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American Heritage Dictionary:

stem cell

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n.
An unspecialized cell that gives rise to a specific specialized cell, such as a blood cell.


Britannica Concise Encyclopedia:

stem cell

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In living organisms, an undifferentiated cell that can produce other cells that eventually make up specialized tissues and organs. There are two major types of stem cells, embryonic and adult. Embryonic stem cells are located in the inner mass of a blastocyst (an embryo at a very early stage of development), and they eventually give rise to every cell type of the adult organism. Adult stem cells are found in some tissues in the adult body, such as the epidermis of the skin, the lining of the small intestine, and the bone marrow, where they serve in the regeneration of old or worn tissue. In cancer treatment, blood-forming adult stem cells are routinely harvested from bone marrow, stored, and then reinfused into patients to replace blood cells destroyed by chemotherapy or radiation therapy. This potential for replacing damaged tissues has aroused great interest in using embryonic stem cells to treat a number of other conditions, such as Parkinson disease, severe burns, and damage to the spinal cord. Mouse embryonic stem cells are widely used to create genetically modified mice that serve as models for investigating human disease. However, the use of human embryonic stem cells, which requires destroying the blastocysts from which they are obtained, has raised objections by those who feel blastocyst-stage embryos are human beings. The first human stem cell line was created in 1998, using cells harvested from embryos produced through in vitro fertilization. The use of human embryonic stem cells is allowed in some countries and prohibited or restricted in others.

For more information on stem cell, visit Britannica.com.

McGraw-Hill Science & Technology Encyclopedia:

Stem cells

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Cells that have the ability to self-replicate and give rise to specialized cells. Stem cells can be found at different stages of fetal development and are present in a wide range of adult tissues. Many of the terms used to distinguish stem cells are based on their origins and the cell types of their progeny.

There are three basic types of stem cells. Totipotent stem cells, meaning their potential is total, have the capacity to give rise to every cell type of the body and to form an entire organism. Pluripotent stem cells, such as embryonic stem cells, are capable of generating virtually all cell types of the body but are unable to form a functioning organism. Multipotent stem cells can give rise only to a limited number of cell types. For example, adult stem cells, also called organ- or tissue-specific stem cells, are multipotent stem cells found in specialized organs and tissues after birth. Their primary function is to replenish cells lost from normal turnover or disease in the specific organs and tissues in which they are found.

Totipotent stem cells occur at the earliest stage of embryonic development. The union of sperm and egg creates a single totipotent cell. This cell divides into identical cells in the first hours after fertilization. All these cells have the potential to develop into a fetus when they are placed into the uterus. The first differentiation of totipotent cells forms a hollow sphere of cells called the blastocyst, which has an outer layer of cells and an inner cell mass inside the sphere. The outer layer of cells will form the placenta and other supporting tissues during fetal development, whereas cells of the inner cell mass go on to form all three primary germ layers: ectoderm, mesoderm, and endoderm. The three germ layers are the embryonic source of all types of cells and tissues of the body. Embryonic stem cells are derived from the inner cell mass of the blastocyst. They retain the capacity to give rise to cells of all three germ layers. However, embryonic stem cells cannot form a complete organism because they are unable to generate the entire spectrum of cells and structures required for fetal development. Thus, embryonic stem cells are pluripotent, not totipotent, stem cells.

Embryonic germ (EG) cells differ from embryonic stem cells in the tissue sources from which they are derived, but appear to be similar to embryonic stem cells in their pluripotency. Human embryonic germ cell lines are established from the cultures of the primordial germ cells obtained from the gonadal ridge of late-stage embryos, a specific part that normally develops into the testes or the ovaries. Embryonic germ cells in culture, like cultured embryonic stem cells, form embryoid bodies, which are dense, multilayered cell aggregates consisting of partially differentiated cells. The embryoid body-derived cells have high growth potential. The cell lines generated from cultures of the embryoid body cells can give rise to cells of all three embryonic germ layers, indicating that embryonic germ cells may represent another source of pluripotent stem cells.

Much of the knowledge about embryonic development and stem cells has been accumulated from basic research on mouse embryonic stem cells. Since 1998, however, research teams have succeeded in growing human embryonic stem cells in culture. Human embryonic stem cell lines have been established from the inner cell mass of human blastocysts that were produced through in vitro fertilization procedures. The techniques for growing human embryonic stem cells are similar to those used for growth of mouse embryonic stem cells. However, human embryonic stem cells must be grown on a mouse embryonic fibroblast feeder layer or in media conditioned by mouse embryonic fibroblasts. Human embryonic stem cell lines can be maintained in culture to generate indefinite numbers of identical stem cells for research. As with mouse embryonic stem cells, culture conditions have been designed to direct differentiation into specific cell types (for example, neural and hematopoietic cells).

