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Stem cell

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This article is about the cell type. For the medical therapy, seestem-cell therapy.
"Stem cells" and "Stem cell research" redirect here. For the journals, seeStem Cells(journal)andStem Cell Research(journal).
Stem cell
Transmissionelectron micrographof amesenchymal stem celldisplaying typicalultrastructuralcharacteristics
Details
Identifiers
Latincellula praecursoria
MeSHD013234
THH1.00.01.0.00028, H2.00.01.0.00001
FMA63368
Anatomical terminology

Inmulticellular organisms,stem cellsareundifferentiatedor partially differentiatedcellsthat can change into varioustypes of cellsandproliferateindefinitely to produce more of the same stem cell. They are the earliest type of cell in acell lineage.[1]They are found in bothembryonicand adult organisms, but they have slightly different properties in each. They are usually distinguished fromprogenitor cells,which cannot divide indefinitely, andprecursoror blast cells, which are usually committed to differentiating into one cell type.

Inmammals,roughly 50 to 150 cells make up theinner cell massduring theblastocyststage ofembryonic development,around days 5–14. These have stem-cell capability.In vivo,they eventually differentiate into all of the body's cell types (making thempluripotent). This process starts with the differentiation into the threegerm layers– theectoderm,mesodermandendoderm– at thegastrulationstage. However, when they are isolated andculturedin vitro,they can be kept in the stem-cell stage and are known asembryonic stem cells(ESCs).

Adult stem cellsare found in a few select locations in the body, known asniches,such as those in thebone marroworgonads.They exist to replenish rapidly lost cell types and aremultipotentor unipotent, meaning they only differentiate into a few cell types or one type of cell. In mammals, they include, among others,hematopoietic stem cells,which replenish blood and immune cells,basal cells,which maintain the skinepithelium,andmesenchymal stem cells,which maintain bone,cartilage,muscle and fat cells. Adult stem cells are a small minority of cells; they are vastly outnumbered by the progenitor cells and terminally differentiated cells that they differentiate into.[1]

Research into stem cells grew out of findings by Canadian biologistsErnest McCulloch,James Tilland Andrew J. Becker at theUniversity of Torontoand the Ontario Cancer Institute in the 1960s.[2][3]As of 2016,the only establishedmedical therapy using stem cellsishematopoietic stem cell transplantation,[4]first performed in 1958 by French oncologistGeorges Mathé.Since 1998 however, it has been possible to culture and differentiate human embryonic stem cells (instem-cell lines). The process of isolating these cells has beencontroversial,because it typically results in the destruction of the embryo. Sources for isolating ESCs have beenrestrictedin some European countries and Canada, but others such as the UK and China have promoted the research.[5]Somatic cell nuclear transferis acloningmethod that can be used to create a cloned embryo for the use of its embryonic stem cells in stem cell therapy.[6]In 2006, a Japanese team led byShinya Yamanakadiscovered a method to convert mature body cells back into stem cells. These were termedinduced pluripotent stem cells(iPSCs).[7]

History

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The termstem cellwas coined byTheodor BoveriandValentin Haeckerin late 19th century.[8]Pioneering works in theory of blood stem cell were conducted in the beginning of 20th century byArtur Pappenheim,Alexander Maximow,Franz Ernst Christian Neumann.[8]

The key properties of a stem cell were first defined byErnest McCullochandJames Tillat 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 studentAndrew John Beckerand senior scientistLouis Siminovitch,confirmed that each lump did in fact arise from a single cell. Their results were published inNaturein 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 abone marrow transplantperformed by French oncologistGeorges Mathéin 1956 on five workers at theVinča Nuclear InstituteinYugoslaviawho had been affected by acriticality accident.The workers all survived.[10]

In 1981, embryonic stem (ES) cells were first isolated and successfully cultured using mouse blastocysts by British biologistsMartin EvansandMatthew 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. In 1991, a process that allowed the human stem cell to be isolated was patented by Ann Tsukamoto. By 1998, human embryonic stem cells were first isolated by American biologistJames 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 femalemaned wolf,run over by a truck, underwent stem cell treatment at theZoo Brasília,this being the first recorded case of the use of stem cells to heal injuries in a wild animal.[11][12]

Properties

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

Self-renewal

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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 disrupts 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]

H.

