stem cell

The term stem cell was coined by Theodor Boveri and Valentin Haecker in late 19th century.{{cite journal |last1=Ramalho-Santos |first1=Miguel |last2=Willenbring |first2=Holger |title=On the Origin of the Term 'Stem Cell' |journal=Cell Stem Cell |date=June 2007 |volume=1 |issue=1 |pages=35–38 |doi=10.1016/j.stem.2007.05.013 |pmid=18371332 |doi-access=free }} Pioneering works in theory of blood stem cell were conducted in the beginning of 20th century by Artur Pappenheim, Alexander A. Maximow, Franz Ernst Christian Neumann.

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.{{cite web|url=https://news.usask.ca/articles/research/2018/the-accidental-discovery-of-stem-cells.php|title =The Accidental Discovery of Stem Cells|last1=MacPherson|first1=Colleen|website=USask News|publisher=University of Saskatchewan|access-date=3 December 2019|ref=1|name-list-style=vanc}}

The first therapy using stem cells was a bone marrow transplant performed by French oncologist Georges Mathé in 1956 on five workers at the Vinča Nuclear Institute in Yugoslavia who had been affected by a criticality accident. The workers all survived.{{Cite web |title=Vinca reactor accident, 1958 |url=https://www.johnstonsarchive.net/nuclear/radevents/1958YUG1.html |access-date=2024-12-28 |website=www.johnstonsarchive.net|archive-url=https://web.archive.org/web/20110127110604/http://johnstonsarchive.net/nuclear/radevents/1958YUG1.html|archive-date=27 January 2011|first=Wm. Robert |last=Johnston}}

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. 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 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.{{cite web|url=http://sitn.hms.harvard.edu/flash/2014/stem-cells-a-brief-history-and-outlook-2/|title=Stem Cells: A Brief History and Outlook|last1=Ferreira|first1=Leonardo|date=2014-01-03|website=Stem Cells: A Brief History and Outlook – Science in the News|publisher=WordPress|access-date=3 December 2019|ref=2|name-list-style=vanc}}

In 2011, a female maned wolf, run over by a truck, underwent stem cell treatment at the {{Ill|Zoo Brasília|pt|Jardim Zoológico de Brasília}}, this being the first recorded case of the use of stem cells to heal injuries in a wild animal.{{Cite web |last=Boyle |first=Rebecca |date=2011-01-15 |title=Injured Brazilian Wolf Is First Wild Animal Treated With Stem Cells |url=https://www.popsci.com/science/article/2011-01/injured-brazilian-wolf-first-wild-animal-treated-stem-cells/ |access-date=2024-12-28 |website=Popular Science |language=en-US}}{{Cite web |last=suporte |date=2011-01-11 |title=Tratamento |url=https://www.cfmv.gov.br/tratamento/comunicacao/noticias/2011/01/11/ |access-date=2024-12-28 |publisher=Conselho Federal de Medicina Veterinária |language=pt-BR}}

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.
• Potency: the capacity to differentiate into specialized cell types. In the strictest sense, this requires stem cells to be either totipotent or pluripotent—to be able to give rise to any mature cell type, although multipotent or unipotent progenitor cells are sometimes referred to as stem cells. Apart from this, it is said that stem cell function is regulated in a feedback mechanism.

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.Shenghui, H. E., Nakada, D., & Morrison, S. J. (2009). Mechanisms of stem cell self-renewal. Annual Review of Cell and Developmental, 25, 377–406.

H.

Stem cells use telomerase, a protein that restores telomeres, to protect their DNA and extend their cell division limit (the Hayflick limit).{{cite journal | vauthors = Cong YS, Wright WE, Shay JW | title = Human telomerase and its regulation | journal = Microbiology and Molecular Biology Reviews | volume = 66 | issue = 3 | pages = 407–425, table of contents | date = September 2002 | pmid = 12208997 | pmc = 120798 | doi = 10.1128/MMBR.66.3.407-425.2002 | doi-access = free }}

{{Main|Cell potency}}

Image:Stem cells diagram.png, are totipotent, able to become all tissues in the body and the extraembryonic placenta.]]

Image:Human embryonic stem cells.pngnic stem cells
A: Stem cell colonies that are not yet differentiated.
B: Nerve cells, an example of a cell type after differentiation.]]

Potency specifies the differentiation potential (the potential to differentiate into different cell types) of the stem cell.{{cite book |title=Humanbiotechnology as Social Challenge |editor1=Nikolaus Knoepffler |editor2=Dagmar Schipanski |editor3=Stefan Lorenz Sorgner |page=28 |chapter=The Potential of Stem Cells: An Inventory | last = Schöler | first = Hans R. | name-list-style = vanc |publisher=Ashgate Publishing|year=2007 |isbn=978-0-7546-5755-2}}

• Totipotent (also known as 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 fusion of an egg and sperm cell. Cells produced by the first few divisions of the fertilized egg are also totipotent.{{cite book | vauthors = Mitalipov S, Wolf D | chapter = Totipotency, pluripotency and nuclear reprogramming | volume = 114 | pages = 185–199 | year = 2009 | pmid = 19343304 | pmc = 2752493 | doi = 10.1007/10_2008_45 | isbn = 978-3-540-88805-5 | series = Advances in Biochemical Engineering/Biotechnology | bibcode = 2009esc..book..185M | title = Engineering of Stem Cells | publisher = Springer }}
• Pluripotent stem cells are the descendants of totipotent cells and can differentiate into nearly all cells, i.e. cells derived from any of the three germ layers.{{cite journal | vauthors = Ulloa-Montoya F, Verfaillie CM, Hu WS | title = Culture systems for pluripotent stem cells | journal = Journal of Bioscience and Bioengineering | volume = 100 | issue = 1 | pages = 12–27 | date = July 2005 | pmid = 16233846 | doi = 10.1263/jbb.100.12 | url = https://lirias.kuleuven.be/handle/123456789/238336 | url-access = subscription }}
• Multipotent stem cells can differentiate into a number of cell types, but only those of a closely related family of cells.
• Oligopotent stem cells can differentiate into only a few cell types, such as lymphoid or myeloid stem cells.
• Unipotent cells can produce only one cell type, their own, but have the property of self-renewal, which distinguishes them from non-stem cells

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.{{cite journal | vauthors = Friedenstein AJ, Deriglasova UF, Kulagina NN, Panasuk AF, Rudakowa SF, Luriá EA, Ruadkow IA | title = Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method | journal = Experimental Hematology | volume = 2 | issue = 2 | pages = 83–92 | year = 1974 |id={{INIST|PASCAL7536501060}} {{NAID|10025700209}} | pmid = 4455512 }}{{cite journal | vauthors = Friedenstein AJ, Gorskaja JF, Kulagina NN | title = Fibroblast precursors in normal and irradiated mouse hematopoietic organs | journal = Experimental Hematology | volume = 4 | issue = 5 | pages = 267–274 | date = September 1976 | pmid = 976387 }} 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.{{Cite journal | vauthors = Sekhar L, Bisht N |date=2006-09-01 |title=Stem Cell Therapy |journal=Apollo Medicine |volume=3 |issue=3 |pages=271–276 |doi= 10.1016/S0976-0016(11)60209-3 }}

{{Main|Embryonic stem cell}}

Embryonic stem cells (ESCs) are the cells of the inner cell mass of a blastocyst, formed prior to implantation in the uterus.{{cite journal | vauthors = Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM | title = Embryonic stem cell lines derived from human blastocysts | journal = Science | volume = 282 | issue = 5391 | pages = 1145–1147 | date = November 1998 | pmid = 9804556 | doi = 10.1126/science.282.5391.1145 | bibcode = 1998Sci...282.1145T | doi-access = free }} In human embryonic development the blastocyst stage is reached 4–5 days after fertilization, at which time it consists of 50–150 cells. ESCs are pluripotent and give rise during development to all derivatives of the three germ layers: ectoderm, endoderm and mesoderm. In other words, they can develop into each of the more than 200 cell types of the adult body when given sufficient and necessary stimulation for a specific cell type. They do not contribute to the extraembryonic membranes or to the placenta.

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 future central nervous system (CNS).{{cite book |last1=Gilbert |first1=Scott F. |title=Developmental Biology |date=2014 |publisher=Sinauer Associates |isbn=978-0-87893-978-7 }}{{Page needed|date=January 2019}} Later in development, neurulation causes the neurectoderm to form the neural tube. At the neural tube stage, the anterior portion undergoes encephalization 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 neural stem cell.

