Embryonic Stem Cells (ES cells)

Every as yet undifferentiated cell with the capacity for proliferation and differentiation is called a stem cell. According to their origin, stem cells are divided into embryonic (from an embryo), fetal (from a fetus) and adult (from newborn babies, children or adults) stem cells.

The capacity of stem cells to form all different cell types of the body is called pluripotency. However, no independent organism can be created from these cells. Only the cells up to the so-called 8-cell-stage after the fertilisation of the ovum are totipotent and thus able to create an independent organism out of every single cell.

The pluripotent, undifferentiated stem cells develop into the so-called tissue-specific stem cells, which are able to quickly substitute specialised tissue. These tissue-specific stem cells are needed in all organs with a high turnover of cells where the specialised cells are not able to proliferate themselves (e.g. red blood cells, intestinal epithelium cells, skin cells and muscle cells).

The tissue stem cells therefore ensure essential functions in the permanent regeneration of such tissues and organs. In the course of further of development and differentiation, the potential of the stem cells to differentiate into different cell types is decreased. This means that they are then unable to develop into different tissues.

Embryonic Stem cells (ES cells) are prepared from the inside of fertilised ova that are a few days old. Up to the 8-cell-stage (morula, day 3 after fertilisation), the cells of the embryo are totipotent. This union of cells then develops into the blastocyst, and on the fourth day of development after fertilisation, the pluripotent embryonic stem cells can be isolated from the inner cell mass of the blastocyst for research purposes.

In the blastocyst, the 3 germ layers are formed out of which all tissues and organs of the body develop. The endoderm develops into the organs of the gastro-intestinal tract, the mesoderm into bones, muscles, blood vessels, heart and kidneys, and the ectoderm into skin, eyes, glands, and the central nervous system. The ES cells generated from the inner cell mass of a blastocyst can also differentiate into the various tissues in the laboratory („in vitro“).

One of the main characteristics of ES cells is their – theoretical – ability to proliferate endlessly. An enzyme called telomerase seems to be responsible for this ability. Terminally differentiated tissue-cells, which do not express this enzyme, have only a limited capacity for proliferation, because the ends of the chromosomes, the telomers, become shorter with every cell division and the further lifetime of the cells is therefore limited.

Embryonic stem cells are gained once from the inner cell mass of the blastocysts, i.e. before being embedded in the uterus (pre-implantation embryo). Afterwards, they can be reproduced and differentiated as long as desired in the cell culture by means of defined protocols. Consequently, pluripotent embryonic stem cells have three decisive advantages over standard systems:
Under the corresponding cultural conditions, they can be permanently maintained in an undifferentiated, proliferative condition.

  1. They therefore represent an inexhaustible source for the generation of tissue material.
  2. They are pluripotent, i.e. they can be differentiated into almost all organotypical cells – inter alia heart muscle cells (cardiomyocytes), skeletal muscle cells, smooth muscle cells, neurones, glia cells, endothel cells (cells that form blood capillaries), blood cells, and in cartilage cells. This normally occurs in the „embryoid body“ process by means of the so-called hanging drop method or in the new mass culture procedures.
  3. They allow a simple genetic manipulation, i.e. genetic information can be brought into the ES cell DNA („gain of function“) or removed („loss of function“).

Potential therapeutic approaches

Therapies like the use of heart tissue from ES cells in the case of heart attacks that rely on embryonic stem cells involve many imponderables (e.g. tumor formation) and are at such an early pre-clinical stage of development that a commercial application cannot be expected during the next few years. Scientists at AXIOGENESIS® and the University of Bonn were able to demonstrate a significant survival advantage following transplantation with cardiomyocytes in a mouse model for the first time.

However, it has also emerged in the process that it is necessary to inhibit the growth of the ES cells in genetic interventions. If this step is not carried out, an embryonic tumour develops in all transplanted animals: a so-called Terato-carcinoma [Kolossov et al. 2005, Journal of Experimental Medicine].

Embryonic stem cells – from mammals and from humans – can in the best case reproduce themselves in a stable way in the cell culture (as a cell line) over a period of months to years and can theoretically develop into all tissue types of the human body. In 1998 James Thomson from the University of Wisconsin has isolated human embryonic stem cells for the first time.

Yet even if all these obstacles are some day overcome, a great problem still exists with all therapies involving embryonic stem cells: the immune response of the recipient. For just as is the case today with a heart or kidney transplantation with tissue from an external donor, the embryonic stem cells are also not cells from the recipient‘s own body and are likely to be recognized as alien and attacked by the immune system.

George Daley, who conducts research at the WHITEHEAD Institute in Cambridge, Massachusetts into the embryonic stem cells of the mouse, can imagine that one might be able to administer strong immune-suppressive agents, as one also does for organ transplantations today. But since these medicines have numerous side effects, one will have to develop other methods, according to Daley.

Conceivable, yet pure fantasy at the moment, would be a genetically engineered modification of the foreign embryonic stem cells so that they are no longer identified as such by the immune system, or some kind of „education“ of the recipient immune system to accept the foreign cells. 

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