Molecular mechanisms of stem-cell identity and fate Fiona M. Watt and Kevin Eggan Stem cells are characterized by extensive self-renewal. Many have multi- significance in cell and developmental biology and has important biomedical lineage differentiation potential. These properties enable them to generate applications. researchers have been particularly interested in stem functional tissues during development and to regenerate these tissues follow- cells as recent data have indicated that several tumour types, including ing injury or degenerative processes. Stem-cell fate is regulated by the com- germ-cell, breast, brain, haematopoietic and prostate tumours, are probably bination of extrinsic and intrinsic signals, many of which are poorly under- maintained by cancer stem cells. It is now the goal of several cancer research stood. An understanding of the molecular mechanisms that govern stem-cell laboratories to identify definitive markers of tumour stem cells and to find fate and the identification of specific stem-cell markers is of fundamental therapeutic targets that will specifically eradicate these cells.

Fiona M. Watt is at the Wellcome Trust Centre for A glossary for stem-cell biology* Research, , Tennis Court Road, BMP4 Cancer cell of origin Cambridge CB2 1QR, UK and Cancer Research UK, Cambridge Precancerous cell that gives rise to a cancer stem cell. May be a Research Institute, Robinson Way, Cambridge, CB2 ORE, UK. mutated stem cell, or a committed progenitor that has acquired Fiona Watt's homepages: http://www.iscb.cam.ac.uk/fwatt.html | self-renewal capacity through . EGF, http://science.cancerresearchuk.org/research/loc/cambridge/ FGF, ccri/wattf Cancer-initiating cell Notch Kevin Eggan is at the Department of Molecular and Cell Biology, General term that encompasses both cancer cell of origin and Harvard University, 7 Divinity Ave, Room 437, Cambridge, cancer stem cell. Ectoderm Neural stem cells CCND1, LHX2, PAX6, SOX2 Brain Skin and hair Massachusetts, 02138, USA. Cancer stem cell EctoV, Kevin Eggan's homepage: http://www.mcb.harvard.edu/Eggan GFAP, Neural Bulge Self-renewing cell responsible for sustaining a cancer and for LIF Poster design by Vicky Askew. Edited by Ekat Kritikou and BMP4 N-200 stem cells producing differentiated progeny that form the bulk of the Wnt ? LIFR gp130 stem cells Nicola McCarthy. © 2006 Nature Publishing Group. cancer. Cancer stem cells identified in leukaemias and certain BMI1, CD133, HSAlo, nestin, α6-, β1-integrin, www.nature.com/nrm/poster/stemcell solid tumours are critical therapeutic targets. Notch pathway, PNAlo, CD34, CD200, Dkk3 and Wif1 www.nature.com/nrc/poster/stemcell Commitment SHH pathway, SSEA1, expression, K15, SHH pathway, Engaging in a programme leading to differentiation. For a stem Lungs Wnt pathway Wnt pathway Frizzled JAK JAK SP-C cell, this means exit from self-renewal. GSK3 Cancer stem cells Embryonic stem cell GAB1 Lung stem cells Mammary gland Although the existence of cancer stem cells is Pluripotent stem-cell lines derived from early embryos before SHP2 CCSP, Sca1+, SSEA1 formation of the tissue germ layers. β-catenin, SMADs now generally accepted for both blood and solid MEK Mammary gland tissue tumours, the definitive identification of Founder/ancestor/precursor cell stem cells General terms for cell without self-renewal ability that markers for cancer stem cells is still in its ERK + hi contributes to tissue formation. In some cases they generate BMI1, CD24 , CD29 , infancy. Several genes and signalling pathways SOX2–OCT4 NANOG STAT3 CD49fhi, Lin– tissue stem cells. that are known to regulate tissue and embryonic Label-retaining cell Definitive endoderm CER1, FOXA2, stem cells, such as BMI1 and the SHH, Notch and Candidate for adult tissue stem cell because of slow division Wnt/β-catenin pathways, are deregulated in rate and/or immortal strand retention. Interpret