The neural stem cells self-renew and at some point transition into radial glial progenitor cells (RGPs). Early-formed RGPs self-renew by symmetrical division to form a reservoir group of progenitor cells. These cells transition to a neurogenic state and start to divide asymmetrically 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 neurogenesis. The radial glial cell, has a distinctive bipolar morphology with highly elongated processes spanning the thickness of the neural tube wall. It shares some glial characteristics, most notably the expression of glial fibrillary acidic protein (GFAP).{{cite journal | vauthors = Rakic P | title = Evolution of the neocortex: a perspective from developmental biology | journal = Nature Reviews. Neuroscience | volume = 10 | issue = 10 | pages = 724–735 | date = October 2009 | pmid = 19763105 | pmc = 2913577 | doi = 10.1038/nrn2719 }}{{cite journal | vauthors = Noctor SC, Flint AC, Weissman TA, Dammerman RS, Kriegstein AR | title = Neurons derived from radial glial cells establish radial units in neocortex | journal = Nature | volume = 409 | issue = 6821 | pages = 714–720 | date = February 2001 | pmid = 11217860 | doi = 10.1038/35055553 | bibcode = 2001Natur.409..714N | s2cid = 3041502 }} The radial glial cell is the primary neural stem cell of the developing vertebrate CNS, and its cell body resides in the ventricular zone, adjacent to the developing ventricular system. Neural stem cells are committed to the neuronal lineages (neurons, astrocytes, and oligodendrocytes), 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 gelatin as an extracellular matrix (for support) and require the presence of leukemia inhibitory factor (LIF) in serum media. A drug cocktail containing inhibitors to GSK3B and the MAPK/ERK pathway, called 2i, has also been shown to maintain pluripotency in stem cell culture.{{cite journal | vauthors = Ying QL, Wray J, Nichols J, Batlle-Morera L, Doble B, Woodgett J, Cohen P, Smith A | title = The ground state of embryonic stem cell self-renewal | journal = Nature | volume = 453 | issue = 7194 | pages = 519–523 | date = May 2008 | pmid = 18497825 | pmc = 5328678 | doi = 10.1038/nature06968 | bibcode = 2008Natur.453..519Y }} Human ESCs are grown on a feeder layer of mouse embryonic fibroblasts and require the presence of basic fibroblast growth factor (bFGF or FGF-2).

{{cite web|url=http://stemcells.nih.gov/research/NIHresearch/scunit/culture.asp|archive-url=https://web.archive.org/web/20100106111652/http://stemcells.nih.gov/research/NIHresearch/scunit/culture.asp|archive-date=2010-01-06|title=Culture of Human Embryonic Stem Cells (hESC)|publisher=National Institutes of Health|access-date=2010-03-07}} Without optimal culture conditions or genetic manipulation,

{{cite journal | vauthors = Chambers I, Colby D, Robertson M, Nichols J, Lee S, Tweedie S, Smith A | title = Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells|journal = Cell|volume = 113|issue = 5 | pages = 643–655 |date = May 2003| pmid = 12787505 | doi = 10.1016/S0092-8674(03)00392-1 |hdl = 1842/843 |s2cid = 2236779 | hdl-access = free }} 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 Oct-4, Nanog, and Sox2 form the core regulatory network that ensures the suppression of genes that lead to differentiation and the maintenance of pluripotency.

{{cite journal | vauthors = Boyer LA, Lee TI, Cole MF, Johnstone SE, Levine SS, Zucker JP, Guenther MG, Kumar RM, Murray HL, Jenner RG, Gifford DK, Melton DA, Jaenisch R, Young RA | title = Core transcriptional regulatory circuitry in human embryonic stem cells | journal = Cell | volume = 122 | issue = 6 | pages = 947–956 | date = September 2005 | pmid = 16153702 | pmc = 3006442 | doi = 10.1016/j.cell.2005.08.020 }} The cell surface antigens most commonly used to identify hES cells are the glycolipids stage specific embryonic antigen 3 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.

{{cite journal |display-authors=6 |collaboration= The International Stem Cell Initiative | vauthors = Adewumi O, Aflatoonian B, Ahrlund-Richter L, Amit M, Andrews PW, Beighton G, Bello PA, Benvenisty N, Berry LS, Bevan S, Blum B, Brooking J, Chen KG, Choo AB, Churchill GA, Corbel M, Damjanov I, Draper JS, Dvorak P, Emanuelsson K, Fleck RA, Ford A, Gertow K, Gertsenstein M, Gokhale PJ, Hamilton RS, Hampl A, Healy LE, Hovatta O, Hyllner J, Imreh MP, Itskovitz-Eldor J, Jackson J, Johnson JL, Jones M, Kee K, King BL, Knowles BB, Lako M, Lebrin F, Mallon BS, Manning D, Mayshar Y, McKay RD, Michalska AE, Mikkola M, Mileikovsky M, Minger SL, Moore HD, Mummery CL, Nagy A, Nakatsuji N, O'Brien CM, Oh SK, Olsson C, Otonkoski T, Park KY, Passier R, Patel H, Patel M, Pedersen R, Pera MF, Piekarczyk MS, Pera RA, Reubinoff BE, Robins AJ, Rossant J, Rugg-Gunn P, Schulz TC, Semb H, Sherrer ES, Siemen H, Stacey GN, Stojkovic M, Suemori H, Szatkiewicz J, Turetsky T, Tuuri T, van den Brink S, Vintersten K, Vuoristo S, Ward D, Weaver TA, Young LA, Zhang W | title = Characterization of human embryonic stem cell lines by the International Stem Cell Initiative | journal = Nature Biotechnology | volume = 25 | issue = 7 | pages = 803–816 | date = July 2007 | pmid = 17572666 | doi = 10.1038/nbt1318 |s2cid= 13780999 }}

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.,{{cite journal | vauthors = Mahla RS | title = Stem Cells Applications in Regenerative Medicine and Disease Therapeutics | journal = International Journal of Cell Biology | volume = 2016 | issue = 7 | pages = 1–24 | year = 2016 | pmid = 27516776 | pmc = 4969512 | doi = 10.1155/2016/6940283 | doi-access = free }} 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.{{cite news | first1 = Ron | last1 = Winslow | first2 = Alicia | last2 = Mundy | name-list-style = vanc |title= First Embryonic Stem-Cell Trial Gets Approval from the FDA |newspaper= The Wall Street Journal |url= https://www.wsj.com/articles/SB123268485825709415 |date= 23 January 2009 }} 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.{{cite web|url=http://www.sciencedebate.com/science-blog/embryonic-stem-cell-therapy-risk-geron-ends-clinical-trial|publisher=ScienceDebate.com|title=Embryonic Stem Cell Therapy At Risk? Geron Ends Clinical Trial|access-date=2011-12-11|archive-date=2014-08-22|archive-url=https://web.archive.org/web/20140822055210/http://www.sciencedebate.com/science-blog/embryonic-stem-cell-therapy-risk-geron-ends-clinical-trial|url-status=dead}} Differentiating ES cells into usable cells while avoiding transplant rejection are just a few of the hurdles that embryonic stem cell researchers still face.{{cite journal | vauthors = Wu DC, Boyd AS, Wood KJ | title = Embryonic stem cell transplantation: potential applicability in cell replacement therapy and regenerative medicine | journal = Frontiers in Bioscience | volume = 12 | issue = 8–12 | pages = 4525–35 | date = May 2007 | pmid = 17485394 | doi = 10.2741/2407 | s2cid = 6355307 | doi-access = free }} 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.

File:Mouse embryonic stem cells.jpg| Mouse embryonic stem cells with fluorescent marker

File:Human embryonic stem cell colony phase.jpg| Human embryonic stem cell colony on mouse embryonic fibroblast feeder layer

{{Main|Mesenchymal stem cell}}

File:Human mesenchymal stem cells.gif

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.{{cite journal | vauthors = Zomer HD, Vidane AS, Gonçalves NN, Ambrósio CE | title = Mesenchymal and induced pluripotent stem cells: general insights and clinical perspectives | journal = Stem Cells and Cloning: Advances and Applications| volume = 8 | pages = 125–134 | date = 2015-09-28 | pmid = 26451119 | pmc = 4592031 | doi = 10.2147/SCCAA.S88036 | doi-access = free }} 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.{{cite journal | vauthors = Caplan AI | title = Mesenchymal stem cells | journal = Journal of Orthopaedic Research | volume = 9 | issue = 5 | pages = 641–650 | date = September 1991 | pmid = 1870029 | doi = 10.1002/jor.1100090504 | s2cid = 22606668 | doi-access = free }}

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. MSCs injection leads to wound healing primarily through stimulation of angiogenesis.{{Cite journal |last1=Krasilnikova |first1=O. A. |last2=Baranovskii |first2=D. S. |last3=Lyundup |first3=A. V. |last4=Shegay |first4=P. V. |last5=Kaprin |first5=A. D. |last6=Klabukov |first6=I. D. |date=2022-04-27 |title=Stem and Somatic Cell Monotherapy for the Treatment of Diabetic Foot Ulcers: Review of Clinical Studies and Mechanisms of Action |journal=Stem Cell Reviews and Reports |volume=18 |issue=6 |pages=1974–1985 |doi=10.1007/s12015-022-10379-z |issn=2629-3277 |pmid=35476187|s2cid=248402820 }}

{{Further|Cell cycle}}

Embryonic stem cells (ESCs) have the ability to divide indefinitely while keeping their pluripotency, which is made possible through specialized mechanisms of cell cycle control.{{cite journal | vauthors = Koledova Z, Krämer A, Kafkova LR, Divoky V | title = Cell-cycle regulation in embryonic stem cells: centrosomal decisions on self-renewal | journal = Stem Cells and Development | volume = 19 | issue = 11 | pages = 1663–1678 | date = November 2010 | pmid = 20594031 | doi = 10.1089/scd.2010.0136 }} Compared to proliferating somatic cells, ESCs have unique cell cycle characteristics—such as rapid cell division caused by shortened G1 phase, absent G0 phase, and modifications in cell cycle checkpoints—which leaves the cells mostly in S phase at any given time.{{cite journal | vauthors = Barta T, Dolezalova D, Holubcova Z, Hampl A | title = Cell cycle regulation in human embryonic stem cells: links to adaptation to cell culture | journal = Experimental Biology and Medicine | volume = 238 | issue = 3 | pages = 271–275 | date = March 2013 | pmid = 23598972 | doi = 10.1177/1535370213480711 | s2cid = 2028793 }} 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.{{cite journal | vauthors = Zaveri L, Dhawan J | title = Cycling to Meet Fate: Connecting Pluripotency to the Cell Cycle | language = en | journal = Frontiers in Cell and Developmental Biology | volume = 6 | pages = 57 | date = 2018 | pmid = 29974052 | pmc = 6020794 | doi = 10.3389/fcell.2018.00057 | doi-access = free }} 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.

