135 Stem cells | Summary

Stem cells

Stem cells are some of the body's master cells which have the ability to grow into any one of the body's more than 200 cell types. Such cells contribute to the body's ability to renew and repair its tissues. There are different types of stem cells. The first, known as embryonic stem cells, are sourced from embryos formed during the blastocyst phase of embryonic development, which is four or five days after fertilisation. They are usually taken from human embryos left-over from in vitro fertilisation. The second, known as adult or mesenchymal stem cells, are found in different types of tissue, including bone marrow, blood, blood vessels, skeletal muscles, skin and the liver. Stem cells can also be sourced from umbilical cord blood.

Embryonic stem cells stained blue as seen under a microscope. Credit: Nissim Benvenisty, Wikimedia.

Definition

Stem cells are cells which have not yet developed a special structure and function but which have the capacity to mature into cells with the characteristic shapes and specified functions of other cells in the body, such as heart, skin, muscle and nerve cells. Such cells are microscopic in size and can be found in all multi-cellular organisms.

Importance

Stem cells were first used for bone marrow transplants (BMTs), a proceedure that was introduced as a treatment for cancer and genetic blood disorders in the 1960s. Every year stem cells are presently used in about 60,000 BMT operations worldwide. This procedure is increasingly using stem cells sourced from peripheral and umbilical cord blood rather than from the bone marrow. Stem cells are not only vital for BMTs but are being explored for their power to replace or even heal damaged tissues and cells in the body. They have proven particularly valuable for bone grafts. The value of stem cells for bone grafts is expected to be worth US$600 million by 2015. Stem cells have also been approved in Canada and South Korea for the treatment of acute myocardial infarction (heart attack), anal fistula and for cartilage injury and oesteoarthritis. Such cells are additionally used as coatings for synthetic organs produced in the laboratory. A coating with stem cells provides a means to prevent implant rejection. Since 2008 eight patients have successfully received transplants of artificially created windpipes coated with stem cells. The tracheas were made by growing the patient's stem cells on a laboratory-made scaffold. Such an approach is expected to be used in the future creation of other organs such as a replacement oesophagus, heart valve, diaphragm, kidney, or lung. In 2011 the stem cell market was valued at about US$2 billion. Most of this consisted of revenue from BMTs. Syed and Evans predict that the stem cell therapeutics market will be generating US$8.8 billion by 2016. This includes stem cell therapies, stem cell banking and stem cell ancillary products (Nature Reviews Drug Discovery 12, March 2013, 185-6).

Discovery

The concept of a stem cell was first proposed by researchers working on embryonic development in the nineteenth century. They saw such cells as the starting point for biological processes. From the early twentieth century stem cells began to be seen as the source of different kinds of blood cells. Yet, blood stem cells could not be visualised in this period, so many doubted their existence. Knowledge advanced during the Second World War through the identification of a recovery factor in bone marrow which was thought to help regenerate the blood system. This was discovered by the haematologists William Bloom and Leon Jacobson as part of their research into the effects of radiation on the blood system which they carried out as part of the Manhattan Project to build the first atom bomb. It was this observation that laid the basis for the development of the BMT procedure for the treatment of blood cancer (leukaemia). BMTs opened the way to the identification and characterisation of stem cells within the bone marrow in the 1960s. In 1978 stem cells were also discovered to be present in human cord blood and three years later scientists cultivated the first embryonic stem cells from mice blastocysts.

Application

Stem cells are currently used as research tools to understand the signals and mechanism of cell differentiation. This is useful not only for understanding the cause of disease, but also for the development of new therapies. The ability to generate large numbers of specialised cells from stem cells has also led to their use for testing the safety of new medicines, thereby reducing the need for animal testing. Cancer stem cells, for example, are used to screen potential anti-tumour drugs. Stem cells are also being explored for their properties to replace cells lost in degenerative diseases and for repairing cells in damaged tissues, a field known as regenerative medicine. Today more than 1,100 clinical studies, the overwhelming majority of them using adult stem cells, are being conducted to investigate the power of stem cell therapy. This includes treatments for retinal diseases, neurological conditions such as Parkinson's and Alzheimer's disease, heart disease such as post-ischaemic stroke, and type 1 diabetes.

