Stem cell
Stem cell | |
---|---|
ultrastructural characteristics | |
Details | |
Identifiers | |
Latin | cellula praecursoria |
MeSH | D013234 |
TH | H1.00.01.0.00028, H2.00.01.0.00001 |
FMA | 63368 |
Anatomical terminology] |
In
In
Research into stem cells grew out of findings by Canadian biologists
History
The term stem cell was coined by
The key properties of a stem cell were first defined by Ernest McCulloch and James Till at the University of Toronto and the Ontario Cancer Institute in the early 1960s. They discovered the blood-forming stem cell, the hematopoietic stem cell (HSC), through their pioneering work in mice. McCulloch and Till began a series of experiments in which bone marrow cells were injected into irradiated mice. They observed lumps in the spleens of the mice that were linearly proportional to the number of bone marrow cells injected. They hypothesized that each lump (colony) was a clone arising from a single marrow cell (stem cell). In subsequent work, McCulloch and Till, joined by graduate student Andrew John Becker and senior scientist Louis Siminovitch, confirmed that each lump did in fact arise from a single cell. Their results were published in Nature in 1963. In that same year, Siminovitch was a lead investigator for studies that found colony-forming cells were capable of self-renewal, which is a key defining property of stem cells that Till and McCulloch had theorized.[9]
The first therapy using stem cells was a
In 1981, embryonic stem (ES) cells were first isolated and successfully cultured using mouse blastocysts by British biologists Martin Evans and Matthew Kaufman. This allowed the formation of murine genetic models, a system in which the genes of mice are deleted or altered in order to study their function in pathology. By 1998, human embryonic stem cells were first isolated by American biologist James Thomson, which made it possible to have new transplantation methods or various cell types for testing new treatments. In 2006, Shinya Yamanaka's team in Kyoto, Japan converted fibroblasts into pluripotent stem cells by modifying the expression of only four genes. The feat represents the origin of induced pluripotent stem cells, known as iPS cells.[7]
In 2011, a female maned wolf, run over by a truck, underwent stem cell treatment at the Zoo Brasília, this being the first recorded case of the use of stem cells to heal injuries in a wild animal.[11][12]
Properties
The classical definition of a stem cell requires that it possesses two properties:
- Self-renewal: the ability to go through numerous cycles of cell growth and cell division, known as cell proliferation, while maintaining the undifferentiated state.
- unipotent progenitor cellsare sometimes referred to as stem cells. Apart from this, it is said that stem cell function is regulated in a feedback mechanism.
Self-renewal
Two mechanisms ensure that a stem cell population is maintained (does not shrink in size):
1. Asymmetric cell division: a stem cell divides into one mother cell, which is identical to the original stem cell, and another daughter cell, which 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.[13]
2. Stochastic differentiation: when one stem cell grows and divides into two differentiated daughter cells, another stem cell undergoes mitosis and produces two stem cells identical to the original.
Stem cells use
Potency meaning
Potency specifies the differentiation potential (the potential to differentiate into different cell types) of the stem cell.[15]
- Totipotent (also known as omnipotent) stem cells can differentiate into embryonic and extraembryonic cell types. Such cells can construct a complete, viable organism.[15] 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.[16]
- Pluripotent stem cells are the descendants of totipotent cells and can differentiate into nearly all cells,[15] i.e. cells derived from any of the three germ layers.[17]
- Multipotent stem cells can differentiate into a number of cell types, but only those of a closely related family of cells.[15]
- Oligopotent stem cells can differentiate into only a few cell types, such as lymphoid or myeloid stem cells.[15]
- Unipotent cells can produce only one cell type, their own,[15]but have the property of self-renewal, which distinguishes them from non-stem cells
Identification
In practice, stem cells are identified by whether they can regenerate tissue. For example, the defining test for bone marrow or hematopoietic stem cells (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 in vitro, using methods such as clonogenic assays, in which single cells are assessed for their ability to differentiate and self-renew.[18][19] 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 in vivo. There is considerable debate as to whether some proposed adult cell populations are truly stem cells.[20]
Embryonic
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 '
The neural stem cells self-renew and at some point transition into
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
A human embryonic stem cell is also defined by the expression of several transcription factors and cell surface proteins. The transcription factors
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 regenerative medicine and tissue replacement after injury or disease.,[30] 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.[31] However, the human trial was not initiated until October 13, 2010 in Atlanta for spinal cord injury research. On November 14, 2011 the company conducting the trial (Geron Corporation) announced that it will discontinue further development of its stem cell programs.[32] Differentiating ES cells into usable cells while avoiding transplant rejection are just a few of the hurdles that embryonic stem cell researchers still face.[33] 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 teratoma. 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 moratoria or limitations on either human ES cell research or the production of new human ES cell lines.