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.

The cell cycle is regulated by complex network of cyclins, cyclin-dependent kinases (Cdk), cyclin-dependent kinase inhibitors (Cdkn), pocket proteins of the retinoblastoma (Rb) family, and other accessory factors. Foundational insight into the distinctive regulation of ESC cell cycle was gained by studies on mouse ESCs (mESCs). 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 D and Cdk4/6 are active in the G1 phase, while Cyclin E and Cdk2 are active during the late G1 phase and S phase; and Cyclin A and Cdk2 are active in the S phase and G2, while Cyclin B and Cdk1 are active in G2 and M phase. 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, keeping retinoblastoma protein (pRb) hyperphosphorylated and 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. 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.{{cite journal | vauthors = Koledova Z, Kafkova LR, Calabkova L, Krystof V, Dolezel P, Divoky V | title = Cdk2 inhibition prolongs G1 phase progression in mouse embryonic stem cells | journal = Stem Cells and Development | volume = 19 | issue = 2 | pages = 181–194 | date = February 2010 | pmid = 19737069 | doi = 10.1089/scd.2009.0065 }}

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 p21^CipP1, p27^Kip1, and p57^Kip2.{{cite journal | vauthors = Becker KA, Ghule PN, Therrien JA, Lian JB, Stein JL, van Wijnen AJ, Stein GS | title = Self-renewal of human embryonic stem cells is supported by a shortened G1 cell cycle phase | journal = Journal of Cellular Physiology | volume = 209 | issue = 3 | pages = 883–893 | date = December 2006 | pmid = 16972248 | doi = 10.1002/jcp.20776 | s2cid = 24908771 }} 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. 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.

ESCs are also characterized by G1 checkpoint non-functionality, even though the G1 checkpoint is crucial for maintaining genomic stability. In response to DNA 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. Consistent with this idea, ESCs are hypersensitive to DNA damage to minimize mutations passed onto the next generation.

The primitive stem cells located in the organs of fetuses are referred to as fetal stem cells.

{{cite book |editor1=Ariff Bongso |editor2=Eng Hin Lee | title = Stem Cells: From Benchtop to Bedside |url=https://archive.org/details/stemcellsfromben00bong |url-access=limited | chapter = Stem cells: their definition, classification and sources | publisher = World Scientific | year = 2005 | page = [https://archive.org/details/stemcellsfromben00bong/page/n25 5] | isbn = 978-981-256-126-8 | oclc = 443407924 }}

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 abortion. These stem cells are not immortal but have a high level of division and are multipotent.
2. 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.{{cite book |last1=Moore |first1=Keith L. |last2=Persaud |first2=T. V. N. |last3=Torchia |first3=Mark G. |title=Before We are Born: Essentials of Embryology and Birth Defects |date=2013 |publisher=Saunders/Elsevier |isbn=978-1-4377-2001-3 }}{{page needed|date=August 2021}}

{{Main|Adult stem cell}}

Image:Stem cell division and differentiation.svg

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.{{cite web |title=What is a stem cell |url=https://www.anthonynolan.org/patients-and-families/understanding-stem-cell-transplants/what-is-a-stem-cell |website=anthonynolan.org |publisher=Anthony Nolan |access-date=17 February 2022}}

There are three known accessible sources of autologous adult stem cells in humans:

1. Bone marrow, which requires extraction by harvesting, usually from pelvic bones via surgery.{{Cite web|title=Bone marrow (stem cell) donation: MedlinePlus Medical Encyclopedia|url=https://medlineplus.gov/ency/patientinstructions/000839.htm|access-date=2021-10-17|website=medlineplus.gov|language=en}}
2. Adipose tissue (fat cells), which requires extraction by liposuction.{{cite journal | vauthors = Coughlin RP, Oldweiler A, Mickelson DT, Moorman CT | title = Adipose-Derived Stem Cell Transplant Technique for Degenerative Joint Disease | journal = Arthroscopy Techniques | volume = 6 | issue = 5 | pages = e1761–e1766 | date = October 2017 | pmid = 29399463 | pmc = 5795060 | doi = 10.1016/j.eats.2017.06.048 }}
3. 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.{{Cite web |date=2011-02-02 |title=autologous stem cell transplant |url=https://www.cancer.gov/publications/dictionaries/cancer-terms/def/autologous-stem-cell-transplant |access-date=2022-06-26 |website=www.cancer.gov |language=en}}

Stem cells can also be taken from umbilical cord blood 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 their own blood for elective surgical procedures.{{citation needed|date=August 2021}}

Pluripotent adult stem cells are rare and generally small in number, but they can be found in umbilical cord blood and other tissues.{{cite journal | vauthors = Ratajczak MZ, Machalinski B, Wojakowski W, Ratajczak J, Kucia M | title = A hypothesis for an embryonic origin of pluripotent Oct-4(+) stem cells in adult bone marrow and other tissues | journal = Leukemia | volume = 21 | issue = 5 | pages = 860–867 | date = May 2007 | pmid = 17344915 | doi = 10.1038/sj.leu.2404630 | s2cid = 21433689 | doi-access = }} Bone marrow is a rich source of adult stem cells,{{cite journal | vauthors = Narasipura SD, Wojciechowski JC, Charles N, Liesveld JL, King MR | title = P-Selectin coated microtube for enrichment of CD34+ hematopoietic stem and progenitor cells from human bone marrow | journal = Clinical Chemistry | volume = 54 | issue = 1 | pages = 77–85 | date = January 2008 | pmid = 18024531 | doi = 10.1373/clinchem.2007.089896 | doi-access = free }} which have been used in treating several conditions including liver cirrhosis,{{cite journal | vauthors = Terai S, Ishikawa T, Omori K, Aoyama K, Marumoto Y, Urata Y, Yokoyama Y, Uchida K, Yamasaki T, Fujii Y, Okita K, Sakaida I | title = Improved liver function in patients with liver cirrhosis after autologous bone marrow cell infusion therapy | journal = Stem Cells | volume = 24 | issue = 10 | pages = 2292–2298 | date = October 2006 | pmid = 16778155 | doi = 10.1634/stemcells.2005-0542 | s2cid = 5649484 }} chronic limb ischemia{{cite journal | vauthors = Subrammaniyan R, Amalorpavanathan J, Shankar R, Rajkumar M, Baskar S, Manjunath SR, Senthilkumar R, Murugan P, Srinivasan VR, Abraham S | title = Application of autologous bone marrow mononuclear cells in six patients with advanced chronic critical limb ischemia as a result of diabetes: our experience | journal = Cytotherapy | volume = 13 | issue = 8 | pages = 993–999 | date = September 2011 | pmid = 21671823 | doi = 10.3109/14653249.2011.579961 | s2cid = 27251276 }} and endstage heart failure.{{cite journal |url=http://www.pubstemcell.com/monthly/003010700010.htm | vauthors = Madhusankar N | title = Use of Bone Marrow derived Stem Cells in Patients with Cardiovascular Disorders | journal = Journal of Stem Cells and Regenerative Medicine | year = 2007 | volume = 3 | issue = 1 | pages = 28–29 | pmid = 24693021 | pmc = 3908115 }} The quantity of bone marrow stem cells declines with age and is greater in males than females during reproductive years.{{cite journal | vauthors = Dedeepiya VD, Rao YY, Jayakrishnan GA, Parthiban JK, Baskar S, Manjunath SR, Senthilkumar R, Abraham SJ | title = Index of CD34+ Cells and Mononuclear Cells in the Bone Marrow of Spinal Cord Injury Patients of Different Age Groups: A Comparative Analysis | journal = Bone Marrow Research | volume = 2012 | pages = 1–8 | year = 2012 | pmid = 22830032 | pmc = 3398573 | doi = 10.1155/2012/787414 | doi-access = free }} Much adult stem cell research to date has aimed to characterize their potency and self-renewal capabilities.{{cite journal | vauthors = Gardner RL | title = Stem cells: potency, plasticity and public perception | journal = Journal of Anatomy | volume = 200 | issue = Pt 3 | pages = 277–282 | date = March 2002 | pmid = 12033732 | pmc = 1570679 | doi = 10.1046/j.1469-7580.2002.00029.x }} 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).{{cite journal | vauthors = Behrens A, van Deursen JM, Rudolph KL, Schumacher B | title = Impact of genomic damage and ageing on stem cell function | journal = Nature Cell Biology | volume = 16 | issue = 3 | pages = 201–207 | date = March 2014 | pmid = 24576896 | pmc = 4214082 | doi = 10.1038/ncb2928 }}