with caution. GATA4, SOX17 Liver Oval cells A-fetoprotein, A6, CD34+, Sca1+, cancer. Surface markers can be used in Lineage priming Primitive Trophectoderm albumin, Gtar Thy-1 conjunction with assays such as self renewal Promiscuous expression in stem cells of genes associated with endoderm differentiation programmes. in vitro or transplantation in vivo to identify Niche potential tumour stem cells, although in ES cell Brain tumour stem cells Cellular microenvironment providing support and stimuli isolation they are not definitive. The six yellow + necessary to sustain self-renewal. BMI1, CD133 boxes show some of these attributes and the Plasticity Squamous cell carcinoma tumours with which they have been associated. Unproven notion that tissue stem cells may broaden potency in stem cells They are not intended to show definitive cancer response to physiological demands or insults. Deregulated integrin stem-cell markers. Potency ZygoteBlastocyst Late blastocyst Gastrula expression, Notch, The range of commitment options available to a cell. Pancreas Pancreas-derived SHH, Wnt activation Totipotent Insulin, Epiblast multipotent Abcam Sufficient to form entire organism. Totipotency is seen in zygote PAX4, precursors Breast cancer stem cells and plant meristem cells; not demonstrated for any vertebrate –/lo + PDX1 CK19 BMI1, CD24 , CD44 , Stem-cell antibodies you can rely on! stem cell. Wnt pathway active, Pluripotent SHH pathway active? Abcam supplies primary and secondary antibodies Able to form all the body’s cell lineages, including germ cells, and reagents to researchers worldwide. We ship and some or even all extraembryonic cell types. Example: Colon cancer stem cells direct to over 60 countries and have offices in the embryonic stem cells. CD133+ UK, US and Japan, as well as offering customer Multipotent service in English, French, German and Japanese. Can form multiple lineages that constitute an entire tissue or EC cells Trophectoderm Prostate cancer stem cells We have over 20,000 antibodies in our catalogue. tissues. Example: haematopoietic stem cells. CDX2, EOMES AP Trophectoderm Mesoderm Side population CD44+ Oligopotent ICM CD30 Our stem-cell markers range includes over 1,500 AP, CD9, CD30, Intestine Crypt stem cells Able to form two or more lineages within a tissue. Example: a SCF Primitive IFABP antibodies to: neural stem cell that can create a subset of neurons in the brain. CD133, GCTM2, endoderm Bmp pathway, Acute myeloid leukaemia Notch pathway, • Embryonic stem cells Unipotent NANOG, OCT4, GATA4, GATA6 stem cells Wnt pathway BMI1, CD34+, CD38– Forms a single lineage. Example: spermatogonial stem cells. SCF, SOX2, SSEA1, • Embryonic germ cells SSEA3/4, TRA2-54 Progenitor cell ? • Endothelial progenitors Generic term for any dividing cell with the capacity to • Haematopoietic progenitors differentiate. Includes putative stem cells in which self-renewal Teratoma has not yet been demonstrated. • Mesenchymal stem cells Reprogramming Female • Neural stem cells Increase in potency. Occurs naturally in regenerative organisms germ cells • Neural crest stem cells (dedifferentiation). Induced experimentally in mammalian cells Haematopoietic • Ectoderm, mesoderm and endoderm lineages by nuclear transfer, cell fusion, genetic manipulation or in vitro Abbreviations Spermatogonial stem cells culture. • Wnt, TGFβ, Hedgehog and Notch signalling AP, alkaline phosphatase; bFGF, basic LHX2, LIM-homeobox protein-2; Male stem cells bFGF, BMI1, CD34+, CD38–, + + pathways Self-renewal fibroblast growth factor; BMP, bone LIF, leukaemia inhibitory factor; LIFR, LIF Primordial germ cells germ cells BMI1, Bmp pathway, ERM, CD150 , KIT , RUNX1, Cycles of division that repeatedly generate at least one AP, GCTM2, germ-cell nuclear GDNF pathway, Sca1+, TAL1, We are rapidly developing and expanding our daughter equivalent to the mother cell with latent capacity for