide a limited number of cell types. This indicates the ES cells are useful for research and regenerative medicine because of their potential of self renewal and plasticity. Adult stem cells are also known as somatic cells that multiply by cell division to replenish dying cells and regenerate damage tissues. Scientists find a great deal of interest using adult stem cells as it has the ability to divide or self-renew indefinitely and generate all the cell types of the organs from which they have originate and have the potential to regenerate an entire organ from a few cells. An experiment has been conducted in 2008, where a human trachea that has been grown from adult stem cells taken from the bone marrow from the patient was carried out and transplanted successfully.2 Adult stem cells have been used for many years to successfully treat leukemia and related bone/blood cancer utilizing bone marrow transplant. Due to the high success rate in the use of stem cell research in therapy, and the extensive plasticity and self renewal properties, there are high hopes for the implication of stem cells in the treatment of neurodegenerative diseases such as Parkinson's disease and Huntington's disease. Previous researches in both of these neurodegenerative diseases have use embryonic stem cells and adult stem cells treatments.
Huntington's disease (HD) is an inherited 'autosomal dominant neurodegenerative disorder' which is 'fatal, intractable disorder that is characterized by chorea (excessive spontaneous movements) and progressive dementia'.3 this disease is caused by a genetic mutation on either side of the two copies of a specific gene located on chromosome 4. This alteration leads to an extension of the polyglumatine repeats, consequently leading to the destruction of ACH-secreting and GABA-secreting neurons in the basal ganglia and cerebral cortex. The neurological disruption cause symptoms to progressively appear as the basal nuclei and frontal lobes slowly degenerate and individual may suffer from restriction of movement to have symptoms of dementia. 'Despite identification of the HD gene and associated protein, the mechanism involved in pathogenesis of HD'4 there are no cure for HD but there are many treatments to reduce the severity of chorea, using exercise and cognitive therapy to reduce the symptoms. Such as tetrabenzaine, was developed to reduce the severity of symptoms. There are many possible treatments that are currently being investigated, as scientists show greater interest in this particular neurological disease, specifically due to the fact that there is no cure and clinical drug trials of drugs demonstrating an impact on the progression of the disease using the knowledge that stem cells are able to regenerate ad repair damage cells that cause this disease. One research study focused on the use of embryonic stem cells. Using 'a fetal human brain tissue may serve as a useful strategy for reducing neuronal damage in HD brain and a recent study has documented improvements in motor and cognition performance in HD patients following fetal cell transplantation'.5 Another experiment is to use a transgenic rat model for HD was generated by von Hörsten et al (2003) and 'transplantation of both neural tissues (compromising both neurons and glial cells) offer considerable promise for providing radically new methods treating'6 this disease using adult stem cells shown in an experiment from Vazey et al (2006) dissected a cell from the subventricular zone (SVZ) in an adult rat brain and expanded the cell in vitro as neurospheres, and prepared for transplantation after 14 days into a rat model of HD.7
Parkinson's disease (PD) was named after an English apothecary James Parkinson. Who wrote a detailed description of the disease in "An essay on shaking palsy" (1817). This disorder 'is a gradual loss of nigrostriatal dopamine-containing neurons, but degeneration also occurs in systems of non-dopaminegic neurons'.8 Activity of the basal nuclei such as movement and learning are inhibited by the death of neurons in the substantia nigra of the mesencephalon, which specifically releases the neurotransmitter dopamine. The result is gradual, generalized increase in muscle tone and the appearance of symptoms characteristic of Parkinson's disease. People who suffer from PD have difficulty starting voluntary movements, because opposing muscle groups do not relax. 'Current therapies centre on the oral administration of L-dopa and dopamine receptor agonists, and on deep-brain stimulation in the subthalamic nucleus. These treatments are effective for some symptoms, but are associated with side effects and do not stop the progression of the disease'.9 Scientist are interested in using stem cell therapies because it is clinically competitive. This new therapy must have long lasting results and improvement to the current treatments.
There are currently clinical trials using ES cells to treat Parkinson's disease. By transplanting low doses of undifferentiated mouse embryonic stem (ES) cells into the rat striatum results in production of ES cells into fully differentiated fetal dopamine (DA) neurons which caused a gradual ad sustained behavioral restoration of DA-mediated motor asymmetry.10 There are several clinical studies which show the use of adult stem cells to treat PD via transplant (Carrion et al 2009). This experimental study identifies that 'the optimal tissue for neural stem cells (NSCs) transplantation is autologous i.e. from the individual receiving the transplant. NSCs from the rostral migratory stream (RMS) and subventricular zone (SVZ) could be ideal source of adult NSCs to treat PD'.11
Stem cell research is beneficial for regenerative medicine and to improve long-term treatment as current therapies or drugs are short-term treatments and cause side effects when treating a neurodegenerative disease. By definition, stem cells have the ability to self renew continuously and be able to differentiate into various cell types. This is one of the main reasons why scientists are interested in this field and to find the potential treatment or cure for neurodegenerative disease. One of the break-through is to apply stem cells to cure leukemia and other related bone or blood cancer by using bone marrow transplant. This is a huge success in medical history to abolish diseases and cancer. The next step is to achieve neurological disorder and to provide a long term treatment. 'There are still many obstacles to overcome before clinical application of cell therapy in neurological disease patients is adopted'.12 Such as 'it is still uncertain what kind of stem cells would be ideal source'13 and if stem cell transplantation can increase the chance of recovery have the potential to "struck gold". Another interest to use adult and embryonic stem (ES) cells; is previous experiments and research shows that overall stem cells maintain fundamental properties and plasticity to adapt to any environment given. This is a wide prospect to enhance technology and to improve medicine. Many individuals argued that using stem cell is immoral and unnatural and there have been several debates on the ethical implications of using embryonic stem cells. The uses of adult stem cells do not require destroying an embryo or fetus and can be taken from a specific tissue to be generated.