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.).{{cite journal | vauthors = Barrilleaux B, Phinney DG, Prockop DJ, O'Connor KC | title = Review: ex vivo engineering of living tissues with adult stem cells | journal = Tissue Engineering | volume = 12 | issue = 11 | pages = 3007–3019 | date = November 2006 | pmid = 17518617 | doi = 10.1089/ten.2006.12.3007 | citeseerx = 10.1.1.328.2873 }}{{cite journal | vauthors = Gimble JM, Katz AJ, Bunnell BA | title = Adipose-derived stem cells for regenerative medicine | journal = Circulation Research | volume = 100 | issue = 9 | pages = 1249–1260 | date = May 2007 | pmid = 17495232 | pmc = 5679280 | doi = 10.1161/01.RES.0000265074.83288.09 }} 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 of SSEA-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 markers Oct4, Sox2, and Nanog.{{cite journal | vauthors = Kuroda Y, Kitada M, Wakao S, Nishikawa K, Tanimura Y, Makinoshima H, Goda M, Akashi H, Inutsuka A, Niwa A, Shigemoto T, Nabeshima Y, Nakahata T, Nabeshima Y, Fujiyoshi Y, Dezawa M | title = Unique multipotent cells in adult human mesenchymal cell populations | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 19 | pages = 8639–8643 | date = May 2010 | pmid = 20421459 | pmc = 2889306 | doi = 10.1073/pnas.0911647107 | bibcode = 2010PNAS..107.8639K | doi-access = free }}

Adult stem cell treatments have been successfully used for many years to treat leukemia and related bone/blood cancers through bone marrow transplants.{{cite web |url=http://www.ucsfchildrenshospital.org/treatments/leukemia_treatment_options/index.html |title=Bone Marrow Transplant|work=ucsfchildrenshospital.org}} Adult stem cells are also used in veterinary medicine to treat tendon and ligament injuries in horses.{{cite news |first=Ed |last=Kane |title=Stem-cell therapy shows promise for horse soft-tissue injury, disease |url=http://veterinarynews.dvm360.com/dvm/Equine+Medicine/Stem-cell-therapy-shows-promise-for-horse-soft-tis/ArticleStandard/Article/detail/515503 |publisher=DVM Newsmagazine |date=2008-05-01 |access-date=2008-06-12 |archive-date=2008-12-11 |archive-url=https://web.archive.org/web/20081211094448/http://veterinarynews.dvm360.com/dvm/Equine+Medicine/Stem-cell-therapy-shows-promise-for-horse-soft-tis/ArticleStandard/Article/detail/515503 |url-status=dead }}

The use of adult stem cells in research and therapy is not as controversial as the use of embryonic stem cells, because the production of adult stem cells does not require the destruction of an embryo. Additionally, in instances where adult stem cells are obtained from the intended recipient (an autograft), the risk of rejection is essentially non-existent. Consequently, more US government funding is being provided for adult stem cell research.{{cite web |url=https://www.hhs.gov/news/press/2004pres/20040714b.html |archive-url=https://web.archive.org/web/20090109104735/http://www.hhs.gov/news/press/2004pres/20040714b.html |archive-date=2009-01-09 |publisher=US Department of Health and Human Services |title=Stem Cell FAQ |date=2004-07-14}}

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.{{cite journal | vauthors = Oliveira PH, da Silva CL, Cabral JM | title = Genomic Instability in Human Stem Cells: Current Status and Future Challenges | journal = Stem Cells | volume = 32 | issue = 11 | pages = 2824–2832 | date = 2014 | doi = 10.1002/stem.1796 | pmid = 25078438 | s2cid = 41335566 | doi-access = free }}

Hematopoietic stem cells (HSCs) are vulnerable to DNA damage and mutations that increase with age.Zhang L, Mack R, Breslin P, Zhang J. Molecular and cellular mechanisms of aging in hematopoietic stem cells and their niches. J Hematol Oncol. 2020 Nov 23;13(1):157. doi: 10.1186/s13045-020-00994-z. PMID 33228751; PMCID: PMC7686726 This vulnerability may explain the increased risk of slow growing blood cancers (myeloid malignancies) in the elderly. 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.Montazersaheb S, Ehsani A, Fathi E, Farahzadi R. Cellular and Molecular Mechanisms Involved in Hematopoietic Stem Cell Aging as a Clinical Prospect. Oxid Med Cell Longev. 2022 Apr 1;2022:2713483. doi: 10.1155/2022/2713483. PMID 35401928; PMCID: PMC8993567

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.

{{cite journal | vauthors = De Coppi P, Bartsch G, Siddiqui MM, Xu T, Santos CC, Perin L, Mostoslavsky G, Serre AC, Snyder EY, Yoo JJ, Furth ME, Soker S, Atala A | title = Isolation of amniotic stem cell lines with potential for therapy | journal = Nature Biotechnology | volume = 25 | issue = 1 | pages = 100–106 | date = January 2007 | pmid = 17206138 | doi = 10.1038/nbt1274 | s2cid = 6676167 }}

Amniotic stem cells are a topic of active research.

Use of stem cells from amniotic fluid overcomes the ethical objections to using human embryos as a source of cells. Roman Catholic teaching forbids the use of embryonic stem cells in experimentation; accordingly, the Vatican newspaper "Osservatore Romano" called amniotic stem cells "the future of medicine".{{cite news |title=Vatican newspaper calls new stem cell source 'future of medicine' |url=https://www.catholicnewsagency.com/news/18555/vatican-newspaper-calls-new-stem-cell-source-future-of-medicine |work=Catholic News Agency |date=3 February 2010 }}

It is possible to collect amniotic stem cells for donors or for autologous use: the first US amniotic stem cells bank{{cite news |url=https://www.reuters.com/article/pressRelease/idUS166682+22-Oct-2009+PRN20091022 |title=European Biotech Company Biocell Center Opens First U.S. Facility for Preservation of Amniotic Stem Cells in Medford, Massachusetts |work=Reuters |date=2009-10-22 |access-date=2010-03-14 |archive-url=https://web.archive.org/web/20091030150358/https://www.reuters.com/article/pressRelease/idUS166682%2B22-Oct-2009%2BPRN20091022 |archive-date=2009-10-30 }}{{cite news|url=http://www.boston.com/business/ticker/2009/10/europes_biocell.html |title=Europe's Biocell Center opens Medford office – Daily Business Update |work=The Boston Globe |date=2009-10-22 |access-date=2010-03-14}} was opened in 2009 in Medford, MA, by Biocell Center Corporation{{cite web|url=http://www.bostonherald.com/business/general/view/20091022the_ticker/ |title=The Ticker |publisher=BostonHerald.com |date=2009-10-22 |access-date=2010-03-14}}{{cite web |url=http://www.masshightech.com/stories/2009/10/19/daily59-Biocell-Center-opens-amniotic-stem-cell-bank-in-Medford.html |title=Biocell Center opens amniotic stem cell bank in Medford |work=Mass High Tech Business News |date=2009-10-23 |access-date=2012-08-26 |archive-url=https://web.archive.org/web/20121014201617/http://www.masshightech.com/stories/2009/10/19/daily59-Biocell-Center-opens-amniotic-stem-cell-bank-in-Medford.html |archive-date=2012-10-14 }}{{cite web|url=http://www.wbur.org/2009/10/22/stem-cell-bank |title=World's First Amniotic Stem Cell Bank Opens In Medford |date=22 October 2009 |publisher=wbur.org |access-date=2010-03-14}} and collaborates with various hospitals and universities all over the world.{{cite press release|url=http://www.prnewswire.com/news-releases/biocell-center-corporation-partners-with-new-englands-largest-community-based-hospital-network-to-offer-a-unique-service-in-amniotic-fluid-stem-cell-preservation-86848157.html |title=Biocell Center Corporation Partners with New England's Largest Community-Based Hospital Network to Offer a Unique... |location=Medford, Mass. |publisher=Prnewswire.com |access-date=2010-03-14}}