Stem cells usetelomerase,a protein that restorestelomeres,to protect their DNA and extend their cell division limit (theHayflick limit).[14]

Potency meaning

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Main article:Cell potency
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 themorula,are totipotent, able to become all tissues in the body and the extraembryonic placenta.
Humanembryonicstem cells
A: Stem cell colonies that are not yet differentiated.
B:Nervecells, an example of acell typeafter differentiation.

Potencyspecifies 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 thefusionof an egg and sperm cell. Cells produced by the first few divisions of the fertilized egg are also totipotent.[16]
  • Pluripotentstem cells are the descendants of totipotent cells and can differentiate into nearly all cells,[15]i.e. cells derived from any of the threegerm layers.[17]
  • Multipotentstem cells can differentiate into a number of cell types, but only those of a closely related family of cells.[15]
  • Oligopotentstem cells can differentiate into only a few cell types, such as lymphoid or myeloid stem cells.[15]
  • Unipotentcells can produce only one cell type, their own,[15]but have the property of self-renewal, which distinguishes them from non-stem cells

Identification

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In practice, stem cells are identified by whether they can regenerate tissue. For example, the defining test for bone marrow orhematopoietic 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 illustratedin vitro,using methods such asclonogenic 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 vitroculture conditions can alter the behavior of cells, making it unclear whether the cells shall behave in a similar mannerin vivo.There is considerable debate as to whether some proposed adult cell populations are truly stem cells.[20]

Embryonic

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Main article:Embryonic stem cell

Embryonic stem cells(ESCs) are the cells of theinner cell massof ablastocyst,formed prior toimplantationin the uterus.[21]Inhuman embryonic developmenttheblastocyststage is reached 4–5 days afterfertilization,at which time it consists of 50–150 cells. ESCs arepluripotentand give rise during development to all derivatives of the threegerm layers:ectoderm,endodermandmesoderm.In other words, they can develop into each of the more than 200 cell types of the adultbodywhen given sufficient and necessary stimulation for a specific cell type. They do not contribute to theextraembryonic membranesor to theplacenta.

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 'neurectoderm', which will become the futurecentral nervous system.[22]Later in development,neurulationcauses the neurectoderm to form theneural tube.At the neural tube stage, the anterior portion undergoesencephalizationto generate or 'pattern' the basic form of the brain. At this stage of development, the principal cell type of the CNS is considered aneural stem cell.

The neural stem cells self-renew and at some point transition intoradial glial progenitor cells(RGPs). Early-formed RGPs self-renew by symmetrical division to form a reservoir group ofprogenitor cells.These cells transition to aneurogenicstate and start to divideasymmetricallyto 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 calledneurogenesis.The radial glial cell, has a distinctive bipolar morphology with highly elongated processes spanning the thickness of the neural tube wall. It shares someglialcharacteristics, most notably the expression ofglial fibrillary acidic protein(GFAP).[23][24]The radial glial cell is the primary neural stem cell of the developingvertebrateCNS, and its cell body resides in theventricular zone,adjacent to the developingventricular system.Neural stem cells are committed to the neuronal lineages (neurons,astrocytes,andoligodendrocytes), and thus their potency is restricted.[22]

Nearly all research to date has made use of mouse embryonic stem cells (mES) orhuman 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 ofgelatinas anextracellular matrix(for support) and require the presence ofleukemia inhibitory factor(LIF) in serum media. A drug cocktail containing inhibitors toGSK3Band theMAPK/ERK pathway,called 2i, has also been shown to maintain pluripotency in stem cell culture.[25]Human ESCs are grown on a feeder layer of mouse embryonicfibroblastsand require the presence of basic fibroblast growth factor (bFGF or FGF-2).[26]Without optimal culture conditions or genetic manipulation,[27]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 factorsOct-4,Nanog,andSox2form the core regulatory network that ensures the suppression of genes that lead to differentiation and the maintenance of pluripotency.[28]The cell surface antigens most commonly used to identify hES cells are the glycolipidsstage specific embryonic antigen 3and 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.[29]

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 forregenerative medicineand 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 forspinal 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 ateratoma.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 havemoratoriaor limitations on either human ES cell research or the production of new human ES cell lines.

