Stem cells

Stem cells are that can  into other types of cells, and can also  in self-renewal to produce more of the same type of stem cells.

In s, there are two broad types of stem cells: s, which are isolated from the of s in early embryonic development, and s, which are found in various  of fully developed mammals. In organisms, stem cells and s act as a repair system for the body, replenishing adult tissues. In a developing, stem cells can differentiate into all the specialized cells—ectoderm, endoderm and mesoderm (see )—but also maintain the normal turnover of regenerative organs, such as blood, skin, or intestinal tissues.

There are three known accessible sources of adult stem cells in humans: ,, and. Stem cells can also be taken from just after birth. Of all stem cell therapy types, autologous harvesting involves the least risk.

Adult stem cells are frequently used in various medical therapies (e.g., ). Stem cells can now be and transformed (differentiated) into specialized cell types with characteristics consistent with cells of various tissues such as muscles or nerves. Embryonic s and embryonic stem cells generated through  or  have also been proposed as promising candidates for future therapies. Research into stem cells grew out of findings by and  at the  in the 1960s.

Properties
The classical definition of a stem cell requires that it possesses two properties:
 * Self-renewal: the ability to go through numerous of  while maintaining the undifferentiated state.
 * Potency: the capacity to into specialized cell types. In the strictest sense, this requires stem cells to be either  or —to be able to give rise to any mature cell type, although  or  s 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 ensure that a stem cell population is maintained:

1. : a stem cell divides into one mother cell that is identical to the original stem cell, and another daughter cell that is differentiated.

When a stem cell self-renews it divides and does not disrupt the undifferentiated state. This self-renewal demands control of cell cycle as well as upkeep of multipotency or pluripotency, which all depends on the stem cell.

2. Stochastic differentiation: when one stem cell develops into two differentiated daughter cells, another stem cell undergoes and produces two stem cells identical to the original.

Potency meaning
Potency specifies the differentiation potential (the potential to differentiate into different cell types) of the stem cell.
 * (a.k.a. omnipotent) stem cells can differentiate into embryonic and extraembryonic cell types. Such cells can construct a complete, viable organism. These cells are produced from the of an egg and sperm cell. Cells produced by the first few divisions of the fertilized egg are also totipotent.
 * stem cells are the descendants of totipotent cells and can differentiate into nearly all cells, i.e. cells derived from any of the three s.
 * stem cells can differentiate into a number of cell types, but only those of a closely related family of cells.
 * stem cells can differentiate into only a few cell types, such as lymphoid or myeloid stem cells.
 * cells can produce only one cell type, their own, but have the property of self-renewal, which distinguishes them from non-stem cells (e.g. s, which cannot self-renew).

Identification
In practice, stem cells are identified by whether they can regenerate tissue. For example, the defining test for bone marrow or s (HSCs) is the ability to transplant the cells and save an individual without HSCs. This demonstrates that the cells can produce new blood cells over a long term. 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 , using methods such as s, in which single cells are assessed for their ability to differentiate and self-renew. 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 shall behave in a similar manner . There is considerable debate as to whether some proposed adult cell populations are truly stem cells.

Embryonic
s (ESCs) are the cells of the of a, formed prior to  in the uterus. In the  stage is reached 4–5 days after, at which time it consists of 50–150 cells. ESCs are and give rise during development to all derivatives of the three  s:,  and. In other words, they can develop into each of the more than 200 cell types of the adult when given sufficient and necessary stimulation for a specific cell type. They do not contribute to the s or to the.

During embryonic development the cells of the inner cell mass continuously divide and become more specialized. For example, a portion of the ectoderm in the dorsal part of the embryo specializes as '', which will become the future. Later in development, causes the neurectoderm to form the. At the neural tube stage, the anterior portion undergoes to generate or 'pattern' the basic form of the brain. At this stage of development, the principal cell type of the CNS is considered a.

The neural stem cells self-renew and at some point transition into (RGPs). Early-formed RGPs self-renew by symmetrical division to form a reservoir group of s. These cells transition to a state and start to divide  to produce a large diversity of many different neuron types, each with unique gene expression, morphological, and functional characteristics. The process of generating neurons from radial glial cells is called. The radial glial cell, has a distinctive bipolar morphology with highly elongated processes spanning the thickness of the neural tube wall. It shares some characteristics, most notably the expression of  (GFAP). The radial glial cell is the primary neural stem cell of the developing CNS, and its cell body resides in the, adjacent to the developing. Neural stem cells are committed to the neuronal lineages (s, s, and s), and thus their potency is restricted.

