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Stem cellsÂ areÂ cellsÂ found in all multi cellularÂ organisms. They are characterized by the ability to renew themselves throughÂ mitoticÂ cell division andÂ differentiateÂ into a diverse range of specialized cell types. Research in the stem cell field grew out of findings byÂ Ernest A. McCullochÂ and James E. TillÂ at theÂ University of TorontoÂ in the 1960s
The two broad types of mammalian stem cells are:Â embryonic stem cellsÂ that are isolated from theÂ inner cell massÂ ofÂ blastocysts, andÂ adult stem cellsÂ that are found in adult tissues. In a developingÂ embryo, stem cells can differentiate into all of the specialized embryonic tissues. In adultÂ organisms, stem cells andÂ progenitor cellsÂ act as a repair system for the body, replenishing specialized cells, but also maintain the normal turnover of regenerative organs, such as blood, skin, or intestinal tissues.
Stem cells can now be grown and transformed into specialized cells with characteristics consistent with cells of various tissues such as muscles or nerves throughÂ cell culture. Highly plastic adult stem cells from a variety of sources, includingÂ umbilical cord bloodÂ andÂ bone marrow, are routinely used in medical therapies. EmbryonicÂ cell linesÂ andÂ autologousÂ embryonic stem cells generated throughÂ therapeutic cloningÂ have also been proposed as promising candidates for future therapies
1.2Â Potency definitions
6Â Induced pluripotent
9Â Research patents
10Â Key research events
11Â See also
13Â External links
The classical definition of a stem cell requires that it possess two properties:
Self-renewalÂ - the ability to go through numerousÂ cyclesÂ ofÂ cell divisionÂ while maintaining the undifferentiated state.
PotencyÂ - the capacity toÂ differentiateÂ into specialized cell types. In the strictest sense, this requires stem cells to be eitherÂ totipotentÂ orÂ pluripotentÂ - to be able to give rise to any mature cell type, althoughÂ multipotentÂ orÂ unipotentÂ progenitor cellsÂ are sometimes referred to as stem cells.
Two mechanisms exist to ensure that the stem cell population is maintained:
Obligatory asymmetric replicationÂ - a stem cell divides into oneÂ daughter cellÂ that is identical to the original stem cell, and another daughter cell that is differentiated
Stochastic differentiationÂ - when one stem cell develops into two differentiated daughter cells, another stem cell undergoesÂ mitosisÂ and produces two stem cells identical to the original.
Pluripotent, embryonic stem cells originate as inner mass cells within 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.
HumanÂ embryonicÂ stem cells
A: Cell colonies that are not yet differentiated.
B:Â NerveÂ cell
PotencyÂ specifies the differentiation potential (the potential to differentiate into different cell types) of the stem cell.
TotipotentÂ (a.k.aÂ omnipotent) stem cells can differentiate into embryonic and extraembryonic cell types. Such cells can construct a complete, viable, organism.Â These cells are produced from the fusion of an egg and sperm cell. Cells produced by the first few divisions of the fertilized egg are also totipotent.
PluripotentÂ stem cells are the descendants of totipotent cells and can differentiate into nearly all cells,Â i.e. cells derived from any of the threeÂ germ layers.
MultipotentÂ stem cells can differentiate into a number of cells, but only those of a closely related family of cells.
OligopotentÂ stem cells can differentiate into only a few cells, such as lymphoid or myeloid stem cells.
UnipotentÂ cells can produce only one cell type, their own,Â but have the property of self-renewal which distinguishes them from non-stem cells (e.g. muscle stem cells).
The practical definition of a stem cell is the functional definition - a cell that has the potential to regenerate tissue over a lifetime. For example, the gold standard test for a bone marrow or hematopoietic stem cell (HSC) is the ability to transplant one cell and save an individual without HSCs. In this case, a stem cell must be able to produce new blood cells and immune cells over a long term, demonstrating potency. It should also be possible to isolate stem cells from the transplanted individual, which can themselves be transplanted into another individual without HSCs, demonstrating that the stem cell was able to self-renew.
Properties of stem cells can be illustratedÂ in vitro, using methods such asÂ clonogenic assays, where single cells are characterized by their ability to differentiate and self-renew.Â As well, stem cells can be isolated based on a distinctive set of cell surface markers. However,Â in vitroÂ culture conditions can alter the behavior of cells, making it unclear whether the cells will behave in a similar mannerÂ in vivo. Considerable debate exists whether some proposed adult cell populations are truly stem cells.
