Embryonic stem cell

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Human embryonic stem cells in cell culture
Pluripotent, 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 pluripotent stem cells derived from the inner cell mass of the blastocyst, an early-stage embryo[1]. Human embryos reach the blastocyst stage 4–5 days post fertilization, at which time they consist of 50–150 cells. Human embryonic stem cells are currently produced from surplus embryos of in vitro fertilization procedures.

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[edit] Characteristics

Embryonic stem cells are distinguished by two distinctive properties: their pluripotency and their capability to self-renew themselves indefinitely[2].

ES cells are pluripotent, that is, 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 embryonic stem cells from adult stem cells found in adults; while embryonic stem cells can generate all cell types in the body, adult stem cells are multipotent and can only produce a limited number of cell types.

Additionally, under defined conditions, embryonic stem cells are capable of propagating themselves indefinitely. This allows embryonic stem cells to be employed as useful tools for both research and regenerative medicine, because they can produce limitless numbers of themselves for continued research or clinical use.

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. Diseases that could potentially be treated by pluripotent 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 concerns 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, therapeutic cloning, stem cell banks or more recently by reprogramming of somatic cells with defined factors (eg. induced pluripotent stem cells). Other potential uses of embryonic stem cells include investigation of early human development, study of genetic disease and as in vitro systems for toxicology testing.

[edit] Research history and developments

[edit] Isolation and in vitro culture

In 1964, researchers isolated a single type of cell from a teratocarcinoma that replicated and grew in cell culture as a stem cell.[3] Subsequently, researchers isolated a primordial embryonic germ cell (EG cell) that, after replicating and growing in cell culture as a stem cell, was capable of developing into different cell types.

In 1981, embryonic stem cells (ES cells) were first derived from mouse embryos by Martin Evans and Matthew Kaufman at the Department of Genetics, University of Cambridge.[4] and, independently, by Gail R. Martin. Martin is credited with coining the term "Embryonic Stem Cell".[5] In 1998, a breakthrough occurred when researchers, led by James Thomson at the University of Wisconsin–Madison, first developed a technique to isolate and grow in cell culture human embryonic stem cells.[6]

[edit] Contamination by reagents used in cell culture

The online edition of Nature Medicine published a study on January 24, 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.[7] 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.[8]

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.[9]

[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] First Embryonic Stem Cell Trial Approved by the FDA

On January 23, 1969, Phase I clinical trials for transplantation of a human-ES-derived cell population into spinal cord-injured individuals received approval from the U.S. Food and Drug Administration (FDA), marking it the world's first human ES cell human trial [10]. The study leading to this scientific advancement was conducted by Hans Keirstead and colleagues at the University of California, Irvine and supported by Geron Corporation of Menlo Park, CA. The results of this experiment suggested an improvement in locomotor recovery in spinal cord-injured rats after a 7-day delayed transplantation of human ES cells that were pushed towards an oligodendrocytic lineage [11]. In the proposed phase I clinical stidy, about eight to ten paraplegics who have had their injuries no longer than two weeks before the trial begins, will be selected, since the cells must be injected before scar tissue is able to form. However, the researchers are emphasizing that the injections are not expected to fully cure the patients and restore all mobility. Based on the results of the rodent trials, researchers say restoration of myelin sheathes, and an increase in mobility is probable. This first trial is mainly testing the safety of these procedures and if everything goes well, it could lead to future studies that involve people with more severe disabilities.[12]. Unfortunately the trial is on hold since August 2009 due to concerns made by the FDA regarding a small number of microscopic cysts found in several treated rat models. If all goes well with Gerons follow-up experiments the clinical trial should resume by the end of 2010.[13].

[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.[14] 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 was at the time limited to research using embryonic stem cell lines derived prior to August 2001. In March, 2009, the limitation was lifted.[15]

See also: Induced pluripotent stem cell

Recently, it was shown that pluripotent stem cells highly similar to embryonic stem cells can be generated by the delivery of three genes (Oct4, Sox2, and Klf4) to differentiated cells[16]. The delivery of these genes "reprograms" differentiated cells into pluripotent stem cells, allowing for the generation of pluripotent stem cells without the embryo. Because ethical concerns regarding embryonic stem cells typically are about their derivation from terminated embryos, it is believed that reprogramming to these "induced pluripotent stem cells" (iPS cells) may be less controversial. Both human and mouse cells can be reprogrammed by this methodology, generating both human pluripotent stem cells and mouse pluripotent stem cells without an embryo[17]

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.