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Mouse embryonicstem cells with fluorescent marker
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Human embryonic stem cell colony on mouse embryonic fibroblast feeder layer
Mesenchymal stem cells
Mesenchymal stem cells (MSC) or mesenchymal stromal cells, also known as medicinal signaling cells are known to be multipotent, which can be found in adult tissues, for example, in the muscle, liver, bone marrow and adipose tissue. Mesenchymal stem cells usually function as structural support in various organs as mentioned above, and control the movement of substances. MSC can differentiate into numerous cell categories as an illustration of adipocytes, osteocytes, and chondrocytes, derived by the mesodermal layer.[34] Where the mesoderm layer provides an increase to the body's skeletal elements, such as relating to the cartilage or bone. The term "meso" means middle, infusion originated from the Greek, signifying that mesenchymal cells are able to range and travel in early embryonic growth among the ectodermal and endodermal layers. This mechanism helps with space-filling thus, key for repairing wounds in adult organisms that have to do with mesenchymal cells in the dermis (skin), bone, or muscle.[35]
Mesenchymal stem cells are known to be essential for regenerative medicine. They are broadly studied in clinical trials. Since they are easily isolated and obtain high yield, high plasticity, which makes able to facilitate inflammation and encourage cell growth, cell differentiation, and restoring tissue derived from immunomodulation and immunosuppression. MSC comes from the bone marrow, which requires an aggressive procedure when it comes to isolating the quantity and quality of the isolated cell, and it varies by how old the donor. When comparing the rates of MSC in the bone marrow aspirates and bone marrow stroma, the aspirates tend to have lower rates of MSC than the stroma. MSC are known to be heterogeneous, and they express a high level of pluripotent markers when compared to other types of stem cells, such as embryonic stem cells.[34] MSCs injection leads to wound healing primarily through stimulation of angiogenesis.[36]
Cell cycle control
Embryonic stem cells (ESCs) have the ability to divide indefinitely while keeping their
Particularly because G1 phase is the phase in which cells have increased sensitivity to differentiation, shortened G1 is one of the key characteristics of ESCs and plays an important role in maintaining undifferentiated phenotype. Although the exact molecular mechanism remains only partially understood, several studies have shown insight on how ESCs progress through G1—and potentially other phases—so rapidly.[38]
The cell cycle is regulated by complex network of
In human ESCs (hESCs), the duration of G1 is dramatically shortened. This has been attributed to high mRNA levels of G1-related Cyclin D2 and Cdk4 genes and low levels of cell cycle regulatory proteins that inhibit cell cycle progression at G1, such as
ESCs are also characterized by G1 checkpoint non-functionality, even though the G1 checkpoint is crucial for maintaining genomic stability. In response to
Fetal
The primitive stem cells located in the organs of
There are two types of fetal stem cells:
- Fetal proper stem cells come from the tissue of the fetus proper and are generally obtained after an abortion. These stem cells are not immortal but have a high level of division and are multipotent.