  • Mouse embryonic stem cells with fluorescent marker
    Mouseembryonicstem cells with fluorescent marker
  • Human embryonic stem cell colony on mouse embryonic fibroblast feeder layer
    Human embryonic stem cell colony on mouse embryonic fibroblast feeder layer

Mesenchymal stem cells

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Human 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 inclinical 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

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Further information:Cell cycle

Embryonic stem cells (ESCs) have the ability to divide indefinitely while keeping theirpluripotency,which is made possible through specialized mechanisms ofcell cyclecontrol.[37]Compared to proliferatingsomatic cells,ESCs have unique cell cycle characteristics—such as rapid cell division caused by shortenedG1 phase,absentG0 phase,and modifications incell cycle checkpoints—which leaves the cells mostly inS phaseat any given time.[37][38]ESCs' rapid division is demonstrated by their short doubling time, which ranges from 8 to 10 hours, whereas somatic cells have doubling time of approximately 20 hours or longer.[39]As cells differentiate, these properties change: G1 and G2 phases lengthen, leading to longer cell division cycles. This suggests that a specific cell cycle structure may contribute to the establishment of pluripotency.[37]

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 undifferentiatedphenotype.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 ofcyclins,cyclin-dependent kinases(Cdk),cyclin-dependent kinase inhibitors(Cdkn), pocket proteins of the retinoblastoma (Rb) family, and other accessory factors.[39]Foundational insight into the distinctive regulation of ESC cell cycle was gained by studies on mouse ESCs (mESCs).[38]mESCs showed a cell cycle with highly abbreviated G1 phase, which enabled cells to rapidly alternate between M phase and S phase. In a somatic cell cycle, oscillatory activity of Cyclin-Cdk complexes is observed in sequential action, which controls crucial regulators of the cell cycle to induce unidirectional transitions between phases:Cyclin Dand Cdk4/6 are active in the G1 phase, whileCyclin EandCdk2are active during the late G1 phase and S phase; andCyclin Aand Cdk2 are active in the S phase and G2, whileCyclin BandCdk1are active in G2 and M phase.[39]However, in mESCs, this typically ordered and oscillatory activity of Cyclin-Cdk complexes is absent. Rather, the Cyclin E/Cdk2 complex is constitutively active throughout the cycle, keepingretinoblastoma protein(pRb)hyperphosphorylatedand thus inactive. This allows for direct transition from M phase to the late G1 phase, leading to absence of D-type cyclins and therefore a shortened G1 phase.[38]Cdk2 activity is crucial for both cell cycle regulation and cell-fate decisions in mESCs; downregulation of Cdk2 activity prolongs G1 phase progression, establishes a somatic cell-like cell cycle, and induces expression of differentiation markers.[40]

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 asp21CipP1,p27Kip1,and p57Kip2.[37][41]Furthermore, regulators of Cdk4 and Cdk6 activity, such as members of the Ink family of inhibitors (p15, p16, p18, and p19), are expressed at low levels or not at all. Thus, similar to mESCs, hESCs show high Cdk activity, with Cdk2 exhibiting the highest kinase activity. Also similar to mESCs, hESCs demonstrate the importance of Cdk2 in G1 phase regulation by showing that G1 to S transition is delayed when Cdk2 activity is inhibited and G1 is arrest when Cdk2 is knocked down.[37]However unlike mESCs, hESCs have a functional G1 phase. hESCs show that the activities of Cyclin E/Cdk2 and Cyclin A/Cdk2 complexes are cell cycle-dependent and the Rb checkpoint in G1 is functional.[39]

