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Stem Cells in ALS Treatment in Mice
#1
Amyotrophic lateral sclerosis (ALS), common as Lou Gehrig’s disease, is a neurological disease that affects the motor neurons. In ALS, both the upper motor neurons (UMNs) and the lower motor neurons degenerate (LMNs). The disease is characterized by the loss of motor neurons. Motor neurons are subsequently replaced by supporting cells of the nervous system.

Definitive cause of ALS is unknown. Current research focuses on many different possibilities, with some pertaining to enzyme deficiencies, infections, environmental factors, and a whole slew of other possibilities.

Upper motor neurons signs are problems you would foresee with the loss of the normal inhibitory input the UMNs usually have on the LMNs. That would lead one to see a hyperactive state in the musculature, which is indeed the case. Specific findings related to UMN degeneration include hyperreflexia, increased tone, and weakness. As opposed to the UMN, the LMN provides an excitatory component to the muscle groups so that a loss of LMN health leads to a different set of signs and symptoms. LMN signs include fasciculations, atrophy, and weakness. A combination of both UMN and LMN signs often leads a neurologist to consider ALS as the diagnosis, but not before exhausting other possible diagnoses, such as multiple sclerosis, myasthenia gravis, Eaton-Lambert syndrome, and others. For that reason, ALS is termed a diagnosis of exclusion. The ultimate cause of death in ALS patients is the loss of muscle strength to properly breathe.

Treatment

The first drug ever approved for the treatment of ALS is still used today. It is Riluzole. Its exact mechanism of action in prolonging survival in ALS patients is unknown. Riluzole has been shown to decrease glutamate release, preventing any possible toxic effects to motor neurons that could have been caused by overexcitation, something that often involves glutamate. Trials with the drug have shown a median increase in survival time of three months. It should be stressed, however, that Riluzole is by no means a cure for ALS.

The potential for stem cell research lies in the ability to regenerate both UMNs and LMNs. What some researchers emphasize is the importance of understanding the underlying principles, such as the importance of timing and cell delivery, immune modulation, and the need for a multidisciplinary approach. With a better comprehension of these factors, the treatment of amyotrophic lateral sclerosis has a better chance for being successful in patient care.

Neural Stem Cells in ALS Treatment on Mice

Transplantation of neural stem cells or their more mature progeny is considered a potentially curative therapy for patients suffering from neurodegenerative disorders. Because adult neural stem cells, in contrast with fetal neural stem cells, have a more limited capacity to proliferate in vitro, fetal neural stem cells may be the most promising cells for cellular therapy of neurodegenerative disorders. Several studies in animals have transplanted adult neural stem cells. Because the cells receive signals from the brain microenvironment, further maturation to either glial support cells or neurons can be seen. In some cases these cells integrate and contribute to physiological neural circuits. In other cases the cells make glial support cells that can also have significant effects in some animal models of disease.

In a new study, researchers used mice as experimental models. The human neural stem cells were treated with growth factors, and directed to become motor neurons. The mice were treated first with a chemical to induce amyotrophic lateral sclerosis (ALS), and then they received a transplant of the new motor neurons that had been derived from human neuron stem cells taken from human induced pluripotent stem cells.

Pluripotent stem cells are adult cells such as skin cells that have been genetically reprogrammed to an embryonic stem cell-like state. After transplantation, the stem cells migrated to the spinal cord of the mice, matured and multiplied. That study found that human neural stem cell transplantation significantly extended the lifespan of the mice by 20 days and improved their neuromuscular function by 15 percent.

Conclusion

This study showed promise for testing stem cell transplantation in human clinical trials. In amyotrophic lateral sclerosis, motor neurons die, leading to paralysis. In preclinical animal work, neural stem cells made synaptic contact with the host motor neurons and expressed neurotrophic growth factors, which are protective of cells. By analogy to mice neural stem cells, these observations may allow the development of neural stem cells transplantation for a range of disorders. In the future, patients with ALS will be treated with injection of human fetal-derived neural stem cells into the lumbar region of the spinal cord, where they will exert a neuroprotective effect. However, since the preclinical date (safety, dosage, long-term survival, post-mortem biopsy) are insufficient and clinical evidence of improvement is weak, more preclinical studies are needed prior to the development of further clinical applications. Neural stem cells may be the best way to avoid the problems. They can self-renew, make more neural stem cells and differentiate into nerve cells, in this case into motor neurons. They can also rescue nerve cells that don't work properly and help preserve and regenerate neural tissue.

There are currently no clinical trials, but a few unpublished efforts have been disclosed using neural stem cells in humans. With all the excitement and possibilities stem cells have to offer as a therapy, it is important that scientists and clinicians are careful, plan severe studies and most importantly focus on laboratory experiments that will provide answers to the many challenges that still face this therapeutic approach. To be safe and have potential in the clinic, it is important that the appropriate studies are conducted to learn more about the properties and complexities of the various stem cells.
#2
Amyotrophic lateral sclerosis and stem cell transplantation

The original article in this thread highlights the potential of stem cell transplantation for treatment of the devastating neurological disease, amyotrophic lateral sclerosis (ALS), in which motor neurons degenerate with ultimately fatal effects. Identifying reliable sources of stem cells is important in this field. Two very recent papers on mouse models have given promising results.

The first study examined the possibilities of reprogramming adult somatic cells into induced pluripotent stem cells (iPSCs), and hence isolation of specific neural stem cells (NSC). These cells were transplanted into ALS model mice via intrathecal or intravenous injections and in both cases were found to migrate to the central nervous system from where they induced phenotypic improvements compared to control mice, including improved neuromuscular function and motor unit pathology, as well as increased life span. The mechanism behind the improvement appeared to have multiple elements including increased production of neurotrophic factors and reduction of gliosis with a decrease in astrocyte number via the vanilloid receptor TRPV1.

The other study looked at human adipose tissue-derived stem cells (ASC) in an SOD1G93A mouse ALS model. Human ASCs were transplanted into these animals and after four weeks the animals were sacrificed. Migration of human ASC to the lumbar spinal cord was confirmed. Similarly to the other study, delay in onset of clinical symptoms and increased life span was observed in mice transplanted with ASC by an ICV route compared to control mice. Again similarly, up-regulation of neurotrophic factors such as NGF, BDNF, IGF-1 and VEGF was observed and this was found to decrease apoptosis in in CNS and ALS spinal cord cells that were cultured subsequently.
Both these studies confirm the potential of stem cell transplantation for ALS therapy and identify potentially useful stem cell sources.

Sources

KIM, K.S. et al., 2013. Transplantation of human adipose tissue-derived stem cells delays clinical onset and prolongs life span in ALS mouse model. Cell transplantation
,
NIZZARDO, M. et al., 2013. Minimally invasive transplantation of iPSC-derived ALDHhiSSCloVLA4+ neural stem cells effectively improves the phenotype of an amyotrophic lateral sclerosis model. Human molecular genetics
#3
Some great trials for neural stem cells and ALS are being run by the American Neurological Association head Eva Feldman at the University of Michigan and elsewhere. Great results are being posted.
  

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