Stem cells: timeline of key events

Date Event People Places
1882Concept of the stem cell is put forward for the first timeHaeckel, Dantchakoff, Pappenheim, Ehrlich, MaximowUniversity of Jena, Charite Hospital, Koch Institute, Petrograd University
1890 - 1930Debate begins over whether one stem cell provides supply of new cells for the entire blood system or if there is a different stem cell for each constituent cell lineage of the blood system Bloom, MaximowUniversity of Chicago, Petrograd University
1908The term 'stem cell' is coinedMaximovPetrograd University
1942 - 1945Animal experiments launched to investigate the biological effects of acute and chronic exposure to different forms and intensities of ionising radiationJacobson, Zirkle, Bloom University of Chicago
1942 - 1945One part of the blood system, the spleen, offers some form of protection against radiation damageJacobsonUniversity of Chicago
1945Research continues into the damaging effects of ionising radiation upon the blood system - the tissue most sensitive to radiation effectsJacobson, LorenzUniversity of Chicago, National Cancer Institute, MRC RRU
1945Atomic Energy Research Establishment (AERE) foundedAERE
1947Medical Research Council Radiobiological Unit (MRC RU) establishedLoutit, Ford, BarnesMRC RRU
1949First experiments transplanting spleen from non-radiated mice into radiated miceJacobson, Marks, GastonUniversity of Chicago
1951 - 1956Debate about whether the 'recovery factor' present in the spleen and marrow is a hormone or a cellJacobson, Lorenz, Loutit, CongdonUniversity of Chicago, National Cancer Institute, MRC RRU
1951Transfer of marrow into lethally irradiated mice shows that marrow, like spleen, is regenerativeLorenz, Congdon, UphoffNational Cancer Institute
1956Experiments with mice confirm radiation recovery factor is a distinctive cellLoutit, Ford, Barnes, HamertonMRC RRU
1956Mice with leukaemia treated successfully with lethal radiation followed by bone marrow transplantLoutit, Barnes MRC RRU
1956First report of bone marrow transplants performed in human (cancer) patientsThomas, Ferrebee, Lochte, LuBassett Medical Center
January 1957First report of bone marrow transplants performed in human (cancer) patientsThomas, Lochte, Lu, FerrebeeBassett Medical Center
1959Infused allogeneic bone marrow in accidentally irradiated workers shown to give rise to mature blood cellsMatheHopital Saint Louis
1959Bone marrow transplants in two sets of identical twin girls fails to eradicate leukaemiaThomas, Ferrebee, Sahler Bassett Medical Center
1959Experiments in mice prove the existence of resident blood stem cells in marrowThomas Bassett Medical Center
1960Bone marrow transplants being undermined by immunological reactions (especially graft-versus-host-disease (GvHD))ThomasBassett Medical Center
1961Existence and properties of transplantable stem cells in mouse bone marrow established and the first methodology for counting them is devisedJames, Till, McCulloch, Siminovitch, Becker, Wu, FowleOntario Cancer Institute
1962 - 1965Bone marrow transplants in humans abandoned by Thomas group due to graft-versus-host-diseaseThomas Bassett Medical Center
1962Nuclei from adult frog cells reprogrammed to full embryonic potential after transfer into frog eggsGurdon, AltmanCambridge University
1965First successful allogeneic marrow transplant reported in patient with leukaemiaMatheInstitute of Cancer and Immunotherapeutics
1965Distinctive and powerfully regenerative cell resident in bone marrow, known from now on as stem cells
1965Paterson Institute for Cancer Research established as a major centre for blood stem cell researchLajtha, Schofield, Lord, Dexter, PatersonPaterson Institute for Cancer Research, Christie Cancer Hosptial
1965Development of a technique for the in vitro cultivation of bone marrow cellsMetcalf, Bradley, Sachs, PluznikQueen Elizabeth II Hospital, Weizmann Institute
1968First successful bone marrow transplant from a siblingGoodMemorial Sloan Kettering Cancer Center