Adult stem cells occur in mature tissues. Like all stem cells, adult stem cells can self-replicate. Their ability to self-renew can last throughout the lifetime of individual organisms. But unlike embryonic stem cells, it is usually difficult to expand adult stem cells in culture. Adult stem cells reside in specific organs and tissues, but account for a very small number of the cells in tissues. They are responsible for maintaining a stable state of the specialized tissues. To replace lost cells, stem cells typically generate intermediate cells called precursor or progenitor cells, which are no longer capable of self-renewal. However, they continue undergoing cell divisions, coupled with maturation, to yield fully specialized cells. Such stem cells have been identified in many types of adult tissues, including bone marrow, blood, skin, gastrointestinal tract, dental pulp, retina of the eye, skeletal muscle, liver, pancreas, and brain. Adult stem cells are usually designated according to their source and their potential. Adult stem cells are multipotent because their potential is normally limited according to their source and their potential. Adult stem cells are multipotent because their potential is normally limited to one or more lineages of specialized cells. However, a special multipotent stem cell that can be found in bone marrow, called the mesenchymal stem cell, can produce all cell types of bone, cartilage, fat, blood, and connective tissues.

Blood stem cells, or hematopoietic stem cells, are the most studied type of adult stem cells. The concept of hematopoietic stem cells is not new, since it has been long realized that mature blood cells are constantly lost and destroyed. Billions of new blood cells are produced each day to make up the loss. This process of blood cell generation called hematopoiesis, occurs largely in the bone marrow. Another emerging source of blood stem cells is human umbilical cord blood. Similar to bone marrow, umbilical cord blood can be used as a source material of stem cells for transplant therapy. However, because of the limited number of stem cells in umbilical cord blood, most of the procedures are performed for young children of relatively low body weight.

Neural stem cells, the multipotent stem cells that generate nerve cells, are a new focus in stem cell research. Active cellular turnover does not occur in the adult nervous system as it does in renewing tissues such as blood or skin. Because of this observation, it had been a dogma that the adult brain and spinal cord were unable to regenerate new nerve cells. However, since the early 1990s, neural stem cells have been isolated from the adult brain as well as fetal brain tissues. Stem cells in the adult brain are found in the areas called the subventricular zone and the ventricle zone. Another location of brain stem cells occurs in the hippocampus, a special structure of the cerebral cortex related to memory function. Stem cells isolated from these areas are able to divide and to give rise to nerve cells (neurons) and neuron-supporting cell types in culture.

Stem cell plasticity refers to the phenomenon of adult stem cells from one tissue generating the specialized cells of another tissue. The long-standing concept of adult organ-specific stem cells is that they are restricted to producing the cell types of their specific tissues. However, a series of studies have challenged the concept of tissue restriction of adult stem cells. Although the stem cells appear able to cross their tissue-specific boundaries, crossing occurs generally at a low frequency and mostly only under conditions of host organ damage. The finding of stem cell plasticity carries significant implications for potential cell therapy. For example, if differentiation can be redirected, stem cells of abundant source and easy access, such as blood stem cells in bone marrow or umbilical cord blood, could be used to substitute stem cells in tissues that are difficult to isolate, such as heart and nervous system tissue. See also Cell differentiation; Embryology; Embryonic differentiation; Germ layers; Hematopoiesis; Regeneration (biology); Transplantation biology.

Oxford Companion to the Body:

stem cells

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Stem cells are ‘uncommitted’ cells, capable of dividing to make more stem cells, or, under appropriate conditions, to produce the kinds of specialized cells that make up the tissues and organs of the body.

A newly fertilized egg is the ultimate stem cell. It is totipotent - capable of generating all the different types of cells found in the body, and also the fetal part of the placenta and supporting tissues. The fertilized egg splits into two, and those into four, and so on. For the first few divisions, up to at least the 8-cell stage, all the cells of the tiny embryo are totipotent stem cells. Indeed, if these early cells separate, they can each continue to develop, making identical twins, triplets, quadruplets, etc.

About four days after fertilization, the route to commitment starts. Some cells form an outer layer, which becomes part of the placenta, while others make the inner mass, which is the beginning of the true embryo. Initially this consists entirely of pluripotent stem cells, which cannot give rise to placental tissue but can make any component of the fetus itself. As the embryo grows, and the parts of the body start to emerge, the individual stem cells within each future organ or tissue become further specialized so as to be capable of producing only a certain range of possible final cell types. These stem cells are then called multipotent. At a certain stage in the development of each ‘family tree’ of cells, one or both of the daughter cells produced by the division of a stem cell becomes ‘committed’, that is, incapable of further division. These committed daughters continue to differentiate and become the normal functional cells of the heart, skin, brain, kidney, and other organs.

Adult animals still have some multipotent stem cells, especially in tissues such as skin and blood, in which cells last only a short time and have to be replaced. Indeed, even in the adult brain, previously thought to be incapable of making new nerve cells, there are populations of stem cells, which are constantly producing relatively small numbers of new neurons.

