Motor endogenous neuron. This includes the genomic expression

Motor neuron disease (MND), otherwise referred to as Amyotrophic lateral sclerosis (ALS) or Lou Gehrig’s disease, is characterised by steady motor neuronal death and progressive muscular dysfunction. In more advanced forms of MND, the effector neurons which control muscles involved in inspiration and expiration may also become affected by motor neuron loss which can be detrimental to one’s health.

Despite the causes remaining idiopathic, MND patients usually possess motor neurons which contain unusually large clumps of protein such as TDP-43; a neurotoxic DNA binding molecule which regulates mRNA translocation (see Fig.9). In fact, TDP-43 in its hyper-phosphorylated form is closely correlated with frontotemporal dementia and ALS. Over 150 mutations in the SOD1 gene also align with motor neuron degeneration. SOD1 itself is a rather ubiquitous enzyme involved in converting O2-  free radicals into Hydrogen Peroxide.

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However, certain mutations result in mutant pathogenicity as the protein aggregates within motor neurons, as well as by stopping the enzyme from conducting its programmed antioxidant function. From my perspective, an effective stem cell therapy for MND should primarily aim to replenish one’s motor neuron network in addition to protecting existing functional neurons.This hypothesis was investigated further in one study which examined how adult neural stem cells could be manipulated to differentiate into functional motor neurons.

The stem cells were extracted from the subependymal layer of a mature rodent model; brain tissue saturated with multipotent cells. Their cell culture first involved exposure of the stem cells to several factors such as ciliary neurotrophic factor and thyroid hormone T3 to initiate neuronal differentiation. However, to enhance the developmental capabilities of this lineage, a secondary culture was conducted which involved the neural stem cells being exposed to platelet derived growth factor to accelerate maturation.When evaluating the post-transplant data, one must appreciate how most of the fluorescently-tagged neural stem cells displayed all of the vital structural characteristics of an endogenous neuron. This includes the genomic expression of MAP2, GFAP and GalC – all of which play a key role in neurogenesis and myelin-formation. The supraphysiological expression of GalC is most important in my view, due to its strong links with accelerated reconstitution of neural tissue.

A control group of embryonic progenitor cells were also tested to enable cross-comparison of the cell types. After comparing their morphological properties (see Fig.10), I believe that subependymal neural stem cells could be equally effective as embryonic lineages without the added risk of teratoma formation. Human neural stem cells exposed to the same transcriptional factors were explored under greater scrutiny in another study. Here, they were transplanted via lumbar graft into mice whom carried a mutation in SOD1 resulting in over-expression of this gene.

This established an almost identical pathological environment when compared to brain and spinal tissue of MND patients.On average, 68.4% to 75% of the neural stem cells successfully survived the migration and specialisation phase from the lumbar parenchyma into the spinal cord grey and white matter.

However, in my regard the most important discovery was the formation of functional synapses with endogenous motor neurons. This is distinctly exemplified in Fig.11, in which the green region signifies postsynaptic choline acetyltransferase while the red region identifies where neural stem cells have formed synaptic terminals containing human synaptophysin. To evaluate the implications of this level of synaptogenesis, I believe that one must first comment on the updated Kaplan-Meier curves of the mice transplanted with the stem cells. Disease longevity in these test models is standardised as 22.1 days with a standard deviation of 3.5 days. However, the test subjects lived an average of 7 days longer than expected (29.

4 ± 4.6 days) with a p-value of only 0.0469. Moreover, when cross-comparing a control group of mice with the same mutation, those who underwent the therapy experienced much slower muscular dysfunction as well as increased synaptic density in the spinal cord. In my opinion, these findings exemplify how lumbar grafting of adult neural stem cells can not only extend disease longevity and induce synaptogenesis, but can simultaneously decrease the rate of muscular dysfunction in the host. Related to this, I think it is important to appreciate that this study revealed how combined lumbar and cervical grafts are also feasible sites of transplantation for MND induced rodents, and potentially patients suffering from this illness. With regard for the synapses formed, more than half of the stem cell-derived neurons expressed important GABA neurotransmitter phenotypic characteristics.

As a result, I think that the formation of new synapses would massively reduce the effects of MND in patients through ‘buffering glutamate transmission’. This theory is based on the idea that ‘excitotoxicity’ contributes to neuronal degeneration. Although, one could argue that the magnitude of stem cell induced-synaptogenesis is largely limited by the secretion of neurotrophic factors. In particular, I think that more motor neuron-trophic factors must be secreted in order to aid the survival of already diseased motor neurons. Considering this, I conclude that this form of treatment would be very useful as a preventative measure rather than simply as a reactionary treatment in response to the onset of MND.

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