Molecular mechanismsof stem-cell identity and fate
Fiona M. Watt and Kevin Eggan
Stem cells are characterized by extensive self-renewal. Many have multilineage differentiation potential. These properties enable them to generatefunctional tissues during development and to regenerate these tissues following injury or degenerative processes. Stem-cell fate is regulated by the combination of extrinsic and intrinsic signals, many of which are poorly understood. An understanding of the molecular mechanisms that govern stem-cellfate and the identification of specific stem-cell markers is of fundamental

significance in cell and developmental biology and has important biomedical
applications. Cancer researchers have been particularly interested in stem
cells as recent data have indicated that several tumour types, including
germ-cell, breast, brain, haematopoietic and prostate tumours, are probably
maintained by cancer stem cells. It is now the goal of several cancer researchlaboratories to identify definitive markers of tumour stem cells and to findtherapeutic targets that will specifically eradicate these cells.

A glossary for stem-cell biology*BMP4Cancer cell of origin
Precancerous cell that gives rise to a cancer stem cell. May be amutated stem cell, or a committed progenitor that has acquired
self-renewal capacity through mutation.

EGF,
FGF,
Notch

Cancer-initiating cell
General term that encompasses both cancer cell of origin andcancer stem cell.

Neural stem cells

Ectoderm
LIF

Self-renewing cell responsible for sustaining a cancer and for
producing differentiated progeny that form the bulk of thecancer. Cancer stem cells identified in leukaemias and certain
solid tumours are critical therapeutic targets.

BMP4

Wnt?

LIFR

gp130

JAK

JAK

CCND1, LHX2, PAX6, SOX2

EctoV,GFAP,
N-200

Cancer stem cellCommitment
Frizzled

Pluripotent stem-cell lines derived from early embryos before
formation of the tissue germ layers.

β-catenin, SMADs

SHP2

CCSP, Sca1+, SSEA1

Skin and hair
Bulge
stem cells

BMI1, CD133, HSAlo, nestin,
Notch pathway, PNAlo,
SHH pathway, SSEA1,Wnt pathway

α6-integrin, β1-integrin,
CD34, CD200, Dkk3 and Wif1
expression, K15, SHH pathway,
Wnt pathway

Mammary gland
Mammary glandstem cells

MEKFounder/ancestor/precursor cell
General terms for cell without self-renewal ability that
contributes to tissue formation. In some cases they generate
tissue stem cells.

BrainNeuralstem cells

Cancer stem cells
Lung stem cells

GSK3

Embryonic stem cell

Lungs

SP-C

GAB1

Engaging in a programme leading to differentiation. For a stem
cell, this means exit from self-renewal.

ERK
SOX2–OCT4

NANOG

BMI1, CD24+, CD29hi,
CD49fhi, Lin–STAT3

Definitive endoderm

Label-retaining cell

CER1, FOXA2,GATA4, SOX17

Candidate for adult tissue stem cell because of slow division
rate and/or immortal strand retention. Interpret with caution.

Lineage priming
Niche

Liver
A-fetoprotein,albumin, Gtar

Primitive
endoderm

Trophectoderm

Promiscuous expression in stem cells of genes associated withdifferentiation programmes.

Oval cells
A6, CD34+, Sca1+,
Thy-1

ES cellBrain tumour stem cells
BMI1, CD133+

Cellular microenvironment providing support and stimuli
necessary to sustain self-renewal.

Plasticity

Squamous cell carcinoma
stem cells
Deregulated integrin
expression, Notch,SHH, Wnt activation

Unproven notion that tissue stem cells may broaden potency inresponse to physiological demands or insults.

Potency

Fiona M. Watt is at the Wellcome Trust Centre for Stem Cell
Research, University of Cambridge, Tennis Court Road,Cambridge CB2 1QR, UK and Cancer Research UK, Cambridge
Research Institute, Robinson Way, Cambridge, CB2 ORE, UK.
Fiona Watt's homepages: http://www.iscb.cam.ac.uk/fwatt.html |http://science.cancerresearchuk.org/research/loc/cambridge/
ccri/wattf
Kevin Eggan is at the Department of Molecular and Cell Biology,Harvard University, 7 Divinity Ave, Room 437, Cambridge,
Massachusetts, 02138, USA.
Kevin Eggan's homepage: http://www.mcb.harvard.edu/Eggan
Poster design by Vicky Askew. Edited by Ekat Kritikou andNicola McCarthy. © 2006 Nature Publishing Group.
www.nature.com/nrm/poster/stemcell
www.nature.com/nrc/poster/stemcell

ZygoteBlastocyst

Late blastocyst

Gastrula

The range of commitment options available to a cell.

Pancreas

Totipotent

Insulin,
PAX4,
PDX1

Epiblast

Sufficient to form entire organism. Totipotency is seen in zygote
and plant meristem cells; not demonstrated for any vertebratestem cell.

Pancreas-derived
multipotent
precursors

Pluripotent

Breast cancer stem cells
BMI1, CD24–/lo, CD44+,
Wnt pathway active,
SHH pathway active?

Able to form all the body’s cell lineages, including germ cells,
and some or even all extraembryonic cell types. Example:
embryonic stem cells.

Colon cancer stem cells
CD133+

CK19

Multipotent
Can form multiple lineages that constitute an entire tissue ortissues. Example: haematopoietic stem cells.