We now stand at the threshold of a potential revolution in medical treatment for diseases and disorders in which organs stop working properly. At present, some such conditions, such as heart, kidney and liver disease, can be treated by transplantation of a replacement organ from another person. But demand for donor organs is far outstripping supply, and the failure rate of such surgery is quite high, mainly because of the problem of rejection. Many other disorders, such as stroke, diabetes and Alzheimer's disease, cannot presently be treated by transplantation. The great hope is that suitable stem cells, produced in large quantities through cell culture methods and injected into failing tissues and organs, will produce fresh, replacement cells to take over from lost or damaged ones.

Stem cells for such replacement therapy could be produced in a number of different ways. Ultimately, it might be possible to make them with the kind of methods used to produce the first cloned mammal, Dolly the sheep. An ordinary specialized adult cell from the patient could be used to produce a totipotent stem cell by removing the nucleus (with the DNA-containing chromosomes), and inserting it into a human egg from which the nucleus has been removed. But there are many problems with this approach, not least the fact that adult cells may have accumulated genetic errors, which will be transmitted to the stem cells produced. Everyone agrees that formidable technical obstacles must be overcome before the cloning of stem cells from adult cells becomes safe. There is also concern that the development of methods for therapeutic cloning would inevitably lead to the production of whole human beings, who, like Dolly, are genetic replicas of an adult. At present, the vast majority of scientists and clinicians, not to mention ethicists and politicians, are opposed to such reproductive cloning, but it must be said that resistance may decrease if the techniques involved can be made more reliable.

In principle, some of the patient's own stem cells could be harvested (most likely from bone marrow or certain parts of the brain), multi-plied in culture and injected into a diseased or damaged region to produce new cells. Stem cells derived from the patient's own body would have the great advantage that they would not be rejected. This approach has already been successful in experimental animals, with stem cells from bone marrow used to replace damaged heart muscle. It may soon be used in humans to treat heart disease, diabetes, and other such diseases. However, it would not be appropriate for the replacement of tissues that are diseased because of a genetic disorder (such as Huntington's disease or cystic fibrosis), since stem cells from the patient would have the same genetic mistake in their DNA. This strategy would also be inappropriate in acute conditions, demanding immediate treatment, because of the time needed for stem cells to multiply in culture.

The most immediately promising strategy is to isolate pluripotent stem cells from human embryos just a few days after fertilization, to culture them, and to inject them into the patient's diseased or damaged organ. Since such cells carry different DNA from that of the patient, they could be used to treat genetic disorders. On the other hand, this means that precautions would have to be taken to avoid rejection.

Transplantation of immature nerve cells and stem cells from the brains of aborted human embryos has been used for several years to treat the degenerative brain condition, Parkinson's disease, with reasonably encouraging results. Such treatment has not greatly alleviated the characteristic tremor of the hands, and some patients have developed disturbing unintended movements. But most have regained the ability to initiate and control their actions. It is probable that embryonic stem cell injection will soon be used in efforts to treat the degenerative diseases Huntington's disease and Alzheimer's, and even stroke, in which parts of the brain are destroyed becomes of interruption of the blood supply.

There is wide agreement among medical scientists that research on human embryonic stem cells is an important first step towards stem cell therapy, even though it may eventually be possible to use adult stem cells. Yet the prospect of harvesting cells from living human embryos smacks of Frankenstein or Brave New World, and ‘pro-life’ religious groups have mounted stout moral opposition. However, it would not be necessary to fertilize additional human eggs specifically for such research. Present methods for the production of ‘test-tube babies’ involve the production and storage (by freezing) of several fertilized eggs, the unwanted ones simply being destroyed or permanently stored. These surplus eggs could, with parental agreement, provide a ready source of embryos for stem cell collection. Moreover, as long as there are strict limits on the time for which the embryo is allowed to develop, it will have no nervous system or other organs, no possibility of feelings, and nothing approaching an independent life. Also, the indubitable suffering of the many people who might be helped by stem cell therapy ought to weigh heavily in the complex moral equation.

In 2001, the British government authorized stem cell research on human embryos up to 14 days post-conceptual age. Given the huge potential benefits of stem cell therapy, it is likely that other nations will follow suit.

— Colin Blakemore

Bibliography

Further reading:

  • Thomson, J. et al. (1998) Embryonic stem cell lines derived from human blastocysts. Science 282: 1145-1147.
  • US National Institutes of Health website. Stem cells: a primer. http: //www.nih.gov/news/stemcell/primer.htm

See also: antenatal development; assisted reproduction; cloning; disease; gene therapy; genetics, human; organ donation; pregnancy; transplantation.