However, as a first indication that the induced pluripotent stem cell (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 December 6.[18]

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.[19]

[edit] Use of human embryonic stem cells as models for human genetic disorders

In recent years there have been several reports regarding the potential use of human embryonic stem cells as models for human genetic diseases. This issue is especially important due to the species-specific nature of many genetic disorders. The relative inaccessibility of human primary tissue for research is another major hindrance. Several new studies have started to address this issue. This has been done either by genetically manipulating the cells, or more recently by deriving diseased cell lines identified by prenatal genetic diagnosis (PGD). This approach may very well prove invaluable at studying disorders such as Fragile-X syndrome, Cystic fibrosis, and other genetic maladies that have no reliable model system.

Yury Verlinsky (Sept, 1, 1943 – July 16, 2009), a Russian-American medical researcher who specialized in embryo and cellular genetics (genetic cytology), developed prenatal diagnosis testing methods to determine genetic and chromosomal disorders a month and a half earlier than standard amniocentesis. The techniques are now used by many pregnant women and prospective parents, especially those couples with a history of genetic abnormalities or where the woman is over the age of 35, when the risk of genetically-related disorders is higher. In addition, by allowing parents to select an embryo without genetic disorders, they have the potential of saving the lives of siblings that already had similar disorders and diseases using cells from the disease free offspring.[20]


[edit] See also

[edit] References

  1. ^ Thomson et. al (November 1998). "Blastocysts Embryonic Stem Cell Lines Derived from Human". Science 282 (1145): 1145–1147. doi:10.1126/science.282.5391.1145. 
  2. ^ Ying et. al (October 2003). "BMP Induction of Id Proteins Suppresses Differentiation and Sustains Embryonic Stem Cell Self-Renewal in Collaboration with STAT3". Cell 115: 281–292. 
  3. ^ 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. doi:10.1042/BST20051526. PMID 16246161. 
  4. ^ Evans M, Kaufman M (1981). "Establishment in culture of pluripotent cells from mouse embryos". Nature 292 (5819): 154–6. doi:10.1038/292154a0. PMID 7242681. 
  5. ^ 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 USA 78 (12): 7634–8. doi:10.1073/pnas.78.12.7634. PMID 6950406. 
  6. ^ 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. doi:10.1126/science.282.5391.1145. PMID 9804556. 
  7. ^ Ebert, Jessica (24 January 2005). "Human stem cells trigger immune attack". News from "Nature" (London: Nature Publishing Group). doi:10.1038/news050124-1. http://cmbi.bjmu.edu.cn/news/0501/124.htm. Retrieved 2009-02-27. 
  8. ^ Martin MJ, Muotri A, Gage F, Varki A (February 2005). "Human embryonic stem cells express an immunogenic nonhuman sialic acid". Nat. Med. 11 (2): 228–32. doi:10.1038/nm1181. PMID 15685172. 
  9. ^ Klimanskaya I, Chung Y, Meisner L, Johnson J, West MD, Lanza R (2005). "Human embryonic stem cells derived without feeder cells". Lancet 365 (9471): 1636–41. doi:10.1016/S0140-6736(05)66473-2. PMID 15885296. 
  10. ^ "FDA approves human embryonic stem cell study - CNN.com". http://www.cnn.com/2009/HEALTH/01/23/stem.cell/. 
  11. ^ Keirstead HS, Nistor G, Bernal G, et al. (May 2005). "Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury". J. Neurosci. 25 (19): 4694–705. doi:10.1523/JNEUROSCI.0311-05.2005. PMID 15888645. 
  12. ^ Steven Reinberg FDA OKs 1st Embryonic Stem Cell Trial
  13. ^ Geron comments on FDA hold on spinal cord injury trial http://www.geron.com/media/pressview.aspx?id=1188
  14. ^ 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. doi:10.1038/nature05142. PMID 16929302. 
  15. ^ US scientists relieved as Obama lifts ban on stem cell research, The Guardian, 10 March 2009
  16. ^ "Human stem cells may be produced without embryos ‘within months’". Zangani. 2007-07-17. http://www.zangani.com/node/735. 
  17. ^ "Embryonic stem cells made without embryos". Reuters. 2007-11-21. http://www.reuters.com/article/newsOne/idUSN2058175020071121. 
  18. ^ Rick Weiss (2007-12-07). "Scientists Cure Mice Of Sickle Cell Using Stem Cell Technique: New Approach Is From Skin, Not Embryos". Washington Post. pp. A02. http://www.washingtonpost.com/wp-dyn/content/article/2007/12/06/AR2007120602444.html. 
  19. ^ Helen Briggs (2008-01-17). "US team makes embryo clone of men". BBC. pp. A01. http://news.bbc.co.uk/2/hi/science/nature/7194161.stm. 
  20. ^ "Dr. Yury Verlinsky, 1943-2009: Expert in reproductive technology" Chicago Tribune, July 20, 2009

[edit] External links

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Cellular differentiation: Stem cells / progenitor cell
Sources/types
Cell potency
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