Embryonic stem cell

    Embryonic stem cells (ES cells) are stem cells derived from the inner cell mass of an early stage embryo known as a blastocyst. Human embryos reach the blastocyst stage 4-5 days post fertilization, at which time they consist of 50-150 cells.

ES cells are pluripotent. This means they are able to differentiate into all derivatives of the three primary germ layers: ectoderm, endoderm, and mesoderm. These include each of the more than 220 cell types in the adult body. Pluripotency distinguishes ES cells from multipotent progenitor cells found in the adult; these only form a limited number of cell types. When given no stimuli for differentiation, (i.e. when grown in vitro), ES cells maintain pluripotency through multiple cell divisions. The presence of pluripotent adult stem cells remains a subject of scientific debate, however, research has demonstrated that pluripotent stem cells can be directly generated from adult fibroblast cultures.^[1]

Because of their plasticity and potentially unlimited capacity for self-renewal, ES cell therapies have been proposed for regenerative medicine and tissue replacement after injury or disease. However, to date, no approved medical treatments have been derived from embryonic stem cell research (ESCR). Adult stem cells and cord blood stems cells have thus far been the only stem cells used to successfully treat any diseases. Diseases treated by these non-embryonic stem cells include a number of blood and immune-system related genetic diseases, cancers, and disorders; juvenile diabetes; Parkinson's; blindness and spinal cord injuries. Besides the ethical problems of stem cell therapy (see stem cell controversy), there is a technical problem of graft-versus-host disease associated with allogeneic stem cell transplantation. However, these problems associated with histocompatibility may be solved using autologous donor adult stem cells or via therapeutic cloning.

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Research history and developments

Isolation and in vitro culture

Stem cells were discovered from analysis of a type of cancer called a teratocarcinoma. In 1964, researchers noted that a single cell in teratocarcinomas could be isolated and remain undifferentiated in culture. These types of stem cells became known as embryonic carcinoma cells (EC cells).^[2] Researchers learned that primordial embryonic germ cells (EG cells) could be cultured and stimulated to produce many different cell types.

Embryonic stem cells (ES cells) were first derived from mouse embryos in 1981 by Martin Evans and Matthew Kaufman and independently by Gail R. Martin. Gail R. Martin is credited with coining the term 'Embryonic Stem Cell'.^[3][4] A breakthrough in human embryonic stem cell research came in November 1998 when a group led by James Thomson at the University of Wisconsin-Madison first developed a technique to isolate and grow the cells when derived from human blastocysts.^[5]

Production of male gametes

Researchers at the Whitehead Institute announced in 2003 that they had successfully used embryonic stem cells to produce haploid, male gametes. They found embryonic stem cells that had begun to differentiate into embryonic germ cells and then further differentiated into the male haploid cells. When injected into oocytes, these haploid cells restored the somatic diploid complement of chromosomes and formed blastocysts in vitro.^[6]

Contamination by reagents used in cell culture

The online edition of Nature Medicine published a study on January 23, 2005 which stated that the human embryonic stem cells available for federally funded research are contaminated with non-human molecules from the culture medium used to grow the cells. It is a common technique to use mouse cells and other animal cells to maintain the pluripotency of actively dividing stem cells. The problem was discovered when non-human sialic acid in the growth media was found to compromise the potential uses of the embryonic stem cells in humans, according to scientists at the University of California, San Diego.^[7]

However, a study was published in the online edition of Lancet Medical Journal on March 8, 2005 detailed information about a new stem cell line which was derived from human embryos under completely cell- and serum-free conditions. After more than 6 months of undifferentiated proliferation, these cells demonstrated the potential to form derivatives of all three embryonic germ layers both in vitro and in teratomas. These properties were also successfully maintained (for more than 30 passages) with the established stem cell lines. ^[8]

Reducing donor-host rejection

There is also ongoing research to reduce the potential for rejection of the differentiated cells derived from ES cells once researchers are capable of creating an approved therapy from ES cell research. One of the possibilities to prevent rejection is by creating embryonic stem cells that are genetically identical to the patient via therapeutic cloning.

An alternative solution for rejection by the patient to therapies derived from non-cloned ES cells is to derive many well-characterized ES cell lines from different genetic backgrounds and use the cell line that is most similar to the patient; treatment can then be tailored to the patient, minimizing the risk of rejection.

Potential method for new cell line derivation

On August 23, 2006, the online edition of Nature scientific journal published a letter by Dr. Robert Lanza (medical director of Advanced Cell Technology in Worcester, MA) stating that his team had found a way to extract embryonic stem cells without destroying the actual embryo.^[9] This technical achievement would potentially enable scientists to work with new lines of embryonic stem cells derived using public funding. Federal funding is currently limited to research using embryonic stem cell lines derived prior to August 2001.

See also: Induced pluripotent stem cell

Professor Yamanaka had a recent breakthrough^[10] in which the skin cells of laboratory mice were genetically manipulated back to their embryonic state. This work was confirmed by two other groups, demonstrating that the addition of just 4 genes (Oct3/4, Sox3, Klf4, and Myc) could reprogram mouse skin cells into embryonic stem like cells. The ability to reproduce such findings are very important in science and the stem cell field, especially after Hwang Woo-Suk from Korea fabricated data, claiming to have generated human ES cells from cloned embryos. These cells produced by Yamanaka as well as the other laboratories demonstrated all the hallmarks of embryonic stem cells including the ability to form chimeric mice and contribute to the germ-line. One issue with this work is that the mice generated from these ES lines were prone to develop cancer due to the use of Myc, which is a known oncogene.

On 20th of November, 2007, two research teams, one of which was headed by Professor Yamanaka and the other by James Thompson^[11] announced a similar breakthrough with ordinary human skin cells that were transformed into batches of cells that look and act like embryonic stem cells. This may enable the generation of patient specific ES cell lines that could potentially be used for cell replacement therapies. In addition, this will allow the generation of ES cell lines from patients with a variety of genetic diseases and will provide invaluable models to study those diseases.

While this work is a huge accomplishment for science, there is still much work to be done before this technology can be used for the treatments of disease. First, the genes used to reprogram the skin cells into ES-like cells were added by the use of retroviruses that can cause mutations and lead to the risk of possible cancers. In addition, as shown with the mouse work, one of the genes used to reprogram, Myc, can also cause cancer. The group led by Thompson did not use Myc to reprogram and may not have this difficulty. Future work is aimed at attempting to reprogram without permanent genetic manipulation of the cells with viruses. This could be accomplished by either small molecules or other methodologies to express these reprogramming genes.

However, as a first indication that the induced pluripotent stem (iPS) cell technology can in rapid succession lead to new cures, it was used by a research team headed by Rudolf Jaenisch of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, to cure mice of sickle cell anemia, as reported by Science journal's online edition on 6th of December.^[12]

References

See also

• Embryonic Stem Cell Research Oversight (ESCRO) Committees
• Embryoid body
• Stem cell controversy