- Extraembryonic fetal stem cells come from extraembryonic membranes, 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.[43]
Adult
Adult stem cells, also called somatic (from Greek σωματικóς, "of the body") stem cells, are stem cells which maintain and repair the tissue in which they are found.[44] They can be found in children, as well as adults.[45]
There are three known accessible sources of
- Bone marrow, which requires extraction by harvesting, usually from pelvic bones via surgery.[46]
- Adipose tissue (fat cells), which requires extraction by liposuction.[47]
- Blood, which requires extraction through apheresis, 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.[48]
Stem cells can also be taken from
Pluripotent adult stem cells are rare and generally small in number, but they can be found in umbilical cord blood and other tissues.[49] Bone marrow is a rich source of adult stem cells,[50] which have been used in treating several conditions including liver cirrhosis,[51] chronic limb ischemia[52] and endstage heart failure.[53] The quantity of bone marrow stem cells declines with age and is greater in males than females during reproductive years.[54] Much adult stem cell research to date has aimed to characterize their potency and self-renewal capabilities.[55] 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 DNA damage theory of aging).[56]
Most adult stem cells are lineage-restricted (
Adult stem cell treatments have been successfully used for many years to treat leukemia and related bone/blood cancers through bone marrow transplants.[60] Adult stem cells are also used in veterinary medicine to treat tendon and ligament injuries in horses.[61]
The use of adult stem cells in research and therapy is not as
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.[63]
Hematopoietic stem cells
Hematopoietic stem cells (HSCs) are vulnerable to DNA damage and mutations that increase with age.[64] This vulnerability may explain the increased risk of slow growing blood cancers (myeloid malignancies) in the elderly.[64] Several factors appear to influence HSC aging including responses to the production of reactive oxygen species that may cause DNA damage and genetic mutations as well as altered epigenetic profiling.[65]
Amniotic
Also called perinatal stem cells, these multipotent stem cells are found in amniotic fluid and umbilical cord blood. 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.[66] Amniotic stem cells are a topic of active research.
Use of stem cells from
It is possible to collect amniotic stem cells for donors or for autologous use: the first US amniotic stem cells bank[68][69] was opened in 2009 in Medford, MA, by Biocell Center Corporation[70][71][72] and collaborates with various hospitals and universities all over the world.[73]
Induced pluripotent
Adult stem cells have limitations with their potency; unlike
However,
Induced pluripotent stem cells differ from embryonic stem cells. They share many similar properties, such as
As a result of the success of these experiments,
IPSCs has helped the field of medicine significantly by finding numerous ways to cure diseases. Since human IPSCc has given the advantage to make in vitro models to study toxins and pathogenesis.[82]
Furthermore, induced pluripotent stem cells provide several therapeutic advantages. Like ESCs, they are
Cell cycle control
The key factors controlling the cell cycle also regulate
With the idea that a more rapid cell cycle is a key component of pluripotency, reprogramming efficiency can be improved. Methods for improving pluripotency through manipulation of cell cycle regulators include: overexpression of Cyclin D/Cdk4, phosphorylation of Sox2 at S39 and S253, overexpression of Cyclin A and Cyclin E, knockdown of Rb, and knockdown of members of the Cip/Kip family or the Ink family.[39] Furthermore, reprogramming efficiency is correlated with the number of cell divisions happened during the stochastic phase, which is suggested by the growing inefficiency of reprogramming of older or slow diving cells.[86]
Lineage
Lineage is an important procedure to analyze developing embryos. Since cell lineages shows the relationship between cells at each division. This helps in analyzing stem cell lineages along the way which helps recognize stem cell effectiveness, lifespan, and other factors. With the technique of cell lineage mutant genes can be analyzed in stem cell clones that can help in genetic pathways. These pathways can regulate how the stem cell perform.[87]
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
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.[89][90]
In the United States, Executive Order 13505 established that federal money can be used for research in which approved human embryonic stem-cell (hESC) lines are used, but it cannot be used to derive new lines.[91] The National Institutes of Health (NIH) Guidelines on Human Stem Cell Research, effective July 7, 2009, implemented the Executive Order 13505 by establishing criteria which hESC lines must meet to be approved for funding.[92] The NIH Human Embryonic Stem Cell Registry can be accessed online and has updated information on cell lines eligible for NIH funding.[93] There are 486 approved lines as of January 2022.[94]
Therapies
Stem cell therapy is the use of stem cells to treat or prevent a disease or condition.
