Embryonic stem cell

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Human embryonic stem cell colony.

Pluripotent, embryonic stem cells originate as inner mass cells with in a blastocyst. The stem cells can become any tissue in the body, excluding a placenta. Only the morula's cells are totipotent, able to become all tissues and a placenta.

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

Embryonic stem cells are pluripotent, meaning they are able to differentiate into all derivatives of the three primary germ layers: ectoderm, endoderm and mesoderm. In other words, they can develop into each of the more than 200 cell types of the adult body when given the sufficient and necessary stimulation for a specific cell type. Pluripotency distinguishes ES cells from multipotent progenitor cells found in the adult, which can only form a limited number of different cell types. The presence of pluripotent adult stem cells is a subject of scientific debate.

Stem cells are maintained as undifferientated cell through the actions of transcription factors such as Nanog, Oct4, and Sox2.^[1] When given no stimuli for differentiation, (i.e. when grown in vitro), ES cells will maintain their pluripotency through multiple cell divisions.

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. To date, no approved medical treatments have been derived from embryonic stem cell research. This is not unusual for a new medical research field; in this case, the first human embryonic stem cell line was only reported in 1998. 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 tranplantion. However, these problems associated with histocompatibility may be solved using autologous donor adult stem cells or via therapeutic cloning.

[edit] Research history and developments

[edit] Isolation and in vitro culture

Stem cells were discovered from analysis of a type of cancer called a teratocarcinoma. This type of cancer consists of many different types of cells. A mouse strain was discovered in 1954 that could give a high frequency of testicular teratocarcinoma. In 1964, researchers noted that a single cell in teratocarcinomas could be isolated and remain undifferientated in culture. This type of stem cells became known as embryonic carcinoma cells (EC cells).^[2] Later, 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 two independent research groups.^[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]

[edit] 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]

[edit] 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]

[edit] Xenotransplantation of human ES cells

Recently, in California, researchers have injected embryonic stem cells into mice as they developed in the womb. Upon maturing, it was found that some of the human ES cells had survived and two months after injection, the researchers found that the human ES cells had undertaken "the characteristics of mouse cells".^[9]

Scientists in Australia have grown human prostate tissue in mice through the use of ES cells. The research involved combining human ES cells with mouse prostate cells, and then using a mouse as the host to grow the human prostate. The researchers were able to show the resulting tissue was also functional as a human prostate. This work may enable medical researchers to use a prostate derived in this manner as a model for studying prostate cancer and disease and analysis of future prostate-related drugs.

[edit] 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.

[edit] 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.^[10] This technical achievement would potentially enable scientists to work with new lines of embryonic stem cells derived using public funding. There are currently significant restrictions on federal funding of embryonic stem cell research that limit publicly-funded research to embryonic stem cell lines derived prior to August 2001.

In the experiments, Lanza's team used a single-cell biopsy technique to pluck out a single cell when the embryo was at the 8-to-10 cell stage. This is the same stage used for preimplantation genetic diagnosis, which also requires the removal of a single cell from the blastocyst. As with times where preimplantation genetic diagnosis is used, excising a cell at this point does not interfere with the embryo's development and the excised cell can be used for both purposes at the same time. Using this method, Lanza and his team managed to get two stable human embryonic stem cell lines that behaved like conventional embryonic stem cell lines.

Quickly after its publication, this paper came under some criticism for its representation of the facts. Examination of the paper reveals that the described process is highly inefficient, and in addition, no embryos survived the process. ^[11] Dr. Lanza states that "he never intended to say more than that he had proved a principle"^[12]. The goal of the paper was to demonstrate that an embryonic stem cell line could be derived from a single cell from the inner mass. Given that the embryos in the study were not medically or legally eligible for implantation, more than one cell was removed from the inner cell masses - each to be used in a separate experiment.

Though theoretically very promising, the principle has yet to be demonstrated on an embryo that is to be carried to term. Advanced Cell Technology has pledged cooperation with WiCell Research Institute to derive new stem cell lines using the principle of the Lanza paper, pending federal approval and further research. ^[13]

[edit] References

1. ^ Boyer L, Lee T, Cole M, Johnstone S, Levine S, Zucker J, Guenther M, Kumar R, Murray H, Jenner R, Gifford D, Melton D, Jaenisch R, Young R (2005). "Core transcriptional regulatory circuitry in human embryonic stem cells.". Cell 122 (6): 947-56. PMID 16153702.
2. ^ Andrews P, Matin M, Bahrami A, Damjanov I, Gokhale P, Draper J (2005). "Embryonic stem (ES) cells and embryonal carcinoma (EC) cells: opposite sides of the same coin.". Biochem Soc Trans 33 (Pt 6): 1526-30. PMID 16246161.
3. ^ Evans M, Kaufman M (1981). "Establishment in culture of pluripotential cells from mouse embryos.". Nature 292 (5819): 154-6. PMID 7242681.
4. ^ Martin G (1981). "Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells.". Proc Natl Acad Sci U S A 78 (12): 7634-8. PMID 6950406.
5. ^ Thomson J, Itskovitz-Eldor J, Shapiro S, Waknitz M, Swiergiel J, Marshall V, Jones J (1998). "Embryonic stem cell lines derived from human blastocysts.". Science 282 (5391): 1145-7. PMID 9804556.
6. ^ http://www.nature.com/nature/journal/v427/n6970/abs/nature02247.html
7. ^ http://www.nature.com/nm/journal/vaop/ncurrent/pdf/nm1181.pdf
8. ^ http://www.thelancet.com/journals/lancet/article/PIIS0140673605664732/fulltext (Lancet Medical Journal)
9. ^ http://news.nationalgeographic.com/news/2005/12/1214_051214_stem_cell.html
10. ^ Klimanskaya I, Chung Y, Becker S, Lu SJ, Lanza R. (2006). "Human embryonic stem cell lines derived from single blastomeres.". Nature 444 (7118): 481-5. PMID 16929302.
11. ^ 'Ethical' stem-cell paper under attack
12. ^ http://www.nature.com/nature/journal/v443/n7107/full/443012a.html
13. ^ http://www.advancedcell.com/press-release/wicell-research-institute-and-advanced-cell-technology-offer-to-distribute-new-stem-cell-lines-to-us-researchers-

[edit] External links

• Tell Me About Stem Cells
• Health MSN article on new stem cell extraction
• [1] Harvard Stem Cell Institute's guide to growing and manipulating human embryonic stem cells
• National Institutes of Health
• Stem Cell and Cord Blood information database