{{Main|Induced pluripotent stem cell}}

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

However, reprogramming allows 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 protein transcription factors, pluripotent stem cells with ESC-like capabilities have been derived.{{cite news|title=Making human embryonic stem cells|newspaper=The Economist|url=http://www.economist.com/science/displaystory.cfm?story_id=10170972|date=2007-11-22}}{{cite web|url=https://www.npr.org/templates/story/story.php?storyId=16466265|publisher=National Public Radio|title=Skin Cells Can Become Embryonic Stem Cells| last1 = Brand | first1 = Madeleine | last2 = Palca | first2 = Joe | last3 = Cohen | first3 = Alex | name-list-style = vanc |date=2007-11-20}}{{cite web|url=https://www.pbs.org/newshour/bb/science/july-dec07/stemcells_11-20.html|title=Breakthrough Set to Radically Change Stem Cell Debate|publisher=News Hour with Jim Lehrer|date=2007-11-20|access-date=2017-09-15|archive-date=2014-01-22|archive-url=https://web.archive.org/web/20140122092539/http://www.pbs.org/newshour/bb/science/july-dec07/stemcells_11-20.html|url-status=dead}} The first demonstration of induced pluripotent stem cells was conducted by Shinya Yamanaka and his colleagues at Kyoto University.{{cite journal | vauthors = Kimbrel EA, Lanza R | title = Pluripotent stem cells: the last 10 years | journal = Regenerative Medicine | volume = 11 | issue = 8 | pages = 831–847 | date = December 2016 | pmid = 27908220 | doi = 10.2217/rme-2016-0117 | doi-access = free }} They used the transcription factors Oct3/4, Sox2, c-Myc, and Klf4 to reprogram mouse fibroblast cells into pluripotent cells.{{cite journal | vauthors = Takahashi K, Yamanaka S | title = Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors | journal = Cell | volume = 126 | issue = 4 | pages = 663–676 | date = August 2006 | pmid = 16904174 | doi = 10.1016/j.cell.2006.07.024 | hdl = 2433/159777 | s2cid = 1565219 | hdl-access = free }} Subsequent work used these factors to induce pluripotency in human fibroblast cells.{{cite journal | vauthors = Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S | title = Induction of pluripotent stem cells from adult human fibroblasts by defined factors | journal = Cell | volume = 131 | issue = 5 | pages = 861–872 | date = November 2007 | pmid = 18035408 | doi = 10.1016/j.cell.2007.11.019 | hdl = 2433/49782 | s2cid = 8531539 | hdl-access = free }} Junying Yu, James Thomson, and their colleagues at the University of Wisconsin–Madison used a different set of factors, Oct4, Sox2, Nanog and Lin28, and carried out their experiments using cells from human foreskin.{{cite journal | vauthors = Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA | title = Induced pluripotent stem cell lines derived from human somatic cells | journal = Science | volume = 318 | issue = 5858 | pages = 1917–1920 | date = December 2007 | pmid = 18029452 | doi = 10.1126/science.1151526 | bibcode = 2007Sci...318.1917Y | s2cid = 86129154 }} However, they were able to replicate Yamanaka'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 pluripotency and differentiation potential, the expression of pluripotency genes, epigenetic patterns, embryoid body and teratoma formation, and viable chimera 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 reprogramming and 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 animal Dolly the Sheep, has announced that he will abandon somatic cell nuclear transfer as an avenue of research."His inspiration comes from the research by Prof Shinya Yamanaka at Kyoto University, which suggests a way to create human embryo stem cells without the need for human eggs, which are in extremely short supply, and without the need to create and destroy human cloned embryos, which is bitterly opposed by the pro life movement." {{cite news|url=https://www.telegraph.co.uk/science/science-news/3314696/Dolly-creator-Prof-Ian-Wilmut-shuns-cloning.html|archive-url=https://web.archive.org/web/20090730031336/http://www.telegraph.co.uk/science/science-news/3314696/Dolly-creator-Prof-Ian-Wilmut-shuns-cloning.html|archive-date=2009-07-30|title=Dolly creator Prof Ian Wilmut shuns cloning| last = Highfield | first = Roger | name-list-style = vanc |date=2007-11-16|newspaper=The Telegraph | location=London}}

The ability to induce pluripotency benefits developments in tissue engineering. By providing a suitable scaffold and microenvironment, iPSC can be differentiated into cells of therapeutic application, and for in vitro models to study toxins and pathogenesis.{{cite journal |vauthors=Maldonado M, Luu RJ, Ico G, Ospina A, Myung D, Shih HP, Nam J |date=September 2017 |title=Lineage- and developmental stage-specific mechanomodulation of induced pluripotent stem cell differentiation |journal=Stem Cell Research & Therapy |volume=8 |issue=1 |pages=216 |doi=10.1186/s13287-017-0667-2 |pmc=5622562 |pmid=28962663 |doi-access=free}}

Induced pluripotent stem cells provide several therapeutic advantages. Like ESCs, they are pluripotent. They thus have great differentiation potential; theoretically, they could produce any cell within the human body (if reprogramming to pluripotency was "complete"). Moreover, unlike ESCs, they potentially could allow doctors to create a pluripotent stem cell line for each individual patient.{{cite journal |first1=DA |last1=Robinton |author-link1=Daisy A. Robinton |first2=GQ |last2=Daley | title = The promise of induced pluripotent stem cells in research and therapy | journal = Nature | volume = 481 | issue = 7381 | pages = 295–305 | date = January 2012 | pmid = 22258608 | pmc = 3652331 | doi = 10.1038/nature10761 | bibcode = 2012Natur.481..295R }} Frozen blood samples can be used as a valuable source of induced pluripotent stem cells.{{cite journal | vauthors = Staerk J, Dawlaty MM, Gao Q, Maetzel D, Hanna J, Sommer CA, Mostoslavsky G, Jaenisch R | title = Reprogramming of human peripheral blood cells to induced pluripotent stem cells | journal = Cell Stem Cell | volume = 7 | issue = 1 | pages = 20–24 | date = July 2010 | pmid = 20621045 | pmc = 2917234 | doi = 10.1016/j.stem.2010.06.002}}

• {{lay source |template=cite news |date=2010-07-01 |title=Frozen blood a source of stem cells, study finds |url=http://www.newsdaily.com/stories/tre6604si-us-stemcells-frozen |archive-url=https://web.archive.org/web/20100703175036/http://www.newsdaily.com/stories/tre6604si-us-stemcells-frozen/ |archive-date=2010-07-03 |work=NewsDaily |agency=Reuters}} 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 great potential for future use in medical treatment and research.

The key factors controlling the cell cycle also regulate pluripotency. Thus, manipulation of relevant genes can maintain pluripotency and reprogram somatic cells to an induced pluripotent state. However, reprogramming of somatic cells is often low in efficiency and considered stochastic.{{cite journal | vauthors = Chen X, Hartman A, Guo S | title = Choosing Cell Fate Through a Dynamic Cell Cycle | journal = Current Stem Cell Reports | volume = 1 | issue = 3 | pages = 129–138 | date = 2015-09-01 | pmid = 28725536 | pmc = 5487535 | doi = 10.1007/s40778-015-0018-0 }}

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. 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.{{cite journal | vauthors = Hindley C, Philpott A | title = The cell cycle and pluripotency | journal = The Biochemical Journal | volume = 451 | issue = 2 | pages = 135–143 | date = April 2013 | pmid = 23535166 | pmc = 3631102 | doi = 10.1042/BJ20121627 }}

{{Main|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.{{cite journal |last1=Fox |first1=D.T. |last2=Morris |first2=L.X. |last3=Nystul |first3=T. |last4=Spradling |first4=A.C. |title=Lineage analysis of stem cells |journal=StemBook |year=2008 |doi=10.3824/stembook.1.33.1 |pmid=20614627 |url=https://www.stembook.org/node/542 |doi-access=free }}

To ensure self-renewal, stem cells undergo two types of cell division (see Stem cell division and differentiation diagram). Symmetric division gives rise to two identical daughter cells both endowed with stem cell properties. Asymmetric division, on the other hand, produces only one stem cell and a progenitor cell with limited self-renewal potential. Progenitors can go through several rounds of cell division before terminally differentiating into a mature cell. It is possible that the molecular distinction between symmetric and asymmetric divisions lies in differential segregation of cell membrane proteins (such as receptors) between the daughter cells.{{cite journal |last1=Beckmann |first1=Julia |last2=Scheitza |first2=Sebastian |last3=Wernet |first3=Peter |last4=Fischer |first4=Johannes C. |last5=Giebel |first5=Bernd |title=Asymmetric cell division within the human hematopoietic stem and progenitor cell compartment: identification of asymmetrically segregating proteins |journal=Blood |date=15 June 2007 |volume=109 |issue=12 |pages=5494–5501 |doi=10.1182/blood-2006-11-055921 |pmid=17332245 |doi-access=free }}

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.{{cite journal |last1=Xie |first1=Ting |last2=Spradling |first2=Allan C |title=decapentaplegic Is Essential for the Maintenance and Division of Germline Stem Cells in the Drosophila Ovary |journal=Cell |date=July 1998 |volume=94 |issue=2 |pages=251–260 |doi=10.1016/s0092-8674(00)81424-5 |pmid=9695953 |s2cid=11347213 |doi-access=free }}{{cite journal |last1=Song |first1=X. |last2=Zhu |first2=CH |last3=Doan |first3=C |last4=Xie |first4=T |title=Germline Stem Cells Anchored by Adherens Junctions in the Drosophila Ovary Niches |journal=Science |date=7 June 2002 |volume=296 |issue=5574 |pages=1855–1857 |doi=10.1126/science.1069871 |pmid=12052957 |bibcode=2002Sci...296.1855S |s2cid=25830121 }}

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.{{cite web |date=9 March 2009 |title=Executive Order: Removing barriers to responsible scientific research involving human stem cells |url=https://obamawhitehouse.archives.gov/the_press_office/Removing-Barriers-to-Responsible-Scientific-Research-Involving-Human-Stem-Cells |work=whitehouse.gov |via=National Archives}} 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.{{cite web |title=National Institutes of Health Guidelines on Human Stem Cell Research |url=http://stemcells.nih.gov/policy/pages/2009guidelines.aspx |access-date=24 April 2014}} The NIH Human Embryonic Stem Cell Registry can be accessed online and has updated information on cell lines eligible for NIH funding.{{cite web |title=NIH Human Embryonic Stem Cell Registry |url=https://grants.nih.gov/stem_cells/registry/current.htm |access-date=1 March 2017}} There are 486 approved lines as of January 2022.{{cite web |title=NIH Human Embryonic Stem Cell Registry |url=https://grants.nih.gov/stem_cells/registry/current.htm#hold |access-date=10 February 2022}}