Nearly all research to date has made use of mouse embryonic stem cells (mES) or human embryonic stem cells (hES) derived from the early inner cell mass. 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 as an  (for support) and require the presence of  (LIF) in serum media. A drug cocktail containing inhibitors to and the, called 2i, has also been shown to maintain pluripotency in stem cell culture. Human ESCs are grown on a feeder layer of mouse embryonic and require the presence of basic fibroblast growth factor (bFGF or FGF-2). Without optimal culture conditions or genetic manipulation, 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, , and form the core regulatory network that ensures the suppression of genes that lead to differentiation and the maintenance of pluripotency. The cell surface antigens most commonly used to identify hES cells are the glycolipids 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.

By using human embryonic stem cells to produce specialized cells like nerve cells or heart cells in the lab, scientists can gain access to adult human cells without taking tissue from patients. They can then study these specialized adult cells in detail to try to discern complications of diseases, or to study cell reactions to proposed new drugs.

Because of their combined abilities of unlimited expansion and pluripotency, embryonic stem cells remain a theoretically potential source for and tissue replacement after injury or disease., however, there are currently no approved treatments using ES cells. The first human trial was approved by the US Food and Drug Administration in January 2009. However, the human trial was not initiated until October 13, 2010 in Atlanta for. On November 14, 2011 the company conducting the trial announced that it will discontinue further development of its stem cell programs. Differentiating ES cells into usable cells while avoiding transplant rejection are just a few of the hurdles that embryonic stem cell researchers still face.Embryonic stem cells, being pluripotent, require specific signals for correct differentiation — if injected directly into another body, ES cells will differentiate into many different types of cells, causing a. Ethical considerations regarding the use of unborn human tissue are another reason for the lack of approved treatments using embryonic stem cells. Many nations currently have or limitations on either human ES cell research or the production of new human ES cell lines.

Fetal
The primitive stem cells located in the organs of are referred to as fetal stem cells. There are two types of fetal stem cells:


 * 1) Fetal proper stem cells come from the tissue of the fetus proper, and are generally obtained after an . These stem cells are not immortal but have a high level of division and are multipotent.
 * 2) Extraembryonic fetal stem cells come from s, and are generally not distinguished from adult stem cells. These stem cells are acquired after birth, they are not immortal but have a high level of cell division, and are pluripotent.

Adult
Adult stem cells, also called (from Greek σωματικóς, "of the body") stem cells, are stem cells which maintain and repair the tissue in which they are found. They can be found in children, as well as adults.

There are three known accessible sources of adult stem cells in humans: Stem cells can also be taken from just after birth. 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.
 * , which requires extraction by harvesting, that is, drilling into bone (typically the or ).
 * 1) Adipose tissue (fat cells), which requires extraction by liposuction.
 * 2) Blood, which requires extraction through, wherein blood is drawn from the donor (similar to a blood donation), and passed through a machine that extracts the stem cells and returns other portions of the blood to the donor.

Pluripotent adult stem cells are rare and generally small in number, but they can be found in umbilical cord blood and other tissues. Bone marrow is a rich source of adult stem cells, which have been used in treating several conditions including liver cirrhosis, chronic limb ischemia and endstage heart failure. The quantity of bone marrow stem cells declines with age and is greater in males than females during reproductive years. Much adult stem cell research to date has aimed to characterize their potency and self-renewal capabilities. DNA damage accumulates with age in both stem cells and the cells that comprise the stem cell environment. This accumulation is considered to be responsible, at least in part, for increasing stem cell dysfunction with aging (see ).

Most adult stem cells are lineage-restricted and are generally referred to by their tissue origin (, adipose-derived stem cell,, , etc.). s (multi-lineage differentiating stress enduring cells) are a recently discovered pluripotent stem cell type found in multiple adult tissues, including adipose, dermal fibroblasts, and bone marrow. While rare, muse cells are identifiable by their expression of, a marker for undifferentiated stem cells, and general mesenchymal stem cells markers such as. When subjected to single cell suspension culture, the cells will generate clusters that are similar to embryoid bodies in morphology as well as gene expression, including canonical pluripotency markers, , and.

Adult stem cell treatments have been successfully used for many years to treat leukemia and related bone/blood cancers through bone marrow transplants. 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 as as the use of s, because the production of adult stem cells does not require the destruction of an. Additionally, in instances where adult stem cells are obtained from the intended recipient (an ), the risk of rejection is essentially non-existent. Consequently, more US government funding is being provided for adult stem cell research.

