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.

Embryonic Stem (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. [cite journal | url=http://www.cell.com/content/article/abstract?uid=PIIS0092867406009767 | title=Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors | author=Department of Stem Cell Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto | date=August 25, 2006 | journal=Cell ]

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.

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). [cite journal | author = Andrews P, Matin M, Bahrami A, Damjanov I, Gokhale P, Draper J | title = Embryonic stem (ES) cells and embryonal carcinoma (EC) cells: opposite sides of the same coin | journal = Biochem Soc Trans | volume = 33 | issue = Pt 6 | pages = 1526–30 | year = 2005 | pmid = 16246161 | doi = 10.1042/BST20051526] 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'. [cite journal | author = Evans M, Kaufman M | title = Establishment in culture of pluripotential cells from mouse embryos | journal = Nature | volume = 292 | issue = 5819 | pages = 154–6 | year = 1981 | pmid = 7242681 | doi = 10.1038/292154a0] [cite journal | author = Martin G | title = Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells | journal = Proc Natl Acad Sci U S A | volume = 78 | issue = 12 | pages = 7634–8 | year = 1981 | pmid = 6950406 | doi = 10.1073/pnas.78.12.7634] 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. [cite journal | author = Thomson J, Itskovitz-Eldor J, Shapiro S, Waknitz M, Swiergiel J, Marshall V, Jones J | title = Embryonic stem cell lines derived from human blastocysts | journal = Science | volume = 282 | issue = 5391 | pages = 1145–7 | year = 1998 | pmid = 9804556 | doi = 10.1126/science.282.5391.1145]

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". [cite journal | journal=Nature | date=January 8, 2004 | volume=427 | pages=148–154 | title=Derivation of embryonic germ cells and male gametes from embryonic stem cells | doi= 10.1038/nature02247 | author=Geijsen, Niels ]

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. [ [http://www.nature.com/nm/journal/v11/n2/pdf/nm1181.pdf Access to articles : Nature Medicine ] ]

However, a study 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. [ [http://www.thelancet.com/journals/lancet/article/PIIS0140673605664732/fulltext Lancet Medical Journal] ]

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. [cite journal | author = Klimanskaya I, Chung Y, Becker S, Lu SJ, Lanza R. | title = Human embryonic stem cell lines derived from single blastomeres| journal = Nature | volume = 444 | issue = 7118 | pages = 481–5 | year = 2006 | pmid = 16929302 | doi = 10.1038/nature05142] This technical achievement would potentially enable scientists to work with new lines of embryonic stem cells derived using public funding in the USA, where federal funding is currently limited to research using embryonic stem cell lines derived prior to August 2001.

Professor Yamanaka had a recent breakthrough [cite news | url=http://www.zangani.com/node/735 | title=Human stem cells may be produced without embryos ‘within months’ | date=2007-07-17 | publisher=Zangani] 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, Sox2, Klf4, and c-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 Thomson [cite news | title=Embryonic stem cells made without embryos | url=http://www.reuters.com/article/newsOne/idUSN2058175020071121 | date=2007-11-21 | publisher=Reuters] 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, although recent research by professor Yamanaka's research group has made advances in avoiding this particular problem. [cite news | title=Researchers get closer to safe stem cell treatments | url=http://afp.google.com/article/ALeqM5hA2tIpd1cGv2Y4H-21nArfgM98cA | date=2008-02-14 | publisher=AFP]

In addition, as shown with the mouse work, one of the genes used to reprogram, Myc, can also cause cancer. The group led by Thomson 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. [cite news | url=http://www.washingtonpost.com/wp-dyn/content/article/2007/12/06/AR2007120602444.html | title=Scientists Cure Mice Of Sickle Cell Using Stem Cell Technique: New Approach Is From Skin, Not Embryos | author=Rick Weiss | publisher=Washington Post | date=2007-12-07 | pages=A02]

On January 16, 2008, a California based company, Stemagen, announced that they had created the first mature cloned human embryos from single skin cells taken from adults. These embryos can be harvested for patient matching embryonic stem cells. [cite news | url=http://news.bbc.co.uk/2/hi/science/nature/7194161.stm | title=US team makes embryo clone of men | author=Helen Briggs | publisher=BBC | date=2008-01-17 | pages=A01]

References

External links

* [http://dels.nas.edu/bls/stemcells/booklet.shtml Understanding Stem Cells: A View of the Science and Issues from the National Academies]
* [http://www.adultstemcells.info Scientific Information on Adult & Embryonic Stem Cells and Cloning]
* [http://www.nature.com/stemcells Nature Reports Stem Cells] Introductory material, research advances and debates about stem cell science]
* [http://www.tellmeaboutstemcells.org Tell Me About Stem Cells]
* [http://health.msn.com/healthnews/articlepage.aspx?cp-documentid=100143549&GT1=8404 Health MSN article on new stem cell extraction]
* [http://humanEScellbook.com Harvard Stem Cell Institute's guide to growing and manipulating human embryonic stem cells]
* [http://stemcells.nih.gov/ National Institutes of Health]
* [http://www.stemcellcordblood.net Stem Cell and Cord Blood information database]
* [http://www.researchchannel.org/prog/displayseries.aspx?pID=868&fID=1649 Understanding Biomedical Research Series] The Howard Hughes Medical Institute presents leading scientists discussing groundbreaking biomedical research
* [http://fr.wikipedia.org/wiki/Andr%C3%A9_Gernez Father of stem cell theory]
* [http://www.jove.com/index/details.stp?ID=574 Derivation of Human Embryonic Stem Cells by Immunosurgery]
* [http://www.jove.com/index/details.stp?ID=116 Nuclear Transfer into Mouse Oocytes]

ee also

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