morphogenetic protein; BMPR, BMP receptor; lo, low; M-cadherin, muscle NOS2, PLZF factor, OCT3/4, SSEA3/4, VASA TIE2, VEGF range, looking for new targets and improving our differentiation. This is the defining property of stem cells. receptor; BRA, brachyury; CCND1, cyclin cadherin; MEK, mitogen-activated protein Stem cell D1; CD, cluster designation; CER1, kinase and extracellular signal-regulated Haematopoiesis existing antibodies. To help us with this, we actively A cell that can continuously produce unaltered daughters and cerberus-1; CK19, cytokeratin-19; EC cell, kinase; MESP, mesoderm posterior; NOS2, attend, support and help organize conferences on also has the ability to produce daughter cells that have embryonic carcinoma cell; EGF, epidermal nitric oxide synthase-2; OCT, octamer- stem-cell research. Find out more on our stem cells different, more restricted properties. growth factor; EOMES, eomesodermin; binding transcription factor; PDX1, resource page: Stem-cell homeostasis Satellite stem cells Mesenchymal ERK, extracellular signal-regulated pancreatic and duodenal homeobox gene-1; + www.abcam.com/stemcells Persistence of tissue stem-cell pool throughout life. Requires CD34 , c-MET, stem cells Heart Cardiac progenitors + balancing symmetric self-renewal with differentiative divisions kinase; ERM, ETS-related molecule; PLZF, promyelocytic leukaemia zinc-finger BRA, GATA4, MESP, M-cadherin, BMPR, CD34 , CD44, Quality and honesty are our top priorities ISL1 – + at the population level, or sustained asymmetric self-renewal. ES cell, embryonic stem cell; protein; Sca1, stem-cell antigen-1; NKX2.5 PAX3+, PAX7+ Lin , Sca1 , SCF FGF, fibroblast growth factor; FLK1, fetal SCF, stem-cell factor; SHH, sonic Our Abpromise guarantees full technical support Stemness Muscle Mesenchyme from our experienced team. If an antibody doesn’t Unproven notion that different stem cells are regulated by liver kinase-1; FLT1, fms-related tyrosine hedgehog; SHP2, Src-homology-2 domain- common genes and mechanisms. kinase-1; GAB1, GRB2-associated binder-1; containing protein tyrosine phosphatase-2; work as it says on our datasheet we will give you a Tissue stem cell GCTM2, podocalyxin-like precursor SOX2, SRY-related high mobility group full refund or replacement if you tell us within 90 MYF5, MYF6, Derived from, or resident in, a fetal or adult tissue, with potency isoform-2; GDNF, glial cell line-derived (HMG)-box protein-2; SSEA, stage-specific days. We publish everything we know about every MYOD, PAX3 Vascular cells limited to cells of that tissue. These cells sustain turnover and neurotrophic factor; GFAP, glial fibrillary embryonic antigen; STAT, signal transducer product on our datasheets and our catalogue is repair throughout life in some tissues. acidic protein; GSK3, glucogen synthase and activator of transcription; TAL1, T-cell Mesoderm web-based. This allows daily updates and far more Transit-amplifying cell kinase-3; hi, high; ICM, inner cell mass; acute lymphocytic leukaemia; VE-cadherin, BMP4, BRA, MESP information than in any printed catalogue, including Proliferative stem-cell progeny fated for differentiation. Initially customer reviews, technical enquiries and links to may not be committed and may retain self-renewal. IFABP, intestinal fatty-acid-binding protein; vascular endothelial cadherin; VEGF, CD31, FLK1, FLT1, TIE1, TIE2 publication references. Visit our website today and *We are grateful to Austin Smith for his permission to reproduce the ISL1, islet-1; JAK, Janus kinase; vascular endothelial growth factor. stem-cell glossary, which was produced in association with the European Haemangioblast VE-cadherin, VEGF see for yourself: Consortium for Stem Cell Research. For the full glossary, see: www.abcam.com/stemcells Smith, A. A glossary for stem-cell biology. Nature 441, 1060 (2006).

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