Stem cell

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Mouse embryonic stem cells with fluorescent marker.
Human Embryonic Stem cell colony on mouse embryonic fibroblast feeder layer.

Stem cells are primal cells found in all multi-cellular organisms. They retain the ability to renew themselves through mitotic cell division and can differentiate into a diverse range of specialized cell types. Research in the human stem cell field grew out of findings by Canadian scientists Ernest A. McCulloch and James E. Till in the 1960s.[1][2]

The three broad categories of mammalian stem cells are: embryonic stem cells, derived from blastocysts, adult stem cells, which are found in adult tissues, and cord blood stem cells, which are found in the umbilical cord. In a developing embryo, stem cells can differentiate into all of the specialized embryonic tissues. In adult organisms, stem cells and progenitor cells act as a repair system for the body, replenishing specialized cells.

As stem cells can be grown and transformed into specialized cells with characteristics consistent with cells of various tissues such as muscles or nerves through cell culture, their use in medical therapies has been proposed. In particular, embryonic cell lines, autologous embryonic stem cells generated through therapeutic cloning, and highly plastic adult stem cells from the umbilical cord blood or bone marrow are touted as promising candidates.[3]

Stem cell properties

Defining properties

The rigorous definition of a stem cell requires that it possesses two properties:

  • Self-renewal - the ability to go through numerous cycles of cell division while maintaining the undifferentiated state.
  • Unlimited potency - the capacity to differentiate into any mature cell type. In a strict sense, this requires stem cells to be either totipotent or pluripotent, although some multipotent and/or unipotent progenitor cells are sometimes referred to as stem cells.

These properties can be illustrated in vitro, using methods such as clonogenic assays, where the progeny of a single cell is characterized.[4][5] 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. Considerable debate exists whether some proposed adult cell populations are truly stem cells.

Potency definitions

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.

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

  • Totipotent stem 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. These cells can differentiate into embryonic and extraembryonic cell types.
  • Pluripotent stem cells are the descendants of totipotent cells and can differentiate into cells derived from any of the three germ layers.
  • Multipotent stem cells can produce only cells of a closely related family of cells (e.g. hematopoietic stem cells differentiate into red blood cells, white blood cells, platelets, etc.).
  • Unipotent cells can produce only one cell type, but have the property of self-renewal which distinguishes them from non-stem cells.

Embryonic stem cells

Main article: Embryonic stem cell

Embryonic stem cell lines (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 [6]. 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.

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).[7] 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).[8] Without optimal culture conditions or genetic manipulation,[9] 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 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.[10] The cell surface proteins 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.[11]

After twenty years of research, there are no approved treatments or human trials using embryonic stem cells. Their tendency to produce tumors and malignant carcinomas, cause transplant rejection, and form the wrong kinds of cells are just a few of the hurdles that embryonic stem cell researchers still face.[12] 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.

Adult stem cells

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

The term adult stem cell refers to any cell which is found in a developed organism that has two properties: the ability to divide and create another cell like itself and also divide and create a cell more differentiated than itself. Also known as somatic (from Greek Σωματικóς, "of the body") stem cells, they can be found in children, as well as adults[13]. Pluripotent adult stem cells are rare and generally small in number but can be found in a number of tissues including umbilical cord blood.[14] 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.).[15][16]

A great deal of adult stem cell research has focused on clarifying their capacity to divide or self-renew indefinitely and their differentiation potential.[17] In mice, pluripotent stem cells can be directly generated from adult fibroblast cultures.[18]

While embryonic stem cell potential remains untested, adult stem cell treatments have been used for many years to treat successfully leukemia and related bone/blood cancers through bone marrow transplants.[19] The use of adult stem cells in research and therapy is not as controversial as embryonic stem cells, because the production of adult stem cells does not require the destruction of an embryo. Consequently, more US government funding is being provided for adult stem cell research[20].

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.[21]

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 dpp and adherins junctions that prevent germarium stem cells from differentiating[22][23].

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.[24] However, the need to transform these cells with an oncogene may prevent the use of this approach in therapy.

Treatments

Main article: Stem cell treatments

Medical researchers believe that stem cell therapy has the potential to change radically the treatment of human disease. A number of adult stem cell therapies already exist, particularly bone marrow transplants that are used to treat leukemia.[25] 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, and muscle damage, amongst a number of other impairments and conditions.[26][27] 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.