Columbia Encyclopedia:

stem cells

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stem cells, unspecialized human or animal cells that can produce mature specialized body cells and at the same time replicate themselves. Embryonic stem cells are derived from a blastocyst (the blastula typical of placental mammals; see embryo), which is very young embryo that contains 200 to 250 cells and is shaped like a hollow sphere. The stem cells themselves are the cells in the blastocyst that ultimately would develop into a person or animal. "Adult" stem cells are derived from the umbilical cord and placenta or from blood, bone marrow, skin, and other tissues. The similar embryonic germ line cells come from a fetus that is 5 to 9 weeks old and are derived from tissue that would have developed into the ovaries or testes.

Medical researchers are interested in using stem cells to repair or replace damaged body tissues because stem cells are less likely than other foreign cells to be rejected by the immune system when they are implanted in the body. Embryonic stem cells have the capacity to develop into every type of tissue found in an adult; germ line cells and adult stem cells are less versatile. The processes that control such development, however, are not understood at present. Stem cells have been used experimentally to form the hematopoietic (blood-making) cells of the bone marrow; heart, blood vessel, muscle, tracheal, retinal, and insulin-producing tissue; bone; and sperm cells. Embryonic germ line cells have been used to help paralyzed mice regain some of the ability to move. Since the 1990s umbilical cord blood stem cells have sometimes been used to treat heart and other defects in children who have rare metabolic diseases and to treat children with certain anemias and leukemias. It has been shown that stem cells from this blood can migrate to damaged tissues and repair them.

Human stem cells have typically been extracted from surplus fertilized embryos produced during in vitro fertilization procedures. Some experimenters, however, have used embryos that were fertilized especially to produce stem cells. In so-called therapeutic cloning a nucleus from a patient's body cell, such as a skin cell, would be inserted into an egg that has had its nucleus removed to produce a blastocyst whose stem cells could be used to create tissue that would be compatible with that of the patient. Such a procedure was reported in 2005 to have been successfully undertaken in part by South Korean researchers who produced stem cell lines using genetic material from patients, but the data was subsequently shown to have been fabricated. (It was later determined, however, that the laboratory had produced stem cells using an egg that had developed through parthenogenesis, which does not involve fertilization or result in a viable human embryo.)

Because extraction of embryonic stem cells destroys the embryo, the use of embryonic stem cells has been opposed by opponents of abortion. Japanese researchers used retroviruses in 2007 to transfer genes to human skin cells and induce those cells to become stem cells (called induced pluripotent stem cells); the team had previously (2006) achieved similar results with mouse cells. In 2010 an American team announced that they had induced human skin cells to become stem cells using messenger RNA to reprogram the cells. Studies with mice have shown, however, that unlike embryonic stem cells induced stem cells are subject to attack by the recipient's immune system. Treatment with stem cells in humans is experimental and can have unexpected and damaging side-effects; some methods of producing mouse stem cells with retroviruses have led to significant rates of cancer when those cells have been transferred to mice.

The first embryonic stem cells to be isolated were extracted by British researchers from mouse blastocysts; the first human stem cells isolated and cultured were extracted by American scientists in 1998. In 1994 a National Institutes of Health (NIH) panel argued that creating human embryos for use in certain experiments might be justified, but Congress subsequently enacted (1995) a ban on federal financing for research involving human embryos in reaction to that report. The Dept. of Health and Human Services ruled in 1999, however, that that ban did not apply to financing work with stem cells, and guidelines for financing such research were issued by NIH the next year.

President George W. Bush, who had campaigned against financing embryonic stem cell research, announced in Aug., 2001, that he would support federal funding of research with embryonic stem cells, but only with the estimated 60 stem cell lines then existing. Some scientists challenged the assumption that these 60 stem cell lines would be sufficient for experimental and therapeutic needs, while others said the figure included some stem cell lines that had not yet been determined to be viable. In fact, in 2004, there were only 15 approved stem cell lines available to researchers funded by the U.S. government. The restrictions did not prevent other researchers, in the United States and elsewhere, from developing new embryonic stem cell lines and undertaking research with them using private funding, and California voted (2004) to create a $3 billion fund to underwrite embryonic stem cell research. A federal legislation that would have expanded the number of stem cell lines available for federally funded research was vetoed by the President Bush in July, 2006. The executive order issued by Bush was overturned in Mar., 2009, by President Barack Obama.

See also fetal tissue implant.

Science Q&A:

What are stem cells?

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Stem cells are derived from totipotent cells of the early embryo. As totipotent cells they have the ability to differentiate into all of the cell types ultimately present in the adult, including muscle, blood, nerves or any other tissue.

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Dictionary of Cultural Literacy: Science:

stem cell

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A cell from which a variety of other cells can develop through the process of cellular differentiation. Stem cells can produce only a certain group of cells (as with skin stem cells) or any cell in the body (as with embryonic stem cells).

  • A major controversy involves the question of whether nonembryonic stem cells should be used for medical purposes.