{{Main|Stem cell therapy}}

Stem cell therapy is the use of stem cells to treat or prevent a disease or condition. Bone marrow transplant is a form of stem cell therapy that has been used for many years because it has proven to be effective in clinical trials.{{Cite web |title=Why Perform a Stem Cell Transplant? – Explore Stem Cells |url=https://www.explorestemcells.co.uk/WhyPerformStemCellTransplant.html |access-date=2024-12-28 |website=www.explorestemcells.co.uk|first=Ian |last=Murnaghan }}{{Cite web |date=2015-04-29 |title=Stem Cell and Bone Marrow Transplants for Cancer - NCI |url=https://www.cancer.gov/about-cancer/treatment/types/stem-cell-transplant |access-date=2024-12-28 |website=www.cancer.gov |language=en}} 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.{{cite journal | vauthors = Stamm C, Westphal B, Kleine HD, Petzsch M, Kittner C, Klinge H, Schümichen C, Nienaber CA, Freund M, Steinhoff G | display-authors = 6 | title = Autologous bone-marrow stem-cell transplantation for myocardial regeneration | journal = Lancet | volume = 361 | issue = 9351 | pages = 45–46 | date = January 2003 | pmid = 12517467 | doi = 10.1016/S0140-6736(03)12110-1 | s2cid = 23858666 }}

For over 50 years, hematopoietic stem cell transplantation (HSCT) has been used to treat people with conditions such as leukaemia and lymphoma; this is the only widely practiced form of stem-cell therapy.{{cite journal |vauthors=Karanes C, Nelson GO, Chitphakdithai P, Agura E, Ballen KK, Bolan CD, Porter DL, Uberti JP, King RJ, Confer DL |year=2008 |title=Twenty years of unrelated donor hematopoietic cell transplantation for adult recipients facilitated by the National Marrow Donor Program |journal=Biology of Blood and Marrow Transplantation |volume=14 |issue=9 Suppl |pages=8–15 |doi=10.1016/j.bbmt.2008.06.006 |pmid=18721775 |doi-access=free}} {{As of|2016|}}, the only established therapy using stem cells is hematopoietic stem cell transplantation.{{Cite journal |last1=Müller |first1=Albrecht M. |last2=Huppertz |first2=Sascha |last3=Henschler |first3=Reinhard |date=July 2016 |title=Hematopoietic Stem Cells in Regenerative Medicine: Astray or on the Path? |journal=Transfusion Medicine and Hemotherapy |volume=43 |issue=4 |pages=247–254 |doi=10.1159/000447748 |issn=1660-3796 |pmc=5040947 |pmid=27721700}} This usually takes the form of a bone-marrow transplantation, but the cells can also be derived from umbilical cord blood. Research is underway to develop various sources for stem cells as well as to apply stem-cell treatments for neurodegenerative diseases{{Cite journal |last=Lyon |first=Louisa |date=2018-10-01 |title=Stem cell therapies in neurology: the good, the bad and the unknown |journal=Brain |language=en |volume=141 |issue=10 |pages=e77 |doi=10.1093/brain/awy221 |issn=0006-8950 |pmid=30202947 |doi-access=free}}{{cite journal |vauthors=Mahla RS |year=2016 |title=Stem cells application in regenerative medicine and disease threpeutics |journal=International Journal of Cell Biology |volume=2016 |issue=7 |pages=1–24 |doi=10.1155/2016/6940283 |pmc=4969512 |pmid=27516776 |doi-access=free}}{{Cite web |title=Tế bào gốc là gì |url=https://miraicare.vn/te-bao-goc-la-gi-vai-tro-va-ung-dung-cua-te-bao-goc |access-date=2023-11-27 |website=Mirai Care |language=vi-VN}} and conditions such as diabetes and heart disease.

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.{{cite journal | vauthors = Master Z, McLeod M, Mendez I | title = Benefits, risks and ethical considerations in translation of stem cell research to clinical applications in Parkinson's disease | journal = Journal of Medical Ethics | volume = 33 | issue = 3 | pages = 169–173 | date = March 2007 | pmid = 17329391 | pmc = 2598267 | doi = 10.1136/jme.2005.013169 | jstor = 27719821 }} 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.{{Cite web|title=Comprehensive Stem Cell Training Course|url=https://r3medicaltraining.com/events/comprehensive-stem-cell-training-course/|access-date=2021-05-15|website=R3 Medical Training|language=en-US}} 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.

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.{{Cite journal |date=2000-03-04 |title=Before We Are Born: Essentials of Embryology and Birth Defects, 5th edition |url=https://doi.org/10.1016/s1526-9523(99)00026-4 |journal=Journal of Midwifery & Women's Health |volume=45 |issue=2 |pages=192–192 |doi=10.1016/s1526-9523(99)00026-4 |issn=1526-9523| vauthors = Moore KL, Persaud TV, Torchia MG | location = Philadelphia, PA | publisher = Saunders, Elsevier|url-access=subscription }}

Some stem cells form tumors after transplantation;{{cite news|first=Bernadine |last=Healy |url=http://health.usnews.com/health-news/blogs/heart-to-heart/2009/03/04/why-embryonic-stem-cells-are-obsolete |title=Why Embryonic Stem Cells are obsolete|publisher=US News and world report |access-date=Aug 17, 2015}} 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.{{Cite web|url=https://www.scientificamerican.com/blog/news-blog/embryonic-stem-cells-cause-cancer-i-2009-02-19/|title=Fetal stem cells cause tumor in a teenage boy|first=Coco|last=Ballantyne|website=Scientific American}}

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.{{cite journal |title=Ethical Issues in Stem Cell Research |last1=Lo |first1=Bernard |last2=Parham |first2=Lindsay |journal=Endocrine Reviews |publisher=NIH |date=May 2009 |volume=30 |issue=3 |pages=204–213 |doi=10.1210/er.2008-0031 |pmid=19366754 |pmc=2726839 }} The debate on this issue is mainly a philosophical one, not a scientific one.

Stem cell tourism is the part of the medical tourism industry in which patients travel to obtain stem cell procedures.

{{cite journal |last1=Bauer |first1=G |last2=Elsallab |first2=M |last3=Abou-El-Enein |first3=M |title=Concise Review: A Comprehensive Analysis of Reported Adverse Events in Patients Receiving Unproven Stem Cell-Based Interventions |journal=Stem Cells Translational Medicine |date=September 2018 |volume=7 |issue=9 |pages=676–685 |doi=10.1002/sctm.17-0282 |pmid=30063299 |pmc=6127222}}

The United States has had an explosion of "stem cell clinics".{{Cite news |last=Blackwell |first=Tom |date=2016-07-13 |title=Study reveals explosion of unproven stem-cell treatment in U.S. — and many Canadians are seeking them out |language=en |work=National Post |url=https://nationalpost.com/health/study-reveals-explosion-of-unproven-stem-cell-treatment-in-u-s-and-many-canadians-are-seeking-them-out |access-date=2022-03-22}} 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{{cite journal |last1=Berkowitz |first1=Aaron L. |last2=Miller |first2=Michael B. |last3=Mir |first3=Saad A. |last4=Cagney |first4=Daniel |last5=Chavakula |first5=Vamsidhar |last6=Guleria |first6=Indira |last7=Aizer |first7=Ayal |last8=Ligon |first8=Keith L. |last9=Chi |first9=John H. |title=Glioproliferative Lesion of the Spinal Cord as a Complication of 'Stem-Cell Tourism' |journal=New England Journal of Medicine |date=14 July 2016 |volume=375 |issue=2 |pages=196–198 |doi=10.1056/NEJMc1600188 |pmid=27331440 |doi-access=free }} and death. The high expense can also lead to financial problems. According to researchers, there is a need to educate the public, patients, and doctors about this issue.{{cite journal |last1=Bowman |first1=Michelle |last2=Racke |first2=Michael |last3=Kissel |first3=John |last4=Imitola |first4=Jaime |title=Responsibilities of Health Care Professionals in Counseling and Educating Patients With Incurable Neurological Diseases Regarding 'Stem Cell Tourism': Caveat Emptor |journal=JAMA Neurology |date=1 November 2015 |volume=72 |issue=11 |pages=1342–1345 |doi=10.1001/jamaneurol.2015.1891 |pmid=26322563 }}

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.{{Cite web|url=https://www.isscr.org/news-publicationsss/isscr-news-articles/blog-detail/stem-cells-in-focus/2019/11/12/communicating-about-unproven-stem-cell-treatments-to-the-public|title=Communicating About Unproven Stem Cell Treatments to the Public}}{{cite journal |last1=Tsou |first1=Amy |title=Ethical Considerations When Counseling Patients About Stem Cell Tourism |journal=Continuum: Lifelong Learning in Neurology |date=February 2015 |volume=21 |issue=1 Spinal Cord Disorders |pages=201–205 |doi=10.1212/01.CON.0000461094.76563.be |pmid=25651226 }} 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.{{cite journal |last1=Du |first1=Li |last2=Rachul |first2=Christen |last3=Guo |first3=Zhaochen |last4=Caulfield |first4=Timothy |title=Gordie Howe's 'Miraculous Treatment': Case Study of Twitter Users' Reactions to a Sport Celebrity's Stem Cell Treatment |journal=JMIR Public Health and Surveillance |date=9 March 2016 |volume=2 |issue=1 |pages=e8 |doi=10.2196/publichealth.5264 |pmid=27227162 |pmc=4869214 |doi-access=free }}

