Stem cells are primal cells found in all multi-cellular organisms that 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 readily grown and transformed into specialised 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]

Mouse embryonic stem cells with fluorescent marker.

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 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 with in a blastocyst. The stem cells can become any tissue in the body, excluding a placenta. Only the morula's cells are totipotent, able to become all tissues and a placenta.
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 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. A blastocyst is an early stage embryo - approximately 4 to 5 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.

When given no stimuli for differentiation, ES cells will continue to divide in vitro and each daughter cell will remain pluripotent. The pluripotency of ES cells has been rigorously demonstrated in vitro and in vivo, thus they can be indeed classified as stem cells.

After 20 years of research, there are no approved treatment 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 have been unable to overcome.[6],[7] 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. In practice, such medical advancements are already being made using adult stem cells.


Adult stem cells

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
Adult stem cells are undifferentiated cells found throughout the body that divide to replenish dying cells and regenerate damaged tissues. Also known as somatic (from Greek Σωματικóς, of the body) stem cells, they can be found in children, as well as adults[8].

A great deal of adult stem cell research has focused on clarifying their capacity to divide or self-renew indefinitely and their differentiation potential.[9] Adult stem cells, like embryonic stem cells, have pluripotent potential and can differentiate into cells derived from all three germ layers. Pluripotent stem cells can be directly generated from adult fibroblast cultures.[10]

While embryonic stem cell potential remains theoretical, adult stem cell treatments are already being used to successfully treat many diseases. 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. Adult stem cells also pose no medical dangers to the patient. Among the most stunning advancements in adult stem cell therapy are treatments for Parkinson's disease, juvenile diabetes, and spinal cord injuries. A list of current treatments can be found at Check The Score

In contrast with the embryonic stem cell research, more US government funding is being provided for adult stem cell research. Adult stem cells can be isolated from a tissue sample obtained from an adult (or cord blood, bone marrow, and other adult tissues). They have mainly been studied in humans and model organisms such as mice and rats.


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, however, there is no evidence for this mechanism.

An alternative theory is that stem cells remain undifferentiated from 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[11][12].

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.[13] 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 radically 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.[14] 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.[15][16] 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. [17].


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. Opponents of the research argue that this practice is a slippery slope to reproductive cloning and tantamount to the instrumentalization of a human being. Contrarily, some medical researchers in the field argue that it is necessary to pursue embryonic stem cell research because the resultant technologies could have significant medical potential, and that excess embryos created for invitro fertilisation could be donated with consent and used for the research. This in turn, conflicts with opponents in the pro-life movement, who argue that a human embryo is a human life and is therefore entitled to protection. 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 events in stem cell research
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
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.
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
2003 - Dr. Songtao Shi of NIH discovers new source of adult stem cells in children's primary teeth[18]
02 November, 2004 - California voters approve Proposition 71, which provides $3 billion in state funds over ten years to human embryonic stem cell research.
2004-2005 - Korean researcher Hwang Woo-Suk claims to have created several human embryonic stem cell lines from unfertilised human oocytes. The lines are 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 embryoniclike 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.
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 dollars 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.
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
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.[19][20]
07 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.[2] This may potentially provide an alternative to embryonic stem cells for use in research and therapy. [3]
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. [21]
06 June 2007 - Research reported this week by three different groups shows that normal skin cells can be reprogrammed to an embryonic state in mice. The race is now on to apply the surprisingly straightforward procedure to human cells. [22]