    • Oxford Dictionary of Biochemistry:

    stem cell

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    any member of the various groups of reserve cells that replace cells destroyed during the normal life of the animal, e.g. blood cells, epithelial cells, spermatogonia, and skin cells. Stem cells can divide without limit; after division, the stem cell may remain as a stem cell or proceed to terminal differentiation.

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    Wikipedia on Answers.com:

    Stem cell

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    Stem cell
    Mouse embryonic stem cells.jpg
    Mouse embryonic stem cells with fluorescent marker
    Human embryonic stem cell colony phase.jpg
    Human embryonic stem cell colony on mouse embryonic fibroblast feeder layer
    Latin cellula precursoria
    Code TH H2.00.01.0.00001
    This article is about the cell type. For the medical therapy, see Stem Cell Treatments.

    Stem cells are biological cells found in all multicellular organisms, that can divide (through mitosis) and differentiate into diverse specialized cell types and can self-renew to produce more stem cells. In mammals, there are two broad types of stem cells: embryonic stem cells, which are isolated from the inner cell mass of blastocysts, and adult stem cells, which are found in various tissues. In adult organisms, stem cells and progenitor cells act as a repair system for the body, replenishing adult tissues. In a developing embryo, stem cells can differentiate into all the specialized cells (these are called pluripotent cells), but also maintain the normal turnover of regenerative organs, such as blood, skin, or intestinal tissues.

    There are three sources of autologous adult stem cells: 1) Bone marrow, which requires extraction by harvesting, that is, drilling into bone (typically the femur or iliac crest), 2) Adipose tissue (lipid cells), which requires extraction by liposuction, and 3) Blood, which requires extraction through pheresis, wherein blood is drawn from the donor (similar to a blood donation), passed through a machine that extracts the stem cells and returns other portions of the blood to the donor. Stem cells can also be taken from umbilical cord blood. Of all stem cell types, autologous harvesting involves the least risk. By definition, autologous cells are obtained from one's own body, just as one may bank his or her own blood for elective surgical procedures.

    Highly plastic adult stem cells are routinely used in medical therapies, for example bone marrow transplantation. Stem cells can now be artificially grown and transformed (differentiated) into specialized cell types with characteristics consistent with cells of various tissues such as muscles or nerves through cell culture. Embryonic cell lines and autologous embryonic stem cells generated through therapeutic cloning have also been proposed as promising candidates for future therapies.[1] Research into stem cells grew out of findings by Ernest A. McCulloch and James E. Till at the University of Toronto in the 1960s.[2][3]

    Contents

    Properties

    The classical definition of a stem cell requires that it possess two properties:

    • Self-renewal: the ability to go through numerous cycles of cell division while maintaining the undifferentiated state.
    • Potency: the capacity to differentiate into specialized cell types. In the strictest sense, this requires stem cells to be either totipotent or pluripotent—to be able to give rise to any mature cell type, although multipotent or unipotent progenitor cells are sometimes referred to as stem cells. Apart from this it is said that stem cell function is regulated in a feed back mechanism.

    Self-renewal

    Two mechanisms to ensure that a stem cell population is maintained exist:

    1. Obligatory asymmetric replication: a stem cell divides into one father cell that is identical to the original stem cell, and another daughter cell that is differentiated
    2. Stochastic differentiation: when one stem cell develops into two differentiated daughter cells, another stem cell undergoes mitosis and produces two stem cells identical to the original.

    Potency definitions

    Pluripotent, embryonic stem cells originate as inner cell mass (ICM) cells within a blastocyst. These stem cells can become any tissue in the body, excluding a placenta. Only cells from an earlier stage of the embryo, known as the morula, are totipotent, able to become all tissues in the body and the extraembryonic placenta.
    Human embryonic stem cells
    A: Cell colonies that are not yet differentiated.
    B: Nerve cell
    Main article: Cell potency

    Potency specifies the differentiation potential (the potential to differentiate into different cell types) of the stem cell.[4]

    • Totipotent (a.k.a. omnipotent) stem cells can differentiate into embryonic and extraembryonic cell types. Such cells can construct a complete, viable organism.[4] 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.[5]
    • Pluripotent stem cells are the descendants of totipotent cells and can differentiate into nearly all cells,[4] i.e. cells derived from any of the three germ layers.[6]
    • Multipotent stem cells can differentiate into a number of cells, but only those of a closely related family of cells.[4]
    • Oligopotent stem cells can differentiate into only a few cells, such as lymphoid or myeloid stem cells.[4]
    • Unipotent cells can produce only one cell type, their own,[4] but have the property of self-renewal, which distinguishes them from non-stem cells (e.g., muscle stem cells).

    Identification

    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 defining 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 illustrated in vitro, using methods such as clonogenic assays, in which single cells are assessed for their ability to differentiate and self-renew.[7][8] Stem cells can also be isolated by their possession of a distinctive set of cell surface markers. However, in vitro culture conditions can alter the behavior of cells, making it unclear whether the cells will behave in a similar manner in vivo. There is considerable debate as to whether some proposed adult cell populations are truly stem cells.

