Neural Stem Cell Therapy White Paper

neural stem cell whitepaper

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Stem cells are immature, uncommitted cells that are the precursors to all cells in the body. They are distinguished from other cell types by two important characteristics; firstly they are capable of renewing themselves through cell division, often after a long period of quiescence, and secondly they have the ability to become tissue- or organ-specific under particular physiologic or experimental conditions. Stem cells differ according to their source and their malleability, and can be classed as embryonic (derived from the 3-5 day old blastocystic precursors to embryos) or adult in nature. Embryonic stem cells are pluripotent and can develop in to a wide variety of cell types, while adult stem cells are thought to be limited to differentiating into the cell types of their tissue of origin. Adult stem cells have been identified in a wide range of tissues including brain, bone marrow, peripheral blood, blood vessels, skeletal muscle, hair follicles, skin, teeth, heart, gut, liver, ovarian epithelium, and testis; their primary role is to repair and maintain the tissue in which they are found.

Neural Stem Cells (NSC) are the progenitors to the specialised cells of the Central Nervous System (CNS), and can differentiate in to neurons, astrocytes and oligodendrocytes (1). NSCs have been proposed as a promising therapy for the treatment of a wide variety of neuropathologies and brain/spinal cord injuries. Some of these conditions are discussed below:

  • Amyotrophic Lateral Sclerosis (ALS) is the most common adult-onset motor neuron disease. It is characterised by the degeneration of motor neurons, leading to muscle wasting and death within 5 years of clinical diagnosis, and currently has no effective cure. Motor neurons can be generated in culture from NSCs (2), and the transplantation of these has the potential to be a promising approach for the treatment of ALS. A recent study has shown the transplantation of human motor neurons in to the spinal cord of a mouse ALS model delayed the onset of disease and extended the lifespan of the animals (3)
  • Alzheimer’s Disease (AD) is a form of progressive dementia which results in memory loss and behavioural changes. The mechanisms of AD have not yet been fully elucidated, however the disease is routinely confirmed post-mortem through the detection of Aβ plaques and neurofibrillary tangles, which are accompanied by neuronal loss (4). During the early stages of AD NSCs give rise to neurons, but as the disease progresses reduced concentrations of various neurotrophic factors and increased levels of Fibroblast Growth Factor-2 (FGF-2) arrest the development of these newly generated cells (5). AD is an extremely complex condition however NSC transplantation has been shown to increase cognitive function, synaptic connectivity and neuronal survival in models of AD and may be one possible method of combatting the disease (6).
  • Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition which affects how an individual communicates with and relates to other people. Genetic factors are thought to be responsible for some forms of autism, although no specific genes linked to ASD have yet been identified. Neurological factors are also thought to play an important role in the development of ASD, with evidence from Magnetic Resonance Imaging (MRI) studies suggesting that there are abnormalities in the structure and function of the brains of autistic individuals; for example the brains of children with autism are larger than those of control subjects, possibly due to an excessive number of neurons (7). To better understand autism, a condition where multiple defective genes may be involved in the development of the disorder, NSCs could be used as a powerful model system to study synaptic dysfunction (8).
  • Brain tumours can be primary or secondary in nature; a primary brain tumour originates in the brain, while a secondary brain tumour arises as a result of metastasis. The majority of primary brain tumours are initially treated with surgery if they can be removed without causing harm to the surrounding brain tissue, and radiotherapy is often used as a follow-up treatment.  The less invasive method of using drugs to treat brain tumours is notoriously difficult to implement since many chemical agents are unable to cross the blood-brain barrier (BBB). NSCs offer a novel way to overcome this problem as they have the ability to cross the BBB and selectively target brain tumour sites (9). NSCs have also been recently used in studies to develop effective treatments for head and neck squamous cell carcinomas (10).
  • Epilepsy is defined as the tendency to have recurrent seizures, which occur following a sudden burst of intense electrical activity in the brain. Epilepsy can develop as the result of brain damage, or in rare cases due to the presence of a brain tumour, however in around 60% of affected individuals the cause is unknown. Temporal Lobe Epilepsy (TLE) is characterised by recurrent, unprovoked seizures originating from the medial or lateral temporal lobe region of the brain, and around 30% of individuals with TLE are resistant to treatment with anti-epileptic drugs (11). NSC grafts have been shown to ease seizures in a rat model of TLE (12).
  • Multiple Sclerosis (MS) is an autoimmune disease that causes demyelination and axonal damage within the Central Nervous System (CNS), resulting in problems with movement, balance and vision. The cause of MS has not yet been established. An animal model of autoimmune diseases of the CNS, Experimental Autoimmune Encephalomyelitis (EAE), has been used extensively by researchers to evaluate the pathogenesis of MS, and has been shown to enhance the migration of NSCs from the sub-ventricular zone (SVZ) of the brain to give rise to oligodendrocytes in the regions where damage has occurred (13,14). Transplantation of NSCs is a potential cure for conditions such as MS (15).
  • Parkinson's Disease (PD) is a degenerative condition of the CNS, characterised by the loss of dopaminergic neurons within the substantia nigra region of the brain (16). Dopamine is a neurotransmitter that, among other functions, allows messages to be sent to regions of the brain that are responsible for coordinating movement; individuals affected with PD develop an involuntary tremor and motor impairment, and many experience dementia as the disease progresses. Because the cell loss in PD appears to be restricted to one area of the brain, transplantation of NSCs is of interest, and proof-of-principle studies with foetal brain tissue have already shown this to be a viable treatment option (17).
  • Spinal cord injuries most commonly occur as the result of a blow to the back that damages the vertebrae, which then in turn harm the spinal cord. These injuries can be complete (the cord is unable to transmit signals below the level of the injury, and the individual is paralysed) or incomplete (some movement and sensation below the injury remains).  Transplantation of NSCs in a mouse model of spinal cord injury has been shown to restore motor function; in this particular study valproic acid was administered at the time of transplantation to promote the differentiation of the NSCs into neurons rather than glial cells (18).
  • Stroke occurs when the blood supply to the brain is cut off. It is most often caused by a blockage in one of the blood vessels, and is a major cause of disability; physical effects include weakness and paralysis, while cognitive problems affecting memory and communication are also common. The primary cells which are lost with stroke are neurons and glial cells, and the transplantation of NSCs in order to replace these cells has the potential to aid the recovery of stroke patients. NSCs have been shown to survive and differentiate in to neurons in a rat stroke model (19). In a more recent study NSCs engineered to express the anti-oxidant protein SOD1 were successfully transplanted in to mice, where SOD1 played a key role in protecting the NSCs from the reactive oxygen species produced in the brain following stroke (20).
  • Traumatic Brain Injury (TBI) is defined as an injury to the brain caused by trauma to the head, and has wide-ranging effects including cognitive issues, communication problems and emotional difficulties. A mouse model of TBI has shown that NSC proliferation is stimulated within the adult hippocampus following injury, although many of these cells became glial rather than neuronal, indicating that intervention is necessary to increase neurogenesis (21). In a recent study NSCs were co-transplanted with Olfactory Ensheathing Cells (OEC) within a rat TBI model; OEC promote and assist the growth of axons, and in this model system they enhanced NSC survival and improved neurological function (22).