Looking at clinical studies and trials used on rat or mice models we can see the potential use of using embryonic and adult stem cells. Following to other experiments, the best treatment is to use embryonic stem cell therapy for HD sufferers. 'In contrast to the series of high impact studies in animals model of PD, there are rather few reports of transplanted ES derived stem cells into HD models'.14 The idea was to use stem cells to restore or preserve the brain function by replacing or protecting the striatal neurons and the results was successful and sufficient that these methods are possible to treat individual who suffer from neurodegenerative diseases, such as Huntington's disease, is a great potential. ES cells shows that is very diverse and plasticity is suitable for this treatment. 'Transportation of fetal human brain tissue may serve as a useful strategy for reducing neuronal damage in HD brain, and a recent study has documented improvements in motor and cognition performance in HD patients following fetal cell transplantation'.15 One of the main limiting factor is the ethical issue that is associated with the use of human embryonic tissue and that it's not the transplantation of the fetal striatal that is difficult it is the 'sufficient amounts of embryonic striatal tissue'16 needed for this treatment.
Another best treatment for HD patients is to use NSCs which could replace neurons that have been lost. Instead of using ES cells that adult stem cells has the same fundamental principles to treat neurodegenerative diseases. Vazey et al indicated that 'at the time of grafting, the majority of cells in the neurospheres were phenotypically immature and express the neural progenitor marker'.17 after the cells have been transplanted it has differentiated in vitro and transformed to neurons indicating that the graft have indeed survived. Hence, those NSCs have the ability to 'reduced functional impairments in an animal model of HD'.18 There may be some evidence to show that adult stem cells can developed into neurons or glial cells 'and make synaptic contacts with appropriate target cells' (Toda et al 2001); these observations are rare and reports are limited on models.
The best stem cell treatment for Parkinson's disease is embryonic stem cells rather than adult stem cells. The reason for this is that the application to use cell transplantation in the central nervous system (CNS) has been tested mainly with patients with PD. 'Transplantation of human fetal dopaminergic neurons produce long-lasting improvement in some PD patients. Promisingly, cells with properties of dopaminergic neurons have been generated in vitro from embryonic stem cells and stem cells isolated from bone marrow and fetal brain'.19 This shows that ES cells are efficient and good evidence indicated that replacing striatial cells can provide a function and effective dopamine. As well as 'the prospects of providing regular supplies of large numbers of cells'20 shows that they are efficient.
In recent studies, scientist has shown that neural stem cells in the brain have been an idealistic way to treat Parkinson's disease. This shows that 'a population of neural stem cells/progenitor (NSCs) preserves enough germinal character to maintain neurogenesis throughout'.21 This establishes that NSCs can develop into neural or glial cells from an adult rat. Even though to date, there has been only 'one autologous human NSCs transplanted reported'.22 By adopting this practice we can see that this clinical treatment established 'a true autologous transplantation in an animal model of PD, with ultimate goal of employing this approach for clinical studies'.23
There is another clinical trial, the first to use cell transplantation in PD using adrenal auto grafts. 'In this procedure, one adrenal medulla of the person with Parkinson's disease is removed for dissection of the relevant cells and implanted back into the brain'24 but realistically more studies can benefit this procedure. But, placing into good practical use is limited such as 'to provide sufficient numbers of dopaminergic neurons for one patient with PD, six or seven human fetuses are needed'.25
Neurodegenerative diseases have been using stem cell therapies over the recent years to find suitable and successful treatments. By using embryonic and adult stem cells shows the ability to regenerate loss neurons and glial cells. However, there are more potential researches needed to be carried out on adult stem cells as there are not enough studies to show their true potential. 'NSCs transplantation experiments, to understand the differential efficiencies of different kinds of stem cells in treating PD'.26 This is an exciting new possibility but there are many controversies over the use of embryonic stem cells on 'why oocytes or embryonic or fetal materials should be used to generate stem cells when stem cells could be isolated from adult tissues'.27 This can be argued that embryonic or fetal stem cells are more diverse in cell types and more plastic that adult stem cells. ES cells can provided a better, renewable and sufficient number of cell resources in cell-based therapy for individuals who suffer from neurodegenerative disorder. The ethical issues behind using embryonic stem cells always limit the widespread application and resources in using human clinical trials. 'Transposition of stem cells research to human trial must constitute an ultimate goal'.28 Since, this is limited; there have been alternative methods to provide new treatments for other cell therapeutic application. Such as 'xenografts, stem cells and other genetically manipulated or immortalized cell and cell lines'.29 Using animal models differ from human models and that the level of techniques may differ and the difficult in knowing the plasticity may differ. . 'The ultimate goal of employing this approach for clinical trial'30 is to use human models and no longer use animal models. However, the 'level of optimization is not yet achieved, and the time and effort required'31 is a slow steady process.
The discovery of stem cells has challenged many scientists to become interested in neurodegenerative disease. Studies shows that embryonic stem cells provide better, long-lasting treatment for neurodegenerative diseases than adult stem cells because it is more versatile and the ability to renew and 'remains the one effective source for clinical transplantation at this stage of development of the field, and they remain the gold standard for efficiency'.32