    Embryonic

    Main article: Embryonic stem cell

    Embryonic stem (ES) cell lines are cultures of cells derived from the epiblast tissue of the inner cell mass (ICM) of a blastocyst or earlier morula stage embryos.[9] A blastocyst is an early stage embryo—approximately four to five days old in humans and consisting of 50–150 cells. ES cells are pluripotent and give rise during development to 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 sufficient and necessary stimulation for a specific cell type. They do not contribute to the extra-embryonic membranes or the placenta. The endoderm is composed of the entire gut tube and the lungs, the ectoderm gives rise to the nervous system and skin, and the mesoderm gives rise to muscle, bone, blood—in essence, everything else that connects the endoderm to the ectoderm.

    Nearly all research to date has made use of 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 as an extracellular matrix (for support) and require the presence of leukemia inhibitory factor (LIF).[10] Human ES cells are grown on a feeder layer of mouse embryonic fibroblasts (MEFs) and require the presence of basic fibroblast growth factor (bFGF or FGF-2).[11] Without optimal culture conditions or genetic manipulation,[12] embryonic stem cells will rapidly differentiate.

    A human embryonic stem cell is also defined by the expression of several transcription factors and cell surface proteins. The transcription factors Oct-4, Nanog, and Sox2 form the core regulatory network that ensures the suppression of genes that lead to differentiation and the maintenance of pluripotency.[13] The cell surface antigens most commonly used to identify hES cells are the glycolipids stage specific embryonic antigen 3 and 4 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.[14]

    There are currently no approved treatments using embryonic stem cells. The first human trial was approved by the US Food and Drug Administration in January 2009.[15] However, the human trial was not initiated until October 13, 2010 in Atlanta for spinal injury victims. On November 14, 2011 the company conducting the trial announced that it will discontinue further development of its stem cell programs.[16] 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 a 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.[17] Many nations currently have moratoria 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 for regenerative medicine and tissue replacement after injury or disease.

    Fetal

    The primitive stem cells located in the organs of fetuses are referred to as fetal stem cells.[18]

    Adult

    Main article: Adult stem cell
    Stem cell division and differentiation. 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

    Also known as somatic (from Greek Σωματικóς, "of the body") stem cells and germline (giving rise to gametes) stem cells, they can be found in children, as well as adults.[19]

    Pluripotent adult stem cells are rare and generally small in number but can be found in a number of tissues including umbilical cord blood.[20] A great deal of adult stem cell research to date has had the aim of characterizing the capacity of the cells to divide or self-renew indefinitely and their differentiation potential.[21] In mice, pluripotent stem cells are directly generated from adult fibroblast cultures. Unfortunately, many mice do not live long with stem cell organs.[22]

    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, dental pulp stem cell, etc.).[23][24]

    Adult stem cell treatments have been successfully used for many years to treat leukemia and related bone/blood cancers through bone marrow transplants.[25] Adult stem cells are also used in veterinary medicine to treat tendon and ligament injuries in horses.[26]

    The use of adult stem cells in research and therapy is not as controversial as the use of embryonic stem cells, because the production of adult stem cells does not require the destruction of an embryo. Additionally, in instances where adult stem cells are obtained from the intended recipient (an autograft), the risk of rejection is essentially non-existent. Consequently, more US government funding is being provided for adult stem cell research.[27]

    An extremely rich source for adult mesenchymal stem cells is the developing tooth bud of the mandibular third molar.[28] The stem cells eventually form enamel (ectoderm), dentin, periodontal ligament, blood vessels, dental pulp, nervous tissues, and a minimum of 29 different end organs. Because of extreme ease in collection at 8–10 years of age before calcification and minimal to no morbidity, these will probably constitute a major source of cells for personal banking, research and current or future therapies. These stem cells have been shown capable of producing hepatocytes.[citation needed]

    Amniotic

    Multipotent stem cells are also found in amniotic fluid. These stem cells are very active, expand extensively without feeders and are not tumorigenic. Amniotic stem cells are multipotent and can differentiate in cells of adipogenic, osteogenic, myogenic, endothelial, hepatic and also neuronal lines.[29] All over the world, universities and research institutes are studying amniotic fluid to discover all the qualities of amniotic stem cells, and scientists such as Anthony Atala[30][31] and Giuseppe Simoni [32][33][34] have discovered important results.

