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> Inducible pluripotent stem cells Issue: 2011-1 Section: University

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Inducible Pluripotent Stem Cells

 

Ana Maria IOAN

 

During the last decades the scientific community has made many efforts in order to develop new effective therapy techniques. Health care, transforming as early as possible scientific knowledge into solutions and augmenting life expectancy have become nowadays a primary objective. At the moment investigating with stem cells is a solution, but this type of investigations is conditioned by the society in which we live.

Investigation has made possible obtaining a series of cells that have the capacity of growing and differentiating in laboratory conditions. The mentioned cells are no others than stem cells that can be derived from embryos, from fetuses or from the adult organism. Stem cells are defined as totipotent, pluripotent or multipotent cells which have the capacity of generating one or more types of differentiated cells.

Moreover, a stem cell possesses the capacity of self-renovation. There are three main sources for these cells:

·  Our own body, which possesses a number of undifferentiated cells in some of its organs;

·  Gonadal cells coming from aborted fetuses;

·  Blastocyst phase embryos (between 5 - 14 days after its conception)

The main use of this type of cells is in regenerative medicine. Nevertheless the provenience of stems cells brings with it ethical problems that make their use and application more difficult. However an alternative to this problem has been encountered by the Japanese scientist Shinya Yamanaka in 2006. His discovery are the inducible pluripotent stem cells (IPS), known as IPS. These cells are a type of stem cells that acquire pluripotent qualities. They derive from differentiated cells, with no pluripotential characters, normally adult somatic cells in which the expression of certain genes is induced. In fact, the cell’s DNA is reprogrammed in order to become a stem cell that can differentiate into any type of cell. The antecedent of the IPS has been found in the technique of generating adult animal

clones and it is that of nuclear transfer. The first example of this technique is Dolly, the sheep. The procedure consisted in obtaining the nucleus of a mammary gland cell of an adult white sheep and eventually introducing it into a previously enucleated oocyte of a black sheep. The obtaining oocyte was transferred to the uterus of a third black sheep, which would be the adoptive mother of the embryo. The result was that Dolly was a white sheep, a demonstration that it was a clone of a white sheep and not the natural embryo of a black sheep (1). Obtaining an IPS consist of a process which involves reprogramming the nucleus of the cell instead of eliminating it.

Nuclear reprogramming consists of changing the gene expression so that the cell converts to a completely different cell type. For example, by using this method, an epithelial cell can transform into a hepatocyte or a neuron. Pluripotency can be induced in these cells. The Japanese investigator was the father of this type of reprogramming using a series of transcription factors, known as Oct3/4, Sox2, c-Myc and Klf4.

It was back in 2006 when for the first time a positive result was obtained in creating an induced stem cell (using mouse cells)(2).

Cellular transformation is realized using viral vectors: retrovirus (or lentivirus) that can carry the gene sequence of the four transcriptional factors. Because of the use of this type of vectors the possibility of clinical applications is limited due to the risk of mutations and cancer. Despite this fact, Yamanaka himself tried to solve the problem without using viral vectors and he managed to do so in 2008 (5).

Clinical applications may consist in the next therapeutic scheme: if a patient suffers a disease that affects one type of cells in particular, healthy cells could be taken from him and reprogrammed in order to obtain IPS that would differentiate into the affected cellular type and could replace the damaged cells repairing them. One of the great advantages that this technique brings is that it maintains the immunitary identity of the cells. For example, the IPS can be of use in the case of diagnostic probes and prenatal treatment of genetic diseases. In diagnostic probes amniotic fluid cells and cells from the chorionic villus are used. If these cells were reprogrammed to IPS they could be used in early treatment of the affected fetus. In the second place IPS could be the solution for treating type 1 diabetes, which nowadays affects an important percentage of the population. The therapy would consist in replacing b - cells. For this the IPS obtained from the same patient would differentiate into insulin producing cells. The IPS could also be the solution for cardiac and neurologic diseases.

The discovery of IPS and their continuous development bring a series of advantages and inconveniences. The principal disadvantages are the prospective power of transmitting viral diseases and generate tumors (because of the use of c-Myc which is a known oncogene), but there are also disadvantages of ethical nature, given that these cells could be used to generate germinal cells and therefore create human beings. However, this last use would imply difficult techniques and it would be too early to talk about ethical implications.

The advantages of the IPS consist in their high genetic homogeneity, which favors their possible clinical use, given that they do not induce an immunological response. Moreover they offer the possibility of creating a personalized treatment for each patient. The IPS also provide a less expensive method, taking into account the fact that their obtaining does not imply human oocytes, hence the technique is easier. This fact brings us to the previous ethical point, which this time would cause no polemic given that the IPS are obtained in the laboratory, without the sacrifice of human embryos.

Even though not much is known about the future of the IPS we have to take into account that investigations started in 2006, which is a short period of time ago. We have to hope and we have to provide methods in order to animate and inspire investigation on this subject, which has such a noble purpose as saving human life.

 

Bibliography

  1. Nombela C. Células Madre. Madrid: Editorial Edad; 2007.
  2. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult firoblast cultures by defined factors. Cell. 2006; 126 (4): 663-76.
  3. Yamanaka S. A fresh look at IPS cells. Cell. 2009; 137: 13-17.
  4. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007; 131 (5): 861-72.
  5. Okita K, Nakagawa M, Hyenjong H, Ichisaka T, Yamanaka S. Generation of mouse induced pluripotent stem cells without viral vectors. Science. 2008; 322 (5903): 949-53.
  6. Ye L, Chang JC, Lin C, Sun X, Yu J, Wai Kan Y. Induced pluripotent stem cells offer new approach to therapy in thallasemia and sicke cell anemia and option in prenatal diagnosis in genetic diseases. 2009; PNAS. 24(106):9826-9830.
  7. Maehr R, Chen S, Snitow M et al. Generation of pluripotent stem cells from patients with type 1 diabetes. 2009; 37(106):15768-15773.
  8. Martinez Fernandez A, Nelson JT, Ikeda Y, Terzic A. c-MYC independent nuclear reprogramming favors cardiogenic potential of induced pluripotent stem cells. J Cardiovasc Transl Res. 2010 February 1; 3(1): 13–23.
  9. Osakada F, Takahashi M et al. In Vitro differentiation of retinal cells from human pluripotent stem cells by small-molecule induction. Journal of Cell Science 2009; 122: 3169-3179.
  10. López Moratalla N. Cuad. Bioét. XIX, 2008/2.

 

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Ana Maria Ioan :: 24/10/2011 :: Pageviews: 4335