Embryonic stem cell linesÂ (ES cell lines) are cultures of cells derived from theÂ epiblastÂ tissue of theÂ inner cell massÂ (ICM) of aÂ blastocystÂ or earliermorulaÂ stage embryos.Â A blastocyst is an early stageÂ embryo-approximately four to five days old in humans and consisting of 50-150 cells. ES cells areÂ pluripotentÂ and give rise during development to all derivatives of the three primaryÂ germ layers: ectoderm, endoderm and mesoderm. In other words, they can develop into each of the more than 200 cell types of the adultÂ bodyÂ when given sufficient and necessary stimulation for a specific cell type. They do not contribute to the extra-embryonic membranes or theÂ placenta.
Nearly all research to date has taken place using mouse embryonic stem cells (mES) or human embryonic stem cells (hES). Both have the essential stem cell characteristics, yet they require very different environments in order to maintain an undifferentiated state. Mouse ES cells are grown on a layer of gelatin and require the presence of Leukemia Inhibitory Factor (LIF). Human ES cells are grown on a feeder layer of mouse embryonicÂ fibroblasts(MEFs) and require the presence of basic Fibroblast Growth Factor (bFGF or FGF-2).Â Without optimal culture conditions or genetic manipulation, embryonic stem cells will rapidly differentiate.
A human embryonic stem cell is also defined by the presence of several transcription factors and cell surface proteins. The transcription factorsÂ Oct-4,Nanog, andÂ Sox2Â form the core regulatory network that ensures the suppression of genes that lead to differentiation and the maintenance of pluripotency.Â The cell surface antigens most commonly used to identify hES cells are the glycolipids SSEA3 and SSEA4 and the keratan sulfate antigens Tra-1-60 and Tra-1-81. The molecular definition of a stem cell includes many more proteins and continues to be a topic of research.
After nearly ten years of research,Â there are no approved treatments using embryonic stem cells. The first human trial was approved by the US Food & Drug Administration in January 2009.Â However, as of August 2010, the first human trial had not yet been initiated. Although, The first human medical trial for embryonic stem cells started in Atlanta on October 13, 2010 for spinal injury victims. ES cells, being pluripotent cells, require specific signals for correct differentiation - if injected directly into another body, ES cells will differentiate into many different types of cells, causing aÂ teratoma. Differentiating ES cells into usable cells while avoiding transplant rejection are just a few of the hurdles that embryonic stem cell researchers still face.Â Many nations currently haveÂ moratoriaÂ on either ES cell research or the production of new ES cell lines. Because of their combined abilities of unlimited expansion and pluripotency, embryonic stem cells remain a theoretically potential source forÂ regenerative medicineÂ and tissue replacement after injury or disease.
Also known asÂ somaticÂ (from Greek Î£Ï‰Î¼Î±Ï„Î¹ÎºóÏ‚, "of the body") stem cells andÂ germlineÂ (giving rise to gametes) stem cells, they can be found in children, as well as adults.
Stem cell division and differentiation.Â A - stem cell; B - progenitor cell; C - differentiated cell; 1 - symmetric stem cell division; 2 - asymmetric stem cell division; 3 - progenitor division; 4 - terminal differentiation
Pluripotent adult stem cells are rare and generally small in number but can be found in a number of tissues including umbilical cord blood.Â A great deal of adult stem cell research has focused on clarifying their capacity to divide or self-renew indefinitely and their differentiation potential.Â In mice, pluripotent stem cells are directly generated from adult fibroblast cultures. Unfortunately, many mice don't live long with stem cell organs.
Most adult stem cells are lineage-restricted (multipotent) and are generally referred to by their tissue origin (mesenchymal stem cell, adipose-derived stem cell,endothelial stem cell, etc.).
Adult stem cell treatments have been successfully used for many years to treat leukemia and related bone/blood cancers through bone marrow transplants.Â Adult stem cells are also used in veterinary medicine to treat tendon and ligament injuries in horses.
The use of adult stem cells in research and therapy is not asÂ controversialÂ asÂ embryonic stem cells, because the production of adult stem cells does not require the destruction of anÂ embryo. Additionally, because in some instances adult stem cells can be obtained from the intended recipient, (anÂ autograft) the risk of rejection is essentially non-existent in these situations. Consequently, more US government funding is being provided for adult stem cell research.