    Use of stem cells from amniotic fluid overcomes the ethical objections to using human embryos as a source of cells. Roman Catholic teaching forbids the use of embryonic stem cells in experimentation; accordingly, the Vatican newspaper "Osservatore Romano" called amniotic stem cells "the future of medicine".[35]

    It is possible to collect amniotic stem cells for donors or for autologuous use: the first US amniotic stem cells bank [36][37] was opened in 2009 in Medford, MA, by Biocell Center Corporation [38][39][40] and collaborates with various hospitals and universities all over the world.[41]

    Induced pluripotent

    Main article: Induced pluripotent stem cell

    These are not adult stem cells, but rather adult cells (e.g. epithelial cells) reprogrammed to give rise to pluripotent capabilities. Using genetic reprogramming with protein transcription factors, pluripotent stem cells equivalent to embryonic stem cells have been derived from human adult skin tissue.[42][43][44] Shinya Yamanaka and his colleagues at Kyoto University used the transcription factors Oct3/4, Sox2, c-Myc, and Klf4[42] in their experiments on cells from human faces. Junying Yu, James Thomson, and their colleagues at the University of Wisconsin–Madison used a different set of factors, Oct4, Sox2, Nanog and Lin28,[42] and carried out their experiments using cells from human foreskin.

    As a result of the success of these experiments, Ian Wilmut, who helped create the first cloned animal Dolly the Sheep, has announced that he will abandon somatic cell nuclear transfer as an avenue of research.[45]

    Frozen blood samples can be used as a source of induced pluripotent stem cells, opening a new avenue for obtaining the valued cells.[46]

    Lineage

    Main article: Stem cell line

    To ensure self-renewal, stem cells undergo two types of cell division (see Stem cell division and differentiation 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 a progenitor cell with limited self-renewal potential. Progenitors can go through several rounds of cell division before terminally differentiating 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 as receptors) between the daughter cells.[47]

    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 in Drosophila germarium have identified the signals decapentaplegic and adherens junctions that prevent germarium stem cells from differentiating.[48][49]

    Main article: 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 several transcription factors including the oncogene 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.[22] 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 combined transcription factors can directly induce other defined somatic cell fates; researchers identified three neural-lineage-specific transcription factors that could directly convert mouse fibroblasts (skin cells) into fully functional neurons. This "induced neurons" (iN) cell research inspires the researchers to induce other cell types implies that all cells are totipotent: with the proper tools, all cells may form all kinds of tissue.[50]

    Treatments

    Main article: Stem cell treatments
    Diseases and conditions where stem cell treatment is promising or emerging.[51] Bone marrow transplantation is, as of 2009, the only established use of stem cells.

    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, particularly bone marrow transplants that are used to treat leukemia.[52] In the future, medical researchers anticipate being able to use technologies derived from stem cell research to treat a wider variety of diseases including cancer, Parkinson's disease, spinal cord injuries, Amyotrophic lateral sclerosis, multiple sclerosis, and muscle damage, amongst a number of other impairments and conditions.[53][54] 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 risk that transplanted stem cells could form tumors and become cancerous if cell division continues uncontrollably.[55]

    Stem cells are widely studied, for their potential therapeutic use and for their inherent interest.[56]

    Supporters of embryonic stem cell research argue that such research should be pursued because the resultant treatments could have significant medical potential. It has been proposed that surplus embryos created for in vitro fertilization could be donated with consent and used for the research.

    The recent development of iPS cells has been called a bypass of the legal controversy. Laws limiting the destruction of human embryos have been credited for being the reason for development of iPS cells, but it is still not completely clear whether hiPS cells are equivalent to hES cells. Recent work demonstrates hotspots of aberrant epigenomic reprogramming in hiPS cells (Lister, R., et al., 2011).

    Research patents

    The patents covering a lot of work on human embryonic stem cells are owned by the Wisconsin Alumni Research Foundation (WARF). WARF does not charge academics to study human stem cells but does charge commercial users. WARF sold Geron Corp. 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.[57]

    A request for reviewing the WARF patents 5,843,780; 6,200,806; 7,029,913 US Patent and Trademark Office were filed by non-profit patent-watchdogs The Foundation for Taxpayer & Consumer Rights, and the Public Patent Foundation 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 by James A. Thomson, are rendered obvious by a 1990 paper and two textbooks. Based on this challenge, patent 7,029,913 was rejected in 2010. The two remaining hES WARF patents are due to expire in 2015.

    The outcome of this legal challenge is particularly relevant to the Geron Corp. as it can only license patents that are upheld.[58]