Transplantation of NSCs is a popular approach to the treatment of various neurological conditions, and has been demonstrated with some degree of success in a number of animal model systems. Another method of NSC therapy is to produce pharmaceuticals which could activate dormant NSCs; for example a 2006 study showed the involvement of the Notch and Wnt pathways in activating dormant NSCs within the mammalian retina, and implicated these NSCs as a potential target for manipulation when treating retinal degeneration (23). Other research is focussed on influencing embryonic stem cells to develop specifically into neurons or glial cells; as an example, in 2012 an NSC that resides among normal embryonic stem cell colonies was identified and clonally expanded to produce multipotent NSCs (24).

The 2012 Nobel Prize for Medicine was awarded to Sir John Gordon and Shinya Yamanaka for their discovery of a method of generating induced Pluripotent Stem Cells (iPSC) from somatic cells. iPSC differentiate according to environmental cues, and are a powerful tool for studying cellular development. In terms of neurological research they offer the prospect of providing an unlimited amount of human neurons or astrocytes for drug testing (25).

Before NSC-based therapies can be used in man, it is important that accurate methods are developed for monitoring these cells in vivo. Due to the depth of the brain tissue, and the presence of the blood-brain barrier, in vivo imaging of NSCs in the brain is more challenging than the imaging of stem cells within other tissues, and research is ongoing to establish techniques to track their growth and development (26).

Neural Stem Cell therapy is just one arm of the stem cell research field, but it has huge potential to become a powerful tool in the treatment of a huge diversity of conditions. Novus Biologicals has a wide range of products to aid your research.

PDF download Download the PDF version of the Neural Stem Cell Therapy White paper

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