An extremely rich source for adult mesenchymal stem cells is the developing tooth bud of the mandibular third molar. While considered multipotent they may prove to be pluripotent. The stem cells eventually form enamel (ectodrm), dentin,periodontal ligament, blood vessels, dental pulp, nervous tissues, including a minimum of 29 different unique end organs. Because of extreme ease in collection at 8-10 years of age before calcification and minimal to no morbidity will probably constitute a major source for personal banking, research and multiple therapies. These stem cells have been shown capable of producing hepatocytes.
Multipotent stem cells are also found inÂ amniotic fluid. These stem cells are very active, expand extensively without feeders and are not tumorigenic.Â Amniotic stem cellsÂ are multipotent and can differentiate in cells of adipogenic, osteogenic, myogenic, endothelial, hepatic and also neuronal lines.Â All over the world, universities and research institutes are studyingÂ amniotic fluidÂ to discover all the qualities of amniotic stem cells, and scientists such asÂ Anthony AtalaÂ andÂ Giuseppe SimoniÂ have discovered important results.
From an ethical point of view, stem cells fromÂ amniotic fluidÂ can solve a lot of problems, because it's possible to catch amniotic stem cells without destroying embryos. For example, the Vatican newspaper "Osservatore Romano" called amniotic stem cell "the future of medicine".
It's possible to collect amniotic stem cells for donors or for autologuous use: the first US amniotic stem cells bankÂ opened in Medford, MA, byÂ Biocell CenterÂ CorporationÂ Â and collaborates with various hospitals and universities all over the world
These are not adult stem cells, but rather reprogrammed cells (e.g. epithelial cells) given pluripotent capabilities. Using genetic reprogramming with proteinÂ transcription factors, pluripotent stem cells equivalent toÂ embryonic stem cellsÂ have been derived from human adult skin tissue.Â Shinya YamanakaÂ and his colleagues atÂ Kyoto UniversityÂ used the transcription factors Oct3/4, Sox2, c-Myc, and Klf4Â in their experiments on cells from human faces.Â Junying Yu,Â James Thomson, and their colleagues at theÂ University of Wisconsin-MadisonÂ used a different set of factors, Oct4, Sox2, Nanog and Lin28,Â and carried out their experiments using cells from humanÂ foreskin.
As a result of the success of these experiments,Â Ian Wilmut, who helped create the first cloned animalÂ Dolly the Sheep, has announced that he will abandonÂ nuclear transferÂ as an avenue of research.
Frozen blood samples can be used as a source of induced pluripotent stem cells, opening a new avenue for obtaining the valued cells.
They ensure self-renewal, stem cells undergo two types of cell division (seeÂ Stem cell division and differentiationÂ diagram). Symmetric division gives rise to two identical daughter cells both endowed with stem cell properties. Asymmetric division, on the other hand, produces only one stem cell and aÂ progenitor cellÂ with limited self-renewal potential. Progenitors can go through several rounds of cell division before terminallyÂ differentiatingÂ into a mature cell. It is possible that the molecular distinction between symmetric and asymmetric divisions lies in differential segregation of cell membrane proteins (such asÂ receptors) between the daughter cells.
An alternative theory is that stem cells remain undifferentiated due to environmental cues in their particular niche. Stem cells differentiate when they leave that niche or no longer receive those signals. Studies inÂ DrosophilaÂ germarium have identified the signals dpp and adherens junctions that prevent germarium stem cells from differentiating.
Main article:Â Induced Pluripotent Stem Cell
The signals that lead to reprogramming of cells to an embryonic-like state are also being investigated. These signal pathways include severalÂ transcription factorsÂ including theÂ oncogeneÂ c-Myc. Initial studies indicate that transformation of mice cells with a combination of these anti-differentiation signals can reverse differentiation and may allow adult cells to become pluripotent. However, the need to transform these cells with an oncogene may prevent the use of this approach in therapy.
Challenging the terminal nature of cellular differentiation and the integrity of lineage commitment, it was recently determined that the somatic expression of combinedÂ transcription factorsÂ can directly induce other defined somatic cell fates; researchers identified three neural-lineage-specific transcription factors that could directly convert mouseÂ fibroblastsÂ (skin cells) into fully-functionalÂ neurons. This "induced neurons" (iN) cell research inspires the researchers to induce other cell types implies thatÂ allÂ cells areÂ totipotent: with the proper tools, all cells may form all kinds of tissue.