    Key research events

    • 1908: The term "stem cell" was proposed for scientific use by the Russian histologist Alexander Maksimov (1874–1928) at congress of hematologic society in Berlin. It postulated existence of haematopoietic stem cells.
    • 1960s: Joseph Altman and Gopal Das present scientific evidence of adult neurogenesis, ongoing stem cell activity in the brain; like André Gernez, their reports contradict Cajal's "no new neurons" dogma and are largely ignored.
    • 1963: McCulloch and Till illustrate the presence of self-renewing cells in mouse bone marrow.
    • 1968: Bone marrow transplant between two siblings successfully treats SCID.
    • 1978: Haematopoietic stem cells are discovered in human cord blood.
    • 1981: Mouse embryonic stem cells are derived from the inner cell mass by scientists Martin Evans, Matthew Kaufman, and Gail R. Martin. Gail Martin is attributed for coining the term "Embryonic Stem Cell".
    • 1992: Neural stem cells are cultured in vitro as neurospheres.
    • 1997: Leukemia is shown to originate from a haematopoietic stem cell, the first direct evidence for cancer stem cells.
    • 1998: James Thomson and coworkers derive the first human embryonic stem cell line at the University of Wisconsin–Madison.[59]
    • 1998: John Gearhart (Johns Hopkins University) extracted germ cells from fetal gonadal tissue (primordial germ cells) before developing pluripotent stem cell lines from the original extract.
    • 2000s: Several reports of adult stem cell plasticity are published.
    • 2001: Scientists at Advanced Cell Technology clone first early (four- to six-cell stage) human embryos for the purpose of generating embryonic stem cells.[60]
    • 2003: Dr. Songtao Shi of NIH discovers new source of adult stem cells in children's primary teeth.[61]
    • 2004–2005: Korean researcher Hwang Woo-Suk claims to have created several human embryonic stem cell lines from unfertilised human oocytes. The lines were later shown to be fabricated.
    • 2005: Researchers at Kingston University in England claim to have discovered a third category of stem cell, dubbed cord-blood-derived embryonic-like stem cells (CBEs), derived from umbilical cord blood. The group claims these cells are able to differentiate into more types of tissue than adult stem cells.
    • 2005: Researchers at UC Irvine's Reeve-Irvine Research Center are able to partially restore the ability of rats with paralyzed spines to walk through the injection of human neural stem cells.[62]
    • August 2006: Mouse Induced pluripotent stem cells: the journal Cell publishes Kazutoshi Takahashi and Shinya Yamanaka.[63]
    • October 2006: Scientists at Newcastle University in England create the first ever artificial liver cells using umbilical cord blood stem cells.[64][65]
    • January 2007: Scientists at Wake Forest University led by Dr. Anthony Atala and Harvard University report discovery of a new type of stem cell in amniotic fluid.[66] This may potentially provide an alternative to embryonic stem cells for use in research and therapy.[67]
    • June 2007: Research reported by three different groups shows that normal skin cells can be reprogrammed to an embryonic state in mice.[68] In the same month, scientist Shoukhrat Mitalipov reports the first successful creation of a primate stem cell line through somatic cell nuclear transfer[69]
      Martin Evans, a co-winner of the Nobel Prize in recognition of his gene targeting work.
    • October 2007: Mario Capecchi, Martin Evans, and Oliver Smithies win the 2007 Nobel Prize for Physiology or Medicine for their work on embryonic stem cells from mice using gene targeting strategies producing genetically engineered mice (known as knockout mice) for gene research.[70]
    • November 2007: Human induced pluripotent stem cells: Two similar papers released by their respective journals prior to formal publication: in Cell by Kazutoshi Takahashi and Shinya Yamanaka, "Induction of pluripotent stem cells from adult human fibroblasts by defined factors",[71] and in Science by Junying Yu, et al., from the research group of James Thomson, "Induced pluripotent stem cell lines derived from human somatic cells":[72] pluripotent stem cells generated from mature human fibroblasts. It is possible now to produce a stem cell from almost any other human cell instead of using embryos as needed previously, albeit the risk of tumorigenesis due to c-myc and retroviral gene transfer remains to be determined.
    • January 2008: Robert Lanza and colleagues at Advanced Cell Technology and UCSF create the first human embryonic stem cells without destruction of the embryo[73]
    • January 2008: Development of human cloned blastocysts following somatic cell nuclear transfer with adult fibroblasts[74]
    • February 2008: 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.[75]
    • 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[76]
    • October 2008: Sabine Conrad and colleagues at Tübingen, Germany generate pluripotent stem cells from spermatogonial cells of adult human testis by culturing the cells in vitro under leukemia inhibitory factor (LIF) supplementation.[77]
    • 30 October 2008: Embryonic-like stem cells from a single human hair.[78]
    • 1 March 2009: Andras Nagy, Keisuke Kaji, et al. 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.[79][80][81] The use of electroporation is said to allow for the temporary insertion of genes into the cell.[82][83][84][85]
    • 28 May 2009 Kim et al. 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'.[86]
    • 11 October 2010 First trial of embryonic stem cells in humans.[87]
    • 25 October 2010: Ishikawa et al. write in the Journal of Experimental Medicine that research shows that transplanted cells that contain their new host's nuclear DNA could still be rejected by the invidual's immune system due to foreign mitochondrial DNA. Tissues made from a person's stem cells could therefore be rejected, because mitochondrial genomes tend to accumulate mutations.[88]
    • 2011: Israeli scientist Inbar Friedrich Ben-Nun led a team which produced the first stem cells from endangered species, a breakthrough that could save animals in danger of extinction.[89]

    See also

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