ESCs are also characterized by G1 checkpoint non-functionality, even though the G1 checkpoint is crucial for maintaining genomic stability. In response toDNA damage,ESCs do not stop in G1 to repair DNA damages but instead, depend on S and G2/M checkpoints or undergo apoptosis. The absence of G1 checkpoint in ESCs allows for the removal of cells with damaged DNA, hence avoiding potential mutations from inaccurate DNA repair.[37]Consistent with this idea, ESCs are hypersensitive to DNA damage to minimize mutations passed onto the next generation.[39]

Fetal

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The primitive stem cells located in the organs offetusesare referred to as fetal stem cells.[42]

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 anabortion.These stem cells are not immortal but have a high level of division and are multipotent.
  2. Extraembryonic fetal stem cells come fromextraembryonic 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

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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

Adult stem cells, also calledsomatic(from Greek σωματικóς, "of the body" ) stem cells, are stem cells which maintain and repair the tissue in which they are found.[44]

There are three known accessible sources ofautologousadult stem cells in humans:

  1. Bone marrow,which requires extraction byharvesting,usually from pelvic bones via surgery.[45]
  2. Adipose tissue (fat cells), which requires extraction by liposuction.[46]
  3. Blood, which requires extraction throughapheresis,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.[47]

Stem cells can also be taken fromumbilical cord bloodjust 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 their own blood for elective surgical procedures.[citation needed]

Pluripotent adult stem cells are rare and generally small in number, but they can be found in umbilical cord blood and other tissues.[48]Bone marrow is a rich source of adult stem cells,[49]which have been used in treating several conditions including liver cirrhosis,[50]chronic limb ischemia[51]and endstage heart failure.[52]The quantity of bone marrow stem cells declines with age and is greater in males than females during reproductive years.[53]Much adult stem cell research to date has aimed to characterize their potency and self-renewal capabilities.[54]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 (seeDNA damage theory of aging).[55]

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.).[56][57]Muse cells(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 ofSSEA-3,a marker for undifferentiated stem cells, and general mesenchymal stem cells markers such as CD90,CD105.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 markersOct4,Sox2,andNanog.[58]

Adult stem cell treatments have been successfully used for many years to treat leukemia and related bone/blood cancers through bone marrow transplants.[59]Adult stem cells are also used in veterinary medicine to treat tendon and ligament injuries in horses.[60]

The use of adult stem cells in research and therapy is not ascontroversialas the use ofembryonic stem cells,because the production of adult stem cells does not require the destruction of anembryo.Additionally, in instances where adult stem cells are obtained from the intended recipient (anautograft), the risk of rejection is essentially non-existent. Consequently, more US government funding is being provided for adult stem cell research.[61]

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.[62]

Hematopoietic stem cells

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Hematopoietic stem cells(HSCs) are vulnerable toDNA damageandmutationsthat increase with age.[63]This vulnerability may explain the increased risk of slow growing blood cancers (myeloid malignancies) in the elderly.[63]Several factors appear to influence HSC aging including responses to the production ofreactive oxygen speciesthat may cause DNA damage and genetic mutations as well as alteredepigeneticprofiling.[64]

Amniotic

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Also called perinatal stem cells, these multipotent stem cells are found inamniotic fluidand umbilical cord blood. These stem cells are very active, expand extensively without feeders and are not tumorigenic.Amniotic stem cellsare multipotent and can differentiate in cells of adipogenic, osteogenic, myogenic, endothelial, hepatic and also neuronal lines.[65] Amniotic stem cells are a topic of active research.

Use of stem cells fromamniotic fluidovercomes the ethical objections to using human embryos as a source of cells.Roman Catholicteaching forbids the use of embryonic stem cells in experimentation; accordingly, theVaticannewspaper "Osservatore Romano"called amniotic stem cells" the future of medicine ".[66]

It is possible to collect amniotic stem cells for donors or for autologous use: the first US amniotic stem cells bank[67][68]was opened in 2009 in Medford, MA, byBiocell CenterCorporation[69][70][71]and collaborates with various hospitals and universities all over the world.[72]

Induced pluripotent

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Main article:Induced pluripotent stem cell

Adult stem cells have limitations with their potency; unlikeembryonic stem cells(ESCs), they are not able to differentiate into cells from all threegerm layers.As such, they are deemedmultipotent.