1969Concept of the tumour stem cell is bornFialkow, Pierce, Hamburger, Salmon, Nowell, Damjanov, SolterUniversity of Washington in Seattle
1969First application of cell separation technology to dissect marrow stem cell hierarchy
1970Blood stem cell proves highly elusive as it is difficult to isolate and visualise
1971Cetus Corporation, the first biotechnology was foundedCape, Farley, GlaserCetus
1973First successful bone marrow transplant from unrelated donorGood, O'ReillyMemorial Sloan Kettering Cancer Center
1974Mouse embryonic cancer cells shown to participate in the development of normal tissues as well as teratomas
1975A liquid media is developed for growing bone marrow cells, including the blood stem cellDexterPaterson Institute for Cancer Research
1977Bone marrow transplants is clinically provenDonnallFred Hutchinson, Seattle, New York
1978Transplantable stem cells discovered in human cord bloodEvansCambridge University
1980 - 1990Existence of the blood stem cell is debatedDexter, Lord, Weissmann, Morrison
1981First embryonic stem cells identified in mice EvansCambridge University
July 9, 1981Mouse embryonic stem cells first isolated and cultured in the laboratoryEvans, Kaufman, MartinCambridge University, UCSF
1982Leukaemia emerges as a key means for understanding of the role of the stem cell in cancerDick, LapidotOntario Cancer Institute
1982Amcell, a private biotechnology company, is formed to commercialise blood stem cells
1982Marrow stem cells shown to be distinct from progenitor cells
1982AIS, the first biotechnology company to commercialise blood stem cell-based innovation is establishedAIS
1984A molecular marker, CD34, is identified as specific for a subset of marrow cells containing the blood stem cellCivinJohns Hopkins
1984 - 1996Ongoing litigation between CellPro and Baxter Healthcare Corporation over the use of the CD34 marker for cell separation technologyCellPro, Baxter Healthcare
1984CD34 marker used as the basis for cell separation technology
1984Blood stem cells extensively purified for first time
1986National Marrow Donor Programme established in US
1987First clinical trials of foetal neural cell grafting in patients with Parkinson’s diseaseBjorklund, Lindvall Lund University
1987CellPro, the second biotechnology company is formed to commercialise blood stem cellsCellPro
1988First reported clinical use of umbilical cord bloodBroxmeyerIndiana University
1988SyStemix, the third biotechnology company is established to commercialise blood stem cellsSystemix
July 1, 1988The first hematopoietic stem cells were isolated in miceSpangrude, Heimfeld, WeissmanStanford University
1989Aastrom, a private biotechnology company is formed to commercialise blood stem cells
1990Some companies attempt, but do not succeed, to develop blood stem cell-based businessBaxter Healthcare
1990Discovery of the nesting gene, the most commonly used marker for neural stem cellsLendahlKarolinska Institutet
1990Mouse marrow regenerating stem cells are completely separated from in vivo colony-forming cells for first time
1992First public bank set up for umbilical cord blood bank in New YorkRubinsteinNew York Blood Center
1992Neural stem cells identified in the adult human brain
1992Progenitor, a private biotechnology company is formed to commercialise blood stem cells
1992Stem cells used as vectors to deliver the genes needed to correct the genetic disorder SCIDBordignonVita-Salute San Raffaele University
1993Embryonic stem cells are proven to be pluripotent; having the ability to differentiate into different cell types
1994First separation of cancer stem cells from the majority of cells in a cancer
1994Patients with damaged corneas successfully treated with corneal stem cells
1994Cancer stem cell theory advancedDickOntario Cancer Institute
1994Experiments in adult rats indicate olifactory ensheathing cells could regenerate injured dorsal root axons in spinal cordRamon-Cueto, Nieto-SampedroInstituto Cajal