{{Further|Consumer Watchdog vs. Wisconsin Alumni Research Foundation}}

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.{{Cite web |title=How a University's Patents May Limit Stem-Cell Research |url=https://www.geneticsandsociety.org/article/how-universitys-patents-may-limit-stem-cell-research?id=1896 |access-date=2024-12-28 |language=en|publisher=The Wall Street Journal}}

In 2006, a request for the US Patent and Trademark Office (USPTO) to re-examine the three patents was filed by the Public Patent Foundation{{Cite web |title=Public Patent Foundation - GuideStar Profile |url=https://www.guidestar.org/profile/20-0236613 |access-date=2024-12-28 |website=www.guidestar.org}} on behalf of its client, the non-profit patent-watchdog group Consumer Watchdog (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,{{Cite web |title=WARF Stem Cell Patents Knocked Down in Round One |url=https://patentbaristas.com/archives/2007/04/03/warf-stem-cell-patents-knocked-down-in-round-one/ |access-date=2024-12-28|first=Stephen |last=Jenei |publisher=Patent Baristas|date= April 3, 2007 }} 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.{{Cite web |title=Ding! WARF Wins Round 2 As Stem Cell Patent Upheld |url=https://patentbaristas.com/archives/2008/03/03/ding-warf-wins-round-2-as-stem-cell-patent-upheld/ |access-date=2024-12-28|first=Stephen |last=Jenei |publisher=Patent Baristas|date= March 3, 2008 }}{{Cite news |title=WARF Goes 3 for 3 on Patents |url=https://www.science.org/content/article/warf-goes-3-3-patents |access-date=2024-12-28 |language=en|authorlink=Constance Holden |first=Constance |last=Holden|publisher=Science Now|date=March 12, 2008 }} 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.{{Cite web |last=McKeown |first=Scott |date=2010-05-10 |title=BPAI Rejects WARF Stem Cell Patent Claims in Inter Partes Reexamination Appeal |url=https://www.patentspostgrant.com/2010/05/bpai-rejects-warf-stem-cell-patent-claims-in-inter-partes-reexamination-appeal/ |access-date=2024-12-28 |website=Patents Post-Grant |language=en-US}} 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.{{Cite web |title=The Foundation For Taxpayer & Consumer Rights, Requester And Appellant V. Patent Of Wisconsin Alumni Research Foundation, Appeal 2012-011693, Reexamination Control 95/000,154 Patent 7,029,913 |url=http://e-foia.uspto.gov/Foia/ReterivePdf?system=BPAI&flNm=fd2012011693-01-22-2013-1 |archive-url=http://web.archive.org/web/20130220112912/http://e-foia.uspto.gov/Foia/ReterivePdf?system=BPAI&flNm=fd2012011693-01-22-2013-1 |archive-date=2013-02-20 |access-date=2024-12-28 |website=e-foia.uspto.gov}}

In July 2013, Consumer Watchdog announced that it would appeal the decision to allow the claims of the '913 patent to the US Court of Appeals for the Federal Circuit (CAFC), the federal appeals court that hears patent cases.{{Cite web |date=2013-07-03 |title=Consumer Watchdog, PPF Seek Invalidation of WARF's Stem Cell Patent |url=https://www.genomeweb.com/archive/consumer-watchdog-ppf-seek-invalidation-warfs-stem-cell-patent |access-date=2024-12-28 |website=GenomeWeb |language=en}} At a hearing in December 2013, the CAFC raised the question of whether Consumer Watchdog had legal standing to appeal; the case could not proceed until that issue was resolved.Antoinette Konski for Personalized Medicine Bulletin. February 3, 2014 [http://www.personalizedmedicinebulletin.com/2014/02/03/u-s-government-and-uspto-urges-federal-circuit-to-dismiss-stem-cell-appeal/ U.S. Government and USPTO Urges Federal Circuit to Dismiss Stem Cell Appeal]

File:Stem cell treatments.svg

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

• Diabetes
• Androgenic Alopecia and hair loss{{Cite web|title=Treating Hair Loss with Stem Cell & PRP Therapy|url=https://stemcells.la/treating-hair-loss-with-stem-cell-prp-therapy/|date=2019-02-20|website=Stem Cells LA|language=en-US|access-date=2020-05-30}}{{Cite journal|last1=Gentile|first1=Pietro|last2=Garcovich|first2=Simone|last3=Bielli|first3=Alessandra|last4=Scioli|first4=Maria Giovanna|last5=Orlandi|first5=Augusto|last6=Cervelli|first6=Valerio|date=November 2015|title=The Effect of Platelet-Rich Plasma in Hair Regrowth: A Randomized Placebo-Controlled Trial|journal=Stem Cells Translational Medicine|volume=4|issue=11|pages=1317–1323|doi=10.5966/sctm.2015-0107|issn=2157-6564|pmc=4622412|pmid=26400925}}
• Rheumatoid arthritis
• Parkinson's disease
• Alzheimer's disease
• Respiratory disease{{cite journal |last1=Hynds |first1=R |title=Exploiting the potential of lung stem cells to develop pro-regenerative therapies |journal=Biology Open |date=2022 |volume=11 |issue=10 |doi=10.1242/bio.059423 |pmid=36239242 |pmc=9581519 |doi-access=free }}
• Osteoarthritis{{Cite web |title=Stemcells Redirection |url=http://stemcells.nih.gov/info/basics/pages/basics6.aspx |archive-url=http://web.archive.org/web/20180619214156/https://stemcells.nih.gov/info/basics/pages/basics6.aspx |archive-date=2018-06-19 |access-date=2024-12-28 |website=stemcells.nih.gov |year=2009}}
• Stroke and traumatic brain injury repair{{cite news |last1=Steinberg |first1=Douglas |title=Stem Cells Tapped to Replenish Organs |url=https://www.the-scientist.com/research/stem-cells-tapped-to-replenish-organs-55310 |work=The Scientist Magazine |date=26 November 2000 }}
• Learning disability due to congenital disorder{{Cite web |date=2008-12-25 |title=Israeli scientists reverse brain birth defects using stem cells |url=https://www.israel21c.org/israeli-scientists-reverse-brain-birth-defects-using-stem-cells/ |access-date=2024-12-28 |website=ISRAEL21c |language=en-US}}
• Spinal cord injury repair{{cite journal | vauthors = Kang KS, Kim SW, Oh YH, Yu JW, Kim KY, Park HK, Song CH, Han H | title = A 37-year-old spinal cord-injured female patient, transplanted of multipotent stem cells from human UC blood, with improved sensory perception and mobility, both functionally and morphologically: a case study | journal = Cytotherapy | volume = 7 | issue = 4 | pages = 368–373 | year = 2005 | pmid = 16162459 | doi = 10.1080/14653240500238160 | s2cid = 33471639 }}
• Heart infarction{{cite journal | vauthors = Strauer BE, Schannwell CM, Brehm M | title = Therapeutic potentials of stem cells in cardiac diseases | journal = Minerva Cardioangiologica | volume = 57 | issue = 2 | pages = 249–267 | date = April 2009 | pmid = 19274033 }}
• Anti-cancer treatments
• Baldness reversal{{cite news |last1=DeNoon |first1=Daniel J. |title=Hair Cloning Nears Reality as Baldness Cure |url=https://www.webmd.com/skin-problems-and-treatments/hair-loss/news/20041104/hair-cloning-nears-reality-as-baldness-cure |work=WebMD |date=4 November 2004 }}
• Replace missing teeth{{cite journal | vauthors = Yen AH, Sharpe PT | title = Stem cells and tooth tissue engineering | journal = Cell and Tissue Research | volume = 331 | issue = 1 | pages = 359–372 | date = January 2008 | pmid = 17938970 | doi = 10.1007/s00441-007-0467-6 | s2cid = 23765276 }}
• Repair hearing{{cite magazine|url=https://www.newscientist.com/article/dn7003|title=Gene therapy is first deafness 'cure'|magazine=New Scientist|date=February 14, 2005}}
• Restore vision{{cite news|url=http://news.bbc.co.uk/1/hi/england/southern_counties/4495419.stm|title= Stem cells used to restore vision|work=BBC News|date= 2005-04-28}} and repair damage to the cornea{{cite journal | vauthors = Hanson C, Hardarson T, Ellerström C, Nordberg M, Caisander G, Rao M, Hyllner J, Stenevi U | title = Transplantation of human embryonic stem cells onto a partially wounded human cornea in vitro | journal = Acta Ophthalmologica | volume = 91 | issue = 2 | pages = 127–130 | date = March 2013 | pmid = 22280565 | pmc = 3660785 | doi = 10.1111/j.1755-3768.2011.02358.x }}
• Amyotrophic lateral sclerosis{{cite journal | vauthors = Vastag B | title = Stem cells step closer to the clinic: paralysis partially reversed in rats with ALS-like disease | journal = JAMA | volume = 285 | issue = 13 | pages = 1691–1693 | date = April 2001 | pmid = 11277806 | doi = 10.1001/jama.285.13.1691 }}
• Crohn's disease{{cite journal |last1=Anderson |first1=Querida |title=Osiris Trumpets Its Adult Stem Cell Product |journal=Genetic Engineering and Biotechnology News |date=15 June 2008 |volume=28 |issue=12 |url=https://www.genengnews.com/magazine/94/osiris-trumpets-its-adult-stem-cell-product/ }}
• Wound healing{{cite journal |last1=Gurtner |first1=Geoffrey C. |last2=Callaghan |first2=Matthew J. |last3=Longaker |first3=Michael T. |title=Progress and Potential for Regenerative Medicine |journal=Annual Review of Medicine |date=February 2007 |volume=58 |issue=1 |pages=299–312 |doi=10.1146/annurev.med.58.082405.095329 |pmid=17076602 }}
• Male infertility due to absence of spermatogonial stem cells.{{cite book |vauthors=Hanna V, Gassei K, Orwig KE | chapter = Stem Cell Therapies for Male Infertility: Where Are We Now and Where Are We Going? | veditors = Carrell D, Schlegel P, Racowsky C, Gianaroli L | title = Biennial Review of Infertility | pages = 17–39 | year = 2015 | publisher = Springer | doi = 10.1007/978-3-319-17849-3_3 | isbn = 978-3-319-17849-3 }} Bone marrow transplantation is, as of 2009, the only established use of stem cells. 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.{{cite journal | vauthors = Valli H, Phillips BT, Shetty G, Byrne JA, Clark AT, Meistrich ML, Orwig KE | title = Germline stem cells: toward the regeneration of spermatogenesis | journal = Fertility and Sterility | volume = 101 | issue = 1 | pages = 3–13 | date = January 2014 | pmid = 24314923 | pmc = 3880407 | doi = 10.1016/j.fertnstert.2013.10.052 }}
• 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 (POI).{{cite journal | vauthors = White YA, Woods DC, Takai Y, Ishihara O, Seki H, Tilly JL | title = Oocyte formation by mitotically active germ cells purified from ovaries of reproductive-age women | journal = Nature Medicine | volume = 18 | issue = 3 | pages = 413–421 | date = February 2012 | pmid = 22366948 | pmc = 3296965 | doi = 10.1038/nm.2669 }} New research posted in Science Direct suggests that ovarian follicles could be triggered to grow in the ovarian environment by using stem cells present in bone marrow. This study was conducted by infusing human bone marrow stem cells into immune-deficient mice to improve fertilization.{{Cite journal |last1=Herraiz |first1=Sonia |last2=Buigues |first2=Anna |last3=Díaz-García |first3=César |last4=Romeu |first4=Mónica |last5=Martínez |first5=Susana |last6=Gómez-Seguí |first6=Inés |last7=Simón |first7=Carlos |last8=Hsueh |first8=Aaron J. |last9=Pellicer |first9=Antonio |date=May 2018 |title=Fertility rescue and ovarian follicle growth promotion by bone marrow stem cell infusion |url=https://linkinghub.elsevier.com/retrieve/pii/S0015028218300049 |journal=Fertility and Sterility |volume=109 |issue=5 |pages=908–918.e2 |doi=10.1016/j.fertnstert.2018.01.004 |pmid=29576341 |issn=0015-0282}} Another study conducted using mice with damaged ovarian function from chemothearpy found that in vivo thearpy with bone marrow stem cells can heal the damaged ovaries.{{Cite journal |last1=Badawy |first1=Ahmed |last2=Sobh |first2=Mohamed A. |last3=Ahdy |first3=Mohamed |last4=Abdelhafez |first4=Mohamed Sayed |date=2017-06-15 |title=Bone marrow mesenchymal stem cell repair of cyclophosphamide-induced ovarian insufficiency in a mouse model |journal=International Journal of Women's Health |language=English |volume=9 |pages=441–447 |doi=10.2147/IJWH.S134074 |doi-access=free |pmc=5479293 |pmid=28670143}} Both of these studies are proof-of-concept and need to be furthered tested, but they have the possibility improve fertility for individuals who have POI from chemothearpy treatment.
• Critical Limb Ischemia{{Cite journal |last1=Liew |first1=Aaron |last2=O'Brien |first2=Timothy |date=2012-07-30 |title=Therapeutic potential for mesenchymal stem cell transplantation in critical limb ischemia |journal=Stem Cell Research & Therapy |volume=3 |issue=4 |pages=28 |doi=10.1186/scrt119 |issn=1757-6512 |pmc=3580466 |pmid=22846185 |doi-access=free }}

