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Full Version: Direct Transformation of Adult Stem Cells to Neural Progenitors
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The use of stem cells for treating injuries and disease has many potential complications. Stem cells, whether embryonic, adult, or induced, could potentially turn into any cell in the body. If this occurs after transplantation into a patient, the consequences could be severe. A central nervous system injury, for example, might end up with muscle cells growing around, reducing the likelihood that the injury could be repaired in the future. In addition, due to their highly proliferative nature, stem cells could potentially cause the development of cancerous tumors.

Stem cells transplants from adult cells have a major advantage over embryonic stem cells. A patient could act as a self donor to procure adult stem cells or induced pluripotent stem cells, thereby negating any possible transplant rejection. Embryonic stem cells cannot be obtained directly from the patient, and could possibly be rejected by the recipient. In addition, preparation of stem cells requires a great deal of work and expertise. Embryonic stem cells must be obtained by the destruction of an embryo, which may be ethically questionable. Adult stem cells are mostly obtained from bone marrow, and produce blood cell precursors. These blood cells are not appropriate for treating many disorders outside of the circulatory system. Induced pluripotent stem cells are derived from normal adult cells, which must be reverted to a more embryonic like state. Once they have been reverted, the cells must then be matured into the desired cell type, and expanded in tissue culture.

Researchers from the University of Wisconsin at Madison recently found a method to directly convert normal adult skin cells from both monkeys and humans into neural progenitor cells, without requiring a pluripotent stem cell intermediate. The neural progenitor cells that were produced are able to mature into a variety of neural cells, and can propagate easily in tissue culture as well as the host. A major advantage to this method is that fewer steps are required to develop the desired cell type. In addition, a patient could donate his or her own cells for the procedure, reducing the risk of transplant rejection. The researchers exposed the adult skin cells in culture to a virus called Sendai virus. Sendai virus is advantageous over other viral vectors used during cell reprogramming, because the genetic information of the virus does not become a permanent part of the cell. This is a safer approach than the use of other viral vectors, which have been linked to tumor formation in previous studies.

After the adult skin cells were treated with virus for twenty four hours, the culture was exposed to moderate heat. The heat was sufficient to kill the virus, but not the cells. This is another advantage to procedure, as no live virus is present when the cells are injected into the patient. The researchers were able to isolate neural progenitor cells, which can further mature and differentiate into nerve cells. The neural progenitor cells proliferate easily in culture as well as in the body. Because they have already begun the process of maturation, there is no risk of the cells turning into different tissue types once injected into a patient. The neural progenitor cells were then injected into newborn mice, and proliferated as normal. There were no apparent defects from the neural progenitor cells, such as tumor formation or the production of unwanted tissues.

Any advances made that help develop cells that can be used to therapeutic purposes are always welcome. However, like many other methods of producing neural cells, this method has some drawbacks. Using a virus to induce cellular reprogramming is always worrisome. The body’s cells have special methods to fight viral infection. Even skin cells can produce an innate response that would decrease cellular replication and turn off certain parts of the cells protein making machinery. This helps prevent the virus from growing in the host. The skin cells are able to produce certain proteins that can cause effects on other nearby cells, and may lead to inflammation. This immune response by the cells may actually prove problematic in large scale production of neural progenitors. In addition, if the virus is not sufficiently killed before the cells have been injected into the patient, this could cause serious consequences. Many patients requiring transplants are given immune-suppressant drugs, leaving them at high risk for complications due to infection. Finding the right balance between destroying the virus without harming the newly developed cells will be important before this treatment can be utilized in humans.

Stem cell therapy and the brain

The current interest in stem cell therapy for neurodegenerative diseases, such as in the study described in the previous article, has partially arisen due to the recognition that the dogma that the brain is a static organ with no possibility of cell regeneration in damaged areas is not true. It is now recognised that the adult brain can generate new neurons. Animal models and other studies have prompted hope that neural stem cell therapy will be a breakthrough in treatment of all kinds of neurodegenerative diseases. Results in some cases are promising, but it is important to recognise problems and limitations in the field as well.

In the case of Parkinson's disease, in which dopaminergic neuron cells are lost, promising results have been obtained in rat models of the disease. Rat neural stem cells were constructed to endogenously express the growth factor neurotrophin-3 (NT-3). These cells, termed rNSC-NT3, were transplanted into the Parkinson's disease model,
6-hydroxydopamine (6-OHDA)-treated Parkinsonian rats. Results indicated this reversed the main symptoms of the Parkinson's disease and apomorphine-induced rotational asymmetry and improved spatial learning ability. Furthermore, rNSC-NT3 were able to differentiate into dopaminergic neurons in different areas of the brain and exerted positive effects on neural stems cells via endogenously expressed NT-3. Thus, stem cells expressing NT-3 endogenously would appear to be a good candidate for stem cell therapy in Parkinson's disease. Parkinson's disease is considered to be one of the more promising neurodegenerative diseases for targeting with adult stem cell therapy.

Recent studies have considered the possibilitis for stem cell therapy in autism. A study to determine the safety and efficacy of combined transplantation of human cord blood mononuclear cells (CBMNCs) and umbilical cord-derived mesenchymal stem cells (UCMSCs) in children with autism was recently published in the Journal of Translational Medicine. No safety issues were observed. Treatment groups who received either CBMNC with rehabilitative therapy or both CBMNCs and UCMSCs with rehabilitative therapy showed signifincant therapeutic effects on measures including the Childhood Autism Rating Scale (CARS), Clinical Global Impression (CGI) scale and Aberrant Behavior Checklist (ABC) compared to the control, untreated group.

One drawback in adult stem cell therapy involves the relative scarcity of adult stem cells and also the difficulties inherent in harvesting them. One surprising suggestion for a potential source of neural stem cells are tooth tissues, which are accessible and provide a source of neural crest-derived ectomesenchymal stem cells (EMSCs). These have been successfully used in regenerative dentistry, however they have been suggested as potential sources for neural regeneration as they are highly proliferative and retain a neural-like phenotype in vitro. The local tissue and cell environment can also be a drawback in potential use of stem cell therapy in neurodegenerative diseases. For example, in the case of Amyotrophic lateral sclerosis (ALS), a motor neuron disease with devastating symptoms, in vitro co-culture systems suggest that reactive oxygen and nitrogen species released from the endogenous overactivated microglia directly destroy transplanted human neural stem cells.

Adult neural stem cell transplantaion is an area of promise in treatment of neurodegenerative diseases, but there are still problems to be overcome.


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