1995First derivation of primate embryonic stem cell lines
1996First reports that blood stem cell might be able to give rise to cells other than those of the blood systemBlau, Lagasse, Lemischka, Morrison, Thiese, Krause, Gussoni, Bjornson
1996 - 2002Experiments with rats conducted by different research teams around the world confirm olifactory ensheathing cells help repair spinal cordSmale, Li, Imaizumi, Guntinas-Lichius, Nash, RuitenbergQueen's University, University College London, Yale University, University of Cologne, University of the Health Sciences, Netherlands Institute for Brain Research
January 1996First cloning of a mammalWilmutRoslin Institute
July 5, 1996Dolly the sheep, the first cloned mammal, was bornWilmutRoslin Institute
1998Human brain demonstrated to contain cells with stem-like propertiesEriksson, GageSahlgrenska University Hospital, Salk Institute
October 1998First human embryonic stem cell line derived Thomson, Itskovitz-Eldor, Shapiro, Waknitz, Swiergiel, Marshall, JonesUniversity of Wisconsin-Madison
1999Adult neural stem cells identified as capable of forming new neural stem cellsFrisenKarolinska Institutet
2000Adult stem cells recognised as having potential to generate variety of cells for other organsFrisenKarolinska Institutet
2000Retinal stem cells identified in mice
2001The Stem Cell Network is formed
2001Dermal stem cells identified in adult skin tissue
2001US places restricitions on embryonic stem cell research
October 2001Human embryo cloned to make stem cellsAdvanced Cell Technology
2002International Society for Stem Cell Research (ISCF) established
2002First complete purification of multipotent marrow stem cells from mice
March 2002Canadian Institutes of Health Research unveils guidelines on stem cell research
2003Cancer stem cells isolated in human brain tumours Singh
January 2003Rare human breast cancer stem cells identified Al-Hajj
February 14, 2003Dolly the sheep, the first cloned mammal diedWilmutRoslin Institute
April 22, 2003Stem cells sourced from baby teeth
2004First derivation of dopaminergic cells from human embryonic stem cells
2004International Consortium of Stem Cell Networks (ICSCN) initiated
2005Lasker Prize awarded to James Till and Ernest McCullochTill, McCulloch
2005First evidence for human bone cancer stem cells
2005UK Pattison Report emphasizes stem cells as likely potential therapies for the future
June 2005Canadian researchers created the country's first embryonic stem cell linesNagySamuel Lunenfeld Research Institute
August 2005Adult skin cells reprogrammed to be like embryonic stem cellsCowan, Eggen, Melton, AtienzaHarvard
2006Normal mammary stem cells demonstrated in adult mice
June 2006Four genes identified as important for reprogramming cellsYamanakaKyoto University
August 2006Human embryo cloned to make stem cellsAdvanced Cell Technology
November 2006Stem cell injections reported to ease symptoms in muscular dystrophy in dogs
2007Nobel Prize for Physiology for Medicine awarded for their discoveries enabling germline gene modification in mice by the use of embryonic stem cellsCapecchi, Evans, SmithiesUniversity of North Carolina, University of Utah
2007First physical identification and localization of mammalian intestinal stem cells
2007First evidence for human colon cancer stem cells
January 2007Scientists isolate new stem cell source in amniotic fluid
April 2007Canadian researchers convert normal human blood cells into leukaemia stem cells to investigate leukaemiaDick
June 2007Skin cells reprogrammed to become like embryonic stem cellsYamanakaKyoto University
September 2007British regulators approve human-animal embryo research
November 2007Pluripotent stem cells generated from mature fibroblastsYamanaka, TakahashKyoto University
November 2007Human cells reprogrammed to make pluripotent stem cellsYamanaka, Takahashi
2008Gairdner Prize is awarded to Sam Weiss for the discovery of neural stem cellsWeiss