With the increasing demand of human adult stem cells for both research and clinical purposes (typically 1–5 million cells per kg of body weight are required per treatment) it becomes of utmost importance to bridge the gap between the need to expand the cells in vitro and the capability of harnessing the factors underlying replicative senescence. Adult stem cells are known to have a limited lifespan in vitro and to enter replicative senescence almost undetectably upon starting in vitro culturing.

Amniotic
Multipotent stem cells are also found in. These stem cells are very active, expand extensively without feeders and are not tumorigenic. are multipotent and can differentiate in cells of adipogenic, osteogenic, myogenic, endothelial, hepatic and also neuronal lines. Amniotic stem cells are a topic of active research.

Use of stem cells from overcomes the ethical objections to using human embryos as a source of cells. teaching forbids the use of embryonic stem cells in experimentation; accordingly, the newspaper "" called amniotic stem cells "the future of medicine".

It is possible to collect amniotic stem cells for donors or for autologous use: the first US amniotic stem cells bank was opened in 2009 in Medford, MA, by  Corporation and collaborates with various hospitals and universities all over the world.

Induced pluripotent
Adult stem cells have limitations with their potency; unlike s (ESCs), they are not able to differentiate into cells from all three. As such, they are deemed.

However, allows for the creation of pluripotent cells, s (iPSCs), from adult cells. These are not adult stem cells, but adult cells (e.g. epithelial cells) reprogrammed to give rise to cells with pluripotent capabilities. Using genetic reprogramming with protein, pluripotent stem cells with ESC-like capabilities have been derived. The first demonstration of induced pluripotent stem cells was conducted by and his colleagues at. They used the transcription factors, , , and to reprogram mouse fibroblast cells into pluripotent cells. Subsequent work used these factors to induce pluripotency in human fibroblast cells. ,, and their colleagues at the used a different set of factors, Oct4, Sox2, Nanog and Lin28, and carried out their experiments using cells from human. However, they were able to replicate 's finding that inducing pluripotency in human cells was possible.

Induced pluripotent stem cells differ from embryonic stem cells. They share many similar properties, such as and differentiation potential, the expression of  genes,  patterns,  and  formation, and viable  formation, but there are many differences within these properties. The chromatin of iPSCs appears to be more "closed" or methylated than that of ESCs. Similarly, the gene expression pattern between ESCs and iPSCs, or even iPSCs sourced from different origins. There are thus questions about the "completeness" of and the somatic memory of induced pluripotent stem cells. Despite this, inducing s to be pluripotent appears to be viable.

As a result of the success of these experiments,, who helped create the first cloned animal , has announced that he will abandon as an avenue of research.

Furthermore, induced pluripotent stem cells provide several therapeutic advantages. Like ESCs, they are. They thus have great differentiation potential; theoretically, they could produce any cell within the human body (if to pluripotency was "complete"). Moreover, unlike ESCs, they potentially could allow doctors to create a pluripotent stem cell line for each individual patient. Frozen blood samples can be used as a valuable source of induced pluripotent stem cells. Patient specific stem cells allow for the screening for side effects before drug treatment, as well as the reduced risk of transplantation rejection. Despite their current limited use therapeutically, iPSCs hold create potential for future use in medical treatment and research.

Lineage
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 with limited self-renewal potential. Progenitors can go through several rounds of cell division before terminally 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 ) 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 in Drosophila germarium have identified the signals and adherens junctions that prevent germarium stem cells from differentiating.

Treatments
Stem cell therapy is the use of stem cells to treat or prevent a disease or condition. is a form of stem cell therapy that has been used for many years without controversy.

Advantages
Stem cell treatments may lower symptoms of the disease or condition that is being treated. The lowering of symptoms may allow patients to reduce the drug intake of the disease or condition. Stem cell treatment may also provide knowledge for society to further stem cell understanding and future treatments.

Disadvantages
Stem cell treatments may require because of a requirement for radiation before the transplant to remove the person's previous cells, or because the patient's immune system may target the stem cells. One approach to avoid the second possibility is to use stem cells from the same patient who is being treated.

Pluripotency in certain stem cells could also make it difficult to obtain a specific cell type. It is also difficult to obtain the exact cell type needed, because not all cells in a population differentiate uniformly. Undifferentiated cells can create tissues other than desired types.