For over 90 years,
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.[104] The physicians' creed would be to do no injury, and stem cells make that simpler than ever before. Surgical processes by their character are harmful. Tissue has to be dropped as a way to reach a successful outcome. One may prevent the dangers of surgical interventions using stem cells. Additionally, there's a possibility of disease, and whether the procedure fails, further surgery may be required. Risks associated with anesthesia can also be eliminated with stem cells.[105] On top of that, stem cells have been harvested from the patient's body and redeployed in which they're wanted. Since they come from the patient's own body, this is referred to as an autologous treatment. Autologous remedies are thought to be the safest because there's likely zero probability of donor substance rejection.
Disadvantages
Stem cell treatments may require immunosuppression 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.[106]
Some stem cells form tumors after transplantation;[107] 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.[108]
Ethical concerns are also raised about the practice of using or researching embryonic stem cells. Harvesting cells from the blastocyst results in the death of the blastocyst. The concern is whether or not the blastocyst should be considered as a human life.[109] The debate on this issue is mainly a philosophical one, not a scientific one.
Stem cell tourism
Stem cell tourism is the part of the medical tourism industry in which patients travel to obtain stem cell procedures.[110]
The United States has had an explosion of "stem cell clinics".[111] Stem cell procedures are highly profitable for clinics. The advertising sounds authoritative but the efficacy and safety of the procedures is unproven. Patients sometimes experience complications, such as spinal tumors[112] and death. The high expense can also lead to financial problems.[112] According to researchers, there is a need to educate the public, patients, and doctors about this issue.[113]
According to the International Society for Stem Cell Research, the largest academic organization that advocates for stem cell research, stem cell therapies are under development and cannot yet be said to be proven.[114][115] Doctors should inform patients that clinical trials continue to investigate whether these therapies are safe and effective but that unethical clinics present them as proven.[116]
Research
Some of the fundamental patents covering human embryonic stem cells are owned by the Wisconsin Alumni Research Foundation (WARF) – they are patents 5,843,780, 6,200,806, and 7,029,913 invented by James A. Thomson. WARF does not enforce these patents against academic scientists, but does enforce them against companies.[117]
In 2006, a request for the
In July 2013, Consumer Watchdog announced that it would appeal the decision to allow the claims of the '913 patent to the US
Investigations
Diseases and conditions where stem cell treatment is being investigated include:
- Diabetes[125]
- Androgenic Alopecia and hair loss[126][127]
- Rheumatoid arthritis[125]
- Parkinson's disease[125]
- Alzheimer's disease[125]
- Respiratory disease[128]
- Osteoarthritis[125]
- Stroke and traumatic brain injury repair[129]
- congenital disorder[130]
- Spinal cord injury repair[131]
- Heart infarction[132]
- Anti-cancer treatments[129]
- Baldness reversal[133]
- Replace missing teeth[134]
- Repair hearing[135]
- Restore vision[136] and repair damage to the cornea[137]
- Amyotrophic lateral sclerosis[138]
- Crohn's disease[139]
- Wound healing[140]
- Male infertility due to absence of spermatogonial stem cells.[141] In recent studies, scientists 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.[142]
- Female infertility: oocytes made from embryonic stem cells. Scientists have found the ovarian stem cells, a rare type of cells (0.014%) found in the ovary. They could be used as a treatment not only for infertility, but also for premature ovarian insufficiency.[143]
- Critical Limb Ischemia[144]
Research is underway to develop various sources for stem cells, and to apply stem cell treatments for
In more recent years, with the ability of scientists to isolate and culture
Hepatotoxicity 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 drug development process.[147]
Notable studies
In August 2021, researchers in the Princess Margaret Cancer Centre at the University Health Network published their discovery of a dormancy mechanism in key stem cells which could help develop cancer treatments in the future.[148]
See also
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Further reading
- Manzo, Carlo; Torreno-Pina, Juan A.; Massignan, Pietro; Lapeyre, Gerald J.; Lewenstein, Maciej; Garcia Parajo, Maria F. (25 February 2015). "Weak Ergodicity Breaking of Receptor Motion in Living Cells Stemming from Random Diffusivity". Physical Review X. 5 (1): 011021. S2CID 73582473.