30 March 2012

Stem cells in the treatment of neurodegenerative diseases (1)

Article by Dantuma et al. Stem cells for the treatment of neurodegenerative diseases
published in the journal Stem Cell Research & Therapy 2010, 1:37.
Translated by Evgenia Ryabtseva

Stem cells, their capabilities and limitations

ResumeStem cells provide an incredible number of opportunities to improve our understanding of the mechanisms of functioning of the human body.

One of the considered options for the use of stem cells is autologous therapy. A certain interest is attracted by the possibility of using stem cells for the treatment of neurodegenerative diseases. In the coming years, the volume of clinical use of stem cells for the treatment of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis will increase and, despite the need to be extremely careful when promoting potential therapeutic approaches, there are huge prospects for the use of stem cells.

IntroductionSince its discovery, stem cells have changed the way specialists think about the human body and have revolutionized the field of medical research.

Since then, the understanding of the processes of development and repair of damage to the human body has improved significantly [1]. Thanks to this, we have the opportunity to expand the prospects for the use of stem cells in the human body. The result of this was an increased interest in the therapeutic use of stem cells [1].

Interest in research on the use of stem cells for the treatment of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis is constantly growing in the medical environment. Each of these diseases affects different areas and structures of the central nervous system. The use of stem cells, in the form of replacement or protective therapy, for the treatment of each of these diseases has great potential.

Stem cells, opportunities and limitations of their useStem cells were discovered in the early 60s of the last century [2,3], and the study of their characteristics and composition took a very long time.

In general, stem cells are defined as cells capable of self-renewal and differentiation into cells of various types. Based on the ability to differentiate, stem cells can be classified as totipotent, pluripotent or multipotent. Totipotent cells can differentiate into any type of body cells, including extraembryonic tissues. They can only be isolated from an embryo at the 4-cell stage.

Isolated from the blastocyst, pluripotent cells can differentiate into any cell of the body, that is, they are able to give rise to cells of any of the three main germ leaves: ectoderm, mesoderm and endoderm. Multipotent cells can only transform into certain types of cells. They can be isolated from various tissues of the adult human body. As an organism develops, the ability of its stem cells to differentiate gradually decreases from totipotency to pluripotency and, eventually, to multipotency.

Naturally occurring stem cells mainly include embryonic stem cells (ESCs), fetal stem cells and adult stem cells. The embryonic stem cells obtained from the blastocyst are pluripotent and reproduce quite well in culture. Thus, they meet two important requirements: the possibility of obtaining a large number of cells and the ability to give rise to cells of various types [4]. Based on this, embryonic stem cells are the most attractive for use in clinical settings, but their use raises many ethical issues [5,6] and is associated with the risk of developing undesirable side effects, such as immune reactions, tumor formation, or both [7].

Multipotent cells can be isolated from fetal organs. Their advantages include the ability to adapt to the environment, the ability to migrate, and the absence of the risk of teratoma formation and rejection in the conditions of the body [8].

Traditionally, adult stem cells are defined as multipotent cells whose ability to differentiate is determined by the tissue in which they are contained. Endogenous populations of adult stem cells are part of a large number of body tissues, including bone marrow, muscle tissue, brain and liver [1]. The main advantage of these cells is the possibility of their use for autologous therapy, in which the cells are isolated from the patient himself and subsequently used for his own treatment. This excludes any ethical issues and risks associated with the use of embryonic cells. However, despite their apparent attractiveness, the limited ability to differentiate does not allow adult stem cells to become a universal therapeutic agent.

Due to the limitations associated with the use of natural stem cell variants, researchers have developed a method to increase the pluripotency of non-pluripotent cells. The cells obtained as a result of such reprogramming with the help of specific transcription factors Oct4, Sox2, Klf4 and c-Myc [9-12] were called induced pluripotent stem cells (iPSCs). Some experts claim that only two of these factors are sufficient to obtain iPSC [13,14]. Induced UCS make it possible to use the patient's own reprogrammed somatic cells for therapeutic purposes. However, the possibilities of using iPSC are also limited.

Firstly, the process of creating such cells is ineffective [15]. Therefore, at the initial stage of work, obtaining a large number of initial cells can cause certain difficulties.

Secondly, the use of viral vectors for the transduction of pluripotency factors creates a problem of their possible integration into the cell genome [16].

Finally, iPSCs can give rise to teratomas, although this risk is lower compared to the risk associated with the use of embryonic cells [16].

Researchers have made a number of attempts to overcome these difficulties.

The reason for the low efficiency of IPSC reprogramming may be related to p53-mediated DNA damage [17], therefore, inhibition of p53 activity may increase the yield of iPSC, but it is associated with an increased risk of tumor formation.

The second problem was tried to be solved by two methods. One of them is the use of non-viral transfection [18], however, in this case, the problem of low efficiency persists, and long-term control of gene expression may be problematic. The second approach involves the use of viruses removed by the enzyme Cre-recombinase [19], or the introduction of a recombinant protein [20]. However, scientists still have to prove the functionality and safety of the resulting cells, and other difficulties may arise when developing therapies based on the use of stem cells, but the future of this direction is very promising.

Continuation: therapy of neurodegenerative diseases and stem cells.

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