However,reprogrammingallows for the creation of pluripotent cells,induced pluripotent stem cells(iPSCs), from adult cells. These are not adult stem cells, but somatic cells (e.g. epithelial cells) reprogrammed to give rise to cells with pluripotent capabilities. Using genetic reprogramming with proteintranscription factors,pluripotent stem cells with ESC-like capabilities have been derived.[73][74][75]The first demonstration of induced pluripotent stem cells was conducted byShinya Yamanakaand his colleagues atKyoto University.[76]They used the transcription factorsOct3/4,Sox2,c-Myc,andKlf4to reprogram mouse fibroblast cells into pluripotent cells.[73][77]Subsequent work used these factors to induce pluripotency in human fibroblast cells.[78]Junying Yu,James Thomson,and their colleagues at theUniversity of Wisconsin–Madisonused a different set of factors, Oct4, Sox2, Nanog and Lin28, and carried out their experiments using cells from humanforeskin.[73][79]However, they were able to replicateYamanaka'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 aspluripotencyand differentiation potential, the expression ofpluripotencygenes,epigeneticpatterns,embryoid bodyandteratomaformation, and viablechimeraformation,[76][77]but there are many differences within these properties. The chromatin of iPSCs appears to be more "closed" or methylated than that of ESCs.[76][77]Similarly, the gene expression pattern between ESCs and iPSCs, or even iPSCs sourced from different origins.[76]There are thus questions about the "completeness" ofreprogrammingand the somatic memory of induced pluripotent stem cells. Despite this, inducing somatic cells to be pluripotent appears to be viable.

As a result of the success of these experiments,Ian Wilmut,who helped create the first cloned animalDolly the Sheep,has announced that he will abandonsomatic cell nuclear transferas an avenue of research.[80]

IPSCs has helped the field of medicine significantly by finding numerous ways to cure diseases. Since human IPSCc has given the advantage to makein vitromodels to study toxins and pathogenesis.[81]

Furthermore, induced pluripotent stem cells provide several therapeutic advantages. Like ESCs, they arepluripotent.They thus have great differentiation potential; theoretically, they could produce any cell within the human body (ifreprogrammingto pluripotency was "complete" ).[76]Moreover, unlike ESCs, they potentially could allow doctors to create a pluripotent stem cell line for each individual patient.[82]Frozen blood samples can be used as a valuable source of induced pluripotent stem cells.[83]Patient specific stem cells allow for the screening for side effects before drug treatment, as well as the reduced risk of transplantation rejection.[82]Despite their current limited use therapeutically, iPSCs hold great potential for future use in medical treatment and research.

Cell cycle control

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The key factors controlling the cell cycle also regulatepluripotency.Thus, manipulation of relevant genes can maintain pluripotency and reprogram somatic cells to an induced pluripotent state.[39]However, reprogramming of somatic cells is often low in efficiency and consideredstochastic.[84]

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 ofSox2at S39 and S253, overexpression of Cyclin A and Cyclin E, knockdown of Rb, and knockdown of members of theCip/Kipfamily 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.[85]

Lineage

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Main article:Stem cell line

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.[86]

To ensure self-renewal, stem cells undergo two types of cell division (seeStem cell division and differentiationdiagram). 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 aprogenitor cellwith limited self-renewal potential. Progenitors can go through several rounds of cell division before terminallydifferentiatinginto a mature cell. It is possible that the molecular distinction between symmetric and asymmetric divisions lies in differential segregation of cell membrane proteins (such asreceptors) between the daughter cells.[87]

An alternative theory is that stem cells remain undifferentiated due to environmental cues in their particularniche.Stem cells differentiate when they leave that niche or no longer receive those signals. Studies inDrosophilagermarium have identified the signalsdecapentaplegicand adherens junctions that prevent germarium stem cells from differentiating.[88][89]