Stem cells, however, are already used extensively in research, and some scientists do not see cell therapy as the first goal of the research, but see the investigation of stem cells as a goal worthy in itself. [28]

Controversy surrounding stem cell research

Main article: Stem cell controversy

There exists a widespread controversy over stem cell research that emanates from the techniques used in the creation and usage of stem cells. Human embryonic stem cell research is particularly controversial because, with the present state of technology, starting a stem cell line requires the destruction of a human embryo and/or therapeutic cloning. However, recently, it has been shown in principle that embryonic stem cell lines can be generated using a single-cell biopsy similar to that used in preimplantation genetic diagnosis that may allow stem cell creation without embryonic destruction.[29]

Opponents of the research argue that embryonic stem cell technologies are a slippery slope to reproductive cloning and can fundamentally devalue human life. Those in the pro-life movement argue that a human embryo is a human life and is therefore entitled to protection.

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 for in vitro fertilisation could be donated with consent and used for the research.

The ensuing debate has prompted authorities around the world to seek regulatory frameworks and highlighted the fact that stem cell research represents a social and ethical challenge.

Key stem cell research events

  • 1960s - Joseph Altman and Gopal Das present evidence of adult neurogenesis, ongoing stem cell activity in the brain; 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.
  • 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.
  • 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.[30]
  • 2003 - Dr. Songtao Shi of NIH discovers new source of adult stem cells in children's primary teeth.[31]
  • 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.
  • August 2006 - Cell Journal publishes Kazutoshi Takahashi and Shinya Yamanaka, "Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors".
  • 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.[5] This may potentially provide an alternative to embryonic stem cells for use in research and therapy. [6]
  • March 2007 - Scientists in England create the first ever artificial livers using umbilical cord blood stem cells.[32]
  • June 2007 - Research reported by three different groups shows that normal skin cells can be reprogrammed to an embryonic state in mice. [33] In the same month, scientist Shoukhrat Mitalipov reports the first successful creation of a primate stem cell line through somatic cell nuclear transfer[34]


Stem cell funding & policy debate in the US

  • 1995 - U.S. President Bill Clinton signs into law the Dickey Amendment which prohibited federally appropriated funds to be used for research where human embryos would be either created or destroyed.
  • 02 November, 2004 - California voters approve Proposition 71, which provides $3 billion in state funds over ten years to human embryonic stem cell research.
  • 2001-2006 - U.S. President George W. Bush endorses the Congress in providing federal funding for embryonic stem cell research of approximately $100 million as well as $250 million for research on adult and animal stem cells. He also enacts laws that restrict federally-funded stem cell research on embryonic stem cells to the already derived cell lines.
  • 5 May, 2006 - Senator Rick Santorum introduces bill number S. 2754, or the Alternative Pluripotent Stem Cell Therapies Enhancement Act, into the U.S. Senate.
  • 18 July, 2006 - The U.S. Senate passes the Stem Cell Research Enhancement Act H.R. 810 and votes down Senator Santorum's S. 2754.
  • 19 July, 2006 - President George W. Bush vetoes H.R. 810 (Stem Cell Research Enhancement Act), a bill that would have reversed the Clinton-era law which made it illegal for federal money to be used for research where stem cells are derived from the destruction of an embryo.
  • 07 November, 2006 - The people of the U.S. state of Missouri passed Amendment 2, which allows usage of any stem cell research and therapy allowed under federal law, but prohibits human reproductive cloning.[35]
  • 16 February, 2007 – The California Institute for Regenerative Medicine became the biggest financial backer of human embryonic stem cell research in the United States when they awarded nearly $45 million in research grants. [36]

See also

References

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  19. ^ [3], Bone Marrow Transplant
  20. ^ [4],USDHHS Stem Cell FAQ 2004
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  25. ^ Gahrton G, Björkstrand B (2000). "Progress in haematopoietic stem cell transplantation for multiple myeloma". J Intern Med. 248 (3): 185–201. doi:10.1046/j.1365-2796.2000.00706.x. PMID 10971785.
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  29. ^ http://abcnews.go.com/Health/wireStory?id=3307505
  30. ^ http://www.sciam.com/article.cfm?articleID=0008B8F9-AC62-1C75-9B81809EC588EF21&pageNumber=4&catID=4
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  32. ^ http://discovermagazine.com/2007/mar/good-news-for-alcoholics
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  34. ^ Mitalipov SM, Zhou Q, Byrne JA, Ji WZ, Norgren RB, Wolf DP (2007). "Reprogramming following somatic cell nuclear transfer in primates is dependent upon nuclear remodeling". Hum Reprod. 22 (8): 2232–42. PMID 17562675.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  35. ^ Full-text of Missouri Constitution Amendment 2
  36. ^ Calif. Awards $45M in Stem Cell Grants Associated Press, Feb. 17, 2007.

External links

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