Trophectoderm
CDX2, EOMESICM
AP, CD9, CD30,
CD133, GCTM2,NANOG, OCT4,
SCF, SOX2, SSEA1,SSEA3/4, TRA2-54

Oligopotent
Able to form two or more lineages within a tissue. Example: aneural stem cell that can create a subset of neurons in the brain.

Unipotent
Forms a single lineage. Example: spermatogonial stem cells.

Progenitor cell

EC cells
APCD30SCF

Trophectoderm

Prostate cancer stem cells
Side population CD44+

Mesoderm

Intestine

Primitive
endoderm
GATA4, GATA6IFABPCycles of division that repeatedly generate at least one
daughter equivalent to the mother cell with latent capacity fordifferentiation. This is the defining property of stem cells.

Stem cell
A cell that can continuously produce unaltered daughters andalso has the ability to produce daughter cells that havedifferent, more restricted properties.

Stem-cell homeostasis
Persistence of tissue stem-cell pool throughout life. Requires
balancing symmetric self-renewal with differentiative divisions
at the population level, or sustained asymmetric self-renewal.

Stemness
Unproven notion that different stem cells are regulated bycommon genes and mechanisms.

Tissue stem cellDerived from, or resident in, a fetal or adult tissue, with potency
limited to cells of that tissue. These cells sustain turnover andrepair throughout life in some tissues.

Transit-amplifying cell
Proliferative stem-cell progeny fated for differentiation. Initiallymay not be committed and may retain self-renewal.
*We are grateful to Austin Smith for his permission to reproduce thestem-cell glossary, which was produced in association with the European
Consortium for Stem Cell Research. For the full glossary, see:Smith, A. A glossary for stem-cell biology. Nature 441, 1060 (2006).

Acute myeloid leukaemia
stem cells
BMI1, CD34+, CD38–

Teratoma

Reprogramming

Self-renewal

Bmp pathway,
Notch pathway,Wnt pathway?

Generic term for any dividing cell with the capacity todifferentiate. Includes putative stem cells in which self-renewal
has not yet been demonstrated.
Increase in potency. Occurs naturally in regenerative organisms(dedifferentiation). Induced experimentally in mammalian cellsby nuclear transfer, cell fusion, genetic manipulation or in vitroculture.

Crypt stem cells

Femalegerm cells

AbbreviationsAP, alkaline phosphatase; bFGF, basic
fibroblast growth factor; BMP, bonemorphogenetic protein; BMPR, BMP
receptor; BRA, brachyury; CCND1, cyclin
D1; CD, cluster designation; CER1,cerberus-1; CK19, cytokeratin-19; EC cell,embryonic carcinoma cell; EGF, epidermal
growth factor; EOMES, eomesodermin;
ERK, extracellular signal-regulated
kinase; ERM, ETS-related molecule;
ES cell, embryonic stem cell;
FGF, fibroblast growth factor; FLK1, fetalliver kinase-1; FLT1, fms-related tyrosine
kinase-1; GAB1, GRB2-associated binder-1;
GCTM2, podocalyxin-like precursor
isoform-2; GDNF, glial cell line-derived
neurotrophic factor; GFAP, glial fibrillary
acidic protein; GSK3, glucogen synthasekinase-3; hi, high; ICM, inner cell mass;
IFABP, intestinal fatty-acid-binding protein;
ISL1, islet-1; JAK, Janus kinase;

LHX2, LIM-homeobox protein-2;
LIF, leukaemia inhibitory factor; LIFR, LIF
receptor; lo, low; M-cadherin, muscle
cadherin; MEK, mitogen-activated protein
kinase and extracellular signal-regulatedkinase; MESP, mesoderm posterior; NOS2,nitric oxide synthase-2; OCT, octamerbinding transcription factor; PDX1,pancreatic and duodenal homeobox gene-1;
PLZF, promyelocytic leukaemia zinc-finger
protein; Sca1, stem-cell antigen-1;
SCF, stem-cell factor; SHH, sonichedgehog; SHP2, Src-homology-2 domaincontaining protein tyrosine phosphatase-2;
SOX2, SRY-related high mobility group(HMG)-box protein-2; SSEA, stage-specificembryonic antigen; STAT, signal transducer
and activator of transcription; TAL1, T-cell
acute lymphocytic leukaemia; VE-cadherin,vascular endothelial cadherin; VEGF,
vascular endothelial growth factor.

Primordial germ cells

Malegerm cells

AP, GCTM2, germ-cell nuclear
factor, OCT3/4, SSEA3/4, VASA

Haematopoietic
stem cells

Spermatogonial
stem cells

bFGF, BMI1, CD34+, CD38–,
CD150+, KIT+, RUNX1,
Sca1+, TAL1,TIE2, VEGF

BMI1, Bmp pathway, ERM,
GDNF pathway,
NOS2, PLZF

Haematopoiesis

CD34+, c-MET,

Mesenchymal
stem cells

M-cadherin,
PAX3+, PAX7+

BMPR, CD34+, CD44,Lin–, Sca1+, SCF

MuscleMesenchyme

Satellite stem cells
BRA, GATA4, MESP,NKX2.5

Heart

Cardiac progenitors
ISL1

MYF5, MYF6,MYOD, PAX3

Vascular cells

Mesoderm
BMP4, BRA, MESP

Haemangioblast

CD31, FLK1, FLT1, TIE1, TIE2
VE-cadherin, VEGF