Research is underway to develop various sources for stem cells.{{cite journal | vauthors = Bubela T, Li MD, Hafez M, Bieber M, Atkins H | title = Is belief larger than fact: expectations, optimism and reality for translational stem cell research | journal = BMC Medicine | volume = 10 | pages = 133 | date = November 2012 | pmid = 23131007 | pmc = 3520764 | doi = 10.1186/1741-7015-10-133 | author-link1 = Tania Bubela | doi-access = free }}

Research is attempting to generating organoids using stem cells, which would allow for further understanding of human development, organogenesis, and modeling of human diseases.{{cite journal | vauthors = Ader M, Tanaka EM | title = Modeling human development in 3D culture | journal = Current Opinion in Cell Biology | volume = 31 | pages = 23–28 | date = December 2014 | pmid = 25033469 | doi = 10.1016/j.ceb.2014.06.013 }} Engineered ‘synthetic organizer’ (SO) cells can instruct stem cells to grow into specific tissues and organs. The program used native and synthetic cell adhesion protein molecules (CAMs) that help make cells sticky. The organizer cells self-assembled around mouse ESCs. These cells were engineered to produce morphogens (signaling molecules) that direct cellular development based on their concentration. Delivered morphogens disperse, leaving higher concentrations closer to the source and lower concentrations further away. These gradients signal cells' ultimate roles, such as nerve, skin cell, or connective tissue. The engineered organizer cells were also fitted with a chemical switch that enabled the researchers to turn the delivery of cellular instructions on and off, as well as a ‘suicide switch’ for eliminating the cells when needed. SOs carry spatial and biochemical information, allowing considerable discretion in organoid formation.{{Cite web |last=McClure |first=Paul |date=2024-12-27 |title=Stem cells 'instructed' to form specific tissues and organs |url=https://newatlas.com/medical/stem-cells-organizing-cell-morphogens/ |access-date=2024-12-28 |website=New Atlas |language=en-US}}

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.{{cite journal |last1=Greenhough |first1=Sebastian |last2=Hay |first2=David C. |title=Stem Cell-Based Toxicity Screening: Recent Advances in Hepatocyte Generation |journal=Pharmaceutical Medicine |date=April 2012 |volume=26 |issue=2 |pages=85–89 |doi=10.1007/BF03256896 |s2cid=15893493 }}

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.{{cite journal |last1=García-Prat |first1=Laura |last2=Kaufmann |first2=Kerstin B. |last3=Schneiter |first3=Florin |last4=Voisin |first4=Veronique |last5=Murison |first5=Alex |last6=Chen |first6=Jocelyn |last7=Chan-Seng-Yue |first7=Michelle |last8=Gan |first8=Olga I. |last9=McLeod |first9=Jessica L. |last10=Smith |first10=Sabrina A. |last11=Shoong |first11=Michelle C. |last12=Parris |first12=Darrien |last13=Pan |first13=Kristele |last14=Zeng |first14=Andy G.X. |last15=Krivdova |first15=Gabriela |last16=Gupta |first16=Kinam |last17=Takayanagi |first17=Shin-Ichiro |last18=Wagenblast |first18=Elvin |last19=Wang |first19=Weijia |last20=Lupien |first20=Mathieu |last21=Schroeder |first21=Timm |last22=Xie |first22=Stephanie Z. |last23=Dick |first23=John E. |title=TFEB-mediated endolysosomal activity controls human hematopoietic stem cell fate |journal=Cell Stem Cell |date=August 2021 |volume=28 |issue=10 |pages=1838–1850.e10 |doi=10.1016/j.stem.2021.07.003 |pmid=34343492 |s2cid=236915618 |doi-access=free |hdl=20.500.11850/510219 |hdl-access=free }}

{{div col |colwidth=30em}}

• Cell bank
• Human genome
• Meristem
• Mesenchymal stem cell
• Ovarian stem cell
• Partial cloning
• Plant stem cell
• Stem cell controversy
• Stem cell marker
• Stem cell laws and policy in Iran

{{div col end}}

{{Reflist}}

• {{cite journal |last1=Manzo |first1=Carlo |last2=Torreno-Pina |first2=Juan A. |last3=Massignan |first3=Pietro |last4=Lapeyre |first4=Gerald J. |last5=Lewenstein |first5=Maciej |last6=Garcia Parajo |first6=Maria F. |title=Weak Ergodicity Breaking of Receptor Motion in Living Cells Stemming from Random Diffusivity |journal=Physical Review X |date=25 February 2015 |volume=5 |issue=1 |page=011021 |doi=10.1103/PhysRevX.5.011021 |arxiv=1407.2552 |bibcode=2015PhRvX...5a1021M |s2cid=73582473 }}

{{Commons category|Stem cells}}

{{Library resources box |by=no |onlinebooks=no |others=yes lcheading=Stem cells}}

• {{Cite web |title=National Institutes of Health: Stem Cell Information|url=https://stemcells.nih.gov/ |access-date=2024-12-28 |website=stemcells.nih.gov}}
• {{Cite web |title=Stem cells - Latest research and news {{!}} Nature |url=https://www.nature.com/subjects/stem-cells?wt.ac=search_subjects_stem_cells |access-date=2024-12-28 |website=www.nature.com}}

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Category:Induced stem cells

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