August 2008Scientists create stem cells for 10 disordersHarvard Stem Cell Institute
November 2008First woman given trachea transplant made from the patient's own stem cellsMacchiariniKarolinska Institute
2009Lasker Prize awarded to John Gurdon and Shinya Yamanaka for discoveries in nuclear reprogramming. Yamanaka is also awarded the Gairdner PrizeGurdon, YamanakaCambridge University, Kyoto University
2009Induced pluripotent stem cells created with minimal residual genomic alteration
January 2009Animal tests suggest stem cells may reverse paralysis
March 2009Embryonic like stem cells generated from adult human tissueNagy, WhiteMount Sinai Hospital, Toronto
March 2009U.S. President Barack Obama reverses restrictions on stem cell research imposed by former President George W. Bush
June 2009Stem cell transplants found to improve survival for leukaemia patients
July 2009British scientists create sperm-like cellsHeppellNewcastle University, North East England Stem Cell Institute
2010Adult cells reprogrammed into neurons, cardiac muscle and blood cells
2010Induced pluripotent cells created by transfection of mRNA
2010First clinical trial of human embryonic-derived stem cells for treatment of spinal cord injury
2011Isolation of multipotent human blood stem cells capable of forming all cells in the blood system
March 10, 2011Patient suffering from acute myeloid leukaemia is cured of HIV-1 after receiving bone marrow stem cells transplanted from donor with mutated CCR5 gene. This awakens interest in developing HIV treatment that renders a patient's cells resistant to HIV-1Allers, Hutter, Hofmann, Loddenkemper, RiegerCharite-University Medicine Berlin
April 2011US funding of embryonic stem cell research permitted
July 2011First two patients treated in FDA approved clinical trials for a therapy derived from embryonic stem cells for dry age-related macular degeneration and Stargardt’s macular dystrophy, leading causes of blindness in the elderly and children, respectivelySchwartzUniversity of California Los Angeles
2012John Gurdon and Shinya Yamanaka win the Nobel Prize in Physiology or Medicine for the discovery that mature cells can be reprogrammed to become pluripotent stem cellsGurdon, YamanakaCambridge University, Kyoto University
March 2014Breakthrough for manufacturing stem cellsUniversity of Nottingham
June 5, 2014Cloning successfully deployed to make stem cells from adult human cellsChung, Eum, Lee, Shim, Sepilian, Hong, Lee, Treff, Choi, Kimbrel, Dittman, LonzaUniversity of Pennsylvania
October 2014Stem cells taken from nose demonstrated to repair spinal cord injury Raisman, TabakowUniversity College London, Wroclaw Medical University
September 29, 2015First UK patient recieved experimental stem cell treatment for age-related macular degeneration University College London, National Institute for Health Research
October 20, 2015UK NHS sets up stem cell factory in Liverpool to supply experimental treatment for people with diabetes
March 8, 2016UK scientists link repeated miscarriages to a reduction of stem cells in lining of the wombBrosens, QuenbyUniversity of Warwick
March 9, 2016A dozen infants born with cataracts reported to regain sight after receiving new stem cell therapy to regenerate healthy lenses in their eyes. ZhangUniversity of California San Diego
March 17, 2016Scientists announce the first generation of an embryonic stem cell that carries a single copy of the human genome rather than the usual twoEgli, Benvinsty, Sagi, Chia, Golan-Lev, Peretz, Weissbein, Sui, Sauer, YanukkaColumbia University
June 2, 2016Stem cells reported to provide substantial recovery in patients disabled by strokeStanford University
July 24, 2016Small-scale case study showed power of stem cells to repair damaged scar tissue caused by heart attacksAnastasiadis, Antonitsis, Westaby, Reginald, Sultan, Doumas, Efthimiadis, EvansAHEPA University Hospital, Oxford University, Cardiff University

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