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.[90]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.[91]The NIH Human Embryonic Stem Cell Registry can be accessed online and has updated information on cell lines eligible for NIH funding.[92]There are 486 approved lines as of January 2022.[93]

Therapies

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Main article:Stem cell therapy

Stem cell therapy is the use of stem cells to treat or prevent a disease or condition.Bone marrow transplantis a form of stem cell therapy that has been used for many years because it has proven to be effective in clinical trials.[94][95]Stem cell implantation may help in strengthening the left-ventricle of the heart, as well as retaining the heart tissue to patients who have suffered from heart attacks in the past.[96]

For over 90 years,hematopoietic stem cell transplantation(HSCT) has been used to treat people with conditions such asleukaemiaandlymphoma;this is the only widely practiced form of stem-cell therapy.[94][97][98]As of 2016,the only established therapy using stem cells ishematopoietic stem cell transplantation.[99]This usually takes the form of abone-marrowtransplantation, but the cells can also be derived fromumbilical cord blood.Research is underway to develop various sources for stem cells as well as to apply stem-cell treatments forneurodegenerative diseases[100][101][102]and conditions such asdiabetesandheart disease.

Advantages

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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.[103]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.[104]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

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Stem cell treatments may requireimmunosuppressionbecause 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.[105]

Some stem cells form tumors after transplantation;[106]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.[107]

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.[108]The debate on this issue is mainly a philosophical one, not a scientific one.

Stem cell tourism

[edit]

Stem cell tourism is the part of themedical tourismindustry in which patients travel to obtain stem cell procedures.[109]

The United States has had an explosion of "stem cell clinics".[110]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[111]and death. The high expense can also lead to financial problems.[111]According to researchers, there is a need to educate the public, patients, and doctors about this issue.[112]

According to theInternational 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.[113][114]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.[115]

Research

[edit]
Further information:Consumer Watchdog vs. Wisconsin Alumni Research Foundation

Some of the fundamentalpatentscovering human embryonic stem cells are owned by theWisconsin Alumni Research Foundation(WARF) – they are patents 5,843,780, 6,200,806, and 7,029,913 invented byJames A. Thomson.WARF does not enforce these patents against academic scientists, but does enforce them against companies.[116]

In 2006, a request for theUS Patent and Trademark Office(USPTO) to re-examine the three patents was filed by thePublic Patent Foundationon behalf of its client, the non-profit patent-watchdog groupConsumer Watchdog(formerly the Foundation for Taxpayer and Consumer Rights).[116]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,[117]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.[118][119]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.[120]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.[121]

In July 2013, Consumer Watchdog announced that it would appeal the decision to allow the claims of the '913 patent to the USCourt of Appeals for the Federal Circuit(CAFC), the federal appeals court that hears patent cases.[122]At a hearing in December 2013, the CAFC raised the question of whether Consumer Watchdog hadlegal standingto appeal; the case could not proceed until that issue was resolved.[123]

Investigations

[edit]
Diseases and conditions where stem cell treatment is being investigated

Diseases and conditions where stem cell treatment is being investigated include:

Research is underway to develop various sources for stem cells, and to apply stem cell treatments forneurodegenerative diseasesand conditions,diabetes,heart disease,and other conditions.[144]Research is also underway in generatingorganoidsusing stem cells, which would allow for further understanding of human development,organogenesis,and modeling of human diseases.[145]

In more recent years, with the ability of scientists to isolate and cultureembryonic stem cells,and with scientists' growing ability to create stem cells usingsomatic cell nuclear transferand techniques to createinduced pluripotent stem cells,controversyhas crept in, both related toabortion politicsand tohuman cloning.

Hepatotoxicityand 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 thedrug developmentprocess.[146]

Notable studies

[edit]

In August 2021, researchers in thePrincess Margaret Cancer Centreat theUniversity Health Networkpublished their discovery of a dormancy mechanism in key stem cells which could help develop cancer treatments in the future.[147]

See also

[edit]

References

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