Some stem cells form tumors after transplantation; pluripotency is linked to tumor formation especially in embryonic stem cells, fetal proper stem cells, induced pluripotent stem cells. Fetal proper stem cells form tumors despite multipotency.

Research
Some of the fundamental s covering human embryonic stem cells are owned by the (WARF) – they are patents 5,843,780, 6,200,806, and 7,029,913 invented by. WARF does not enforce these patents against academic scientists, but does enforce them against companies.

In 2006, a request for the (USPTO) to re-examine the three patents was filed by the  on behalf of its client, the non-profit patent-watchdog group  (formerly the Foundation for Taxpayer and Consumer Rights). In the re-examination process, which involves several rounds of discussion between the USPTO and the parties, the USPTO initially agreed with Consumer Watchdog and rejected all the claims in all three patents, however in response, WARF amended the claims of all three patents to make them more narrow, and in 2008 the USPTO found the amended claims in all three patents to be patentable. The decision on one of the patents (7,029,913) was appealable, while the decisions on the other two were not. Consumer Watchdog appealed the granting of the '913 patent to the USPTO's Board of Patent Appeals and Interferences (BPAI) which granted the appeal, and in 2010 the BPAI decided that the amended claims of the '913 patent were not patentable. However, WARF was able to re-open prosecution of the case and did so, amending the claims of the '913 patent again to make them more narrow, and in January 2013 the amended claims were allowed.

In July 2013, Consumer Watchdog announced that it would appeal the decision to allow the claims of the '913 patent to the US (CAFC), the federal appeals court that hears patent cases. At a hearing in December 2013, the CAFC raised the question of whether Consumer Watchdog had to appeal; the case could not proceed until that issue was resolved.

Treatment
Diseases and conditions where stem cell treatment is being investigated include:
 * and repair
 * due to
 * repair
 * Anti- treatments
 * reversal
 * Replace missing
 * Repair
 * Restore  and repair damage to the
 * due to absence of spermatogonial stem cells. In recent studies, scientist have found a way to solve this problem by reprogramming a cell and turning it into a spermatozoon. Other studies have proven the restoration of spermatogenesis by introducing human iPSC cells in mice testicles. This could mean the end of azoospermia.
 * : oocytes made from embryonic stem cells. Recently, scientists have found the ovarian stem cells, a rare type of cells (0,014%) found in the ovary. It is not clear their existence yet, but the impact it could have are limitless. It could be used as a treatment not only for infertility, but also for premature ovarian insufficiency.
 * reversal
 * Replace missing
 * Repair
 * Restore  and repair damage to the
 * due to absence of spermatogonial stem cells. In recent studies, scientist have found a way to solve this problem by reprogramming a cell and turning it into a spermatozoon. Other studies have proven the restoration of spermatogenesis by introducing human iPSC cells in mice testicles. This could mean the end of azoospermia.
 * : oocytes made from embryonic stem cells. Recently, scientists have found the ovarian stem cells, a rare type of cells (0,014%) found in the ovary. It is not clear their existence yet, but the impact it could have are limitless. It could be used as a treatment not only for infertility, but also for premature ovarian insufficiency.
 * due to absence of spermatogonial stem cells. In recent studies, scientist have found a way to solve this problem by reprogramming a cell and turning it into a spermatozoon. Other studies have proven the restoration of spermatogenesis by introducing human iPSC cells in mice testicles. This could mean the end of azoospermia.
 * : oocytes made from embryonic stem cells. Recently, scientists have found the ovarian stem cells, a rare type of cells (0,014%) found in the ovary. It is not clear their existence yet, but the impact it could have are limitless. It could be used as a treatment not only for infertility, but also for premature ovarian insufficiency.
 * : oocytes made from embryonic stem cells. Recently, scientists have found the ovarian stem cells, a rare type of cells (0,014%) found in the ovary. It is not clear their existence yet, but the impact it could have are limitless. It could be used as a treatment not only for infertility, but also for premature ovarian insufficiency.

Research is underway to develop various sources for stem cells, and to apply stem cell treatments for and conditions,, , and other conditions. Research is also underway in generating s using stem cells, which would allow for further understanding of human development,, and modeling of human diseases.

In more recent years, with the ability of scientists to isolate and culture, and with scientists' growing ability to create stem cells using and techniques to create , controversy has crept in, both related to  and to.

and drug-induced liver injury account for a substantial number of failures of new drugs in development and market withdrawal, highlighting the need for screening assays such as stem cell-derived hepatocyte-like cells, that are capable of detecting toxicity early in the process.