Medical researchers believe that stem cell therapy has the potential to dramatically change the treatment of human disease. A number of adult stem cell therapies already exist, particularlyÂ bone marrow transplantsÂ that are used to treatÂ leukemia.Â In the future, medical researchers anticipate being able to use technologies derived from stem cell research to treat a wider variety of diseases includingÂ cancer,ParkinsonHYPERLINK "http://en.wikipedia.org/wiki/Parkinson's_disease"'HYPERLINK "http://en.wikipedia.org/wiki/Parkinson's_disease"s disease,Â spinal cord injuries,Â Amyotrophic lateral sclerosis,Â multiple sclerosis, andÂ muscleÂ damage, amongst a number of other impairments and conditions.Â However, there still exists a great deal of social and scientific uncertainty surrounding stem cell research, which could possibly be overcome through public debate and future research, and further education of the public.
One concern of treatment is the possible risk that transplanted stem cells could form tumors and have the possibility of becoming cancerous if cell division continues uncontrollably.
Stem cells, however, are already studied extensively. While some scientists are hesitant to associate the therapeutic potential of stem cells as the first goal of the research, they find the investigation of stem cells as a goal worthy in itself.
Contrarily, supporters of embryonic stem cell research argue that such research should be pursued because the resultant treatments could have significant medical potential. It is also noted that excess embryos created forÂ in vitro fertilizationÂ could be donated with consent and used for the research
Diseases and conditions where stem cell treatment is promising or emerging.Â Bone marrow transplantation is, as of 2009, the only established use of stem cells.
TheÂ patentsÂ covering a lot of work on human embryonic stem cells are owned by theÂ Wisconsin Alumni Research FoundationÂ (WARF). WARF does not charge academics to study human stem cells but does charge commercial users. WARF soldÂ Geron Corp.Â exclusive rights to work on human stem cells but later sued Geron Corp. to recover some of the previously sold rights. The two sides agreed that Geron Corp. would keep the rights to only three cell types. In 2001, WARF came under public pressure to widen access to human stem-cell technology.
These patents are now in doubt as a request for reviewing theÂ US Patent and Trademark OfficeÂ has been filed by non-profit patent-watchdogsÂ The Foundation for Taxpayer HYPERLINK "http://www.consumerwatchdog.org/"&HYPERLINK "http://www.consumerwatchdog.org/" Consumer Rights, and theÂ Public Patent FoundationÂ as well as molecular biologist Jeanne Loring of the Burnham Institute. According to them, two of the patents granted to WARF are invalid because they cover a technique published in 1993 for which a patent had already been granted to an Australian researcher. Another part of the challenge states that these techniques, developed byÂ James A. Thomson, are rendered obvious by a 1990 paper and two textbooks.
The outcome of this legal challenge is particularly relevant to the Geron Corp. as it can only license patents that are upheld.
January 2008Â - Robert Lanza and colleagues at Advanced Cell Technology and UCSF create the first human embryonic stem cells without destruction of the embryo
January 2008Â - Development of human cloned blastocysts followingÂ somatic cell nuclear transferÂ with adult fibroblasts.
February 2008Â - Generation of pluripotent stem cells from adult mouse liver and stomach: these iPS cells seem to be more similar to embryonic stem cells than the previously developed iPS cells and not tumorigenic, moreover genes that are required for iPS cells do not need to be inserted into specific sites, which encourages the development of non-viral reprogramming techniques.
March 2008-The first published study of successful cartilage regeneration in the human knee using autologous adult mesenchymal stem cells is published by clinicians from Regenerative Sciences.
October 2008Â - Sabine Conrad and colleagues at Tübingen, Germany generateÂ pluripotent stem cellsÂ from spermatogonial cells of adult human testis by culturing the cells in vitro underÂ leukemia inhibitory factorÂ (LIF) supplementation.
30 October 2008Â - Embryonic-like stem cells from a single human hair.
1 March 2009Â - Andras Nagy, Keisuke Kaji,Â et al.Â discover a way to produce embryonic-like stem cells from normal adult cells by using a novel "wrapping" procedure to deliver specific genes to adult cells to reprogram them into stem cells without the risks of using a virus to make the change. The use ofÂ electroporationÂ is said to allow for the temporary insertion of genes into the cell.
28 May 2009Â KimÂ et al.Â announced that they had devised a way to manipulate skin cells to create patient specific "induced pluripotent stem cells" (iPS), claiming it to be the 'ultimate stem cell solution'.
11 October 2010Â First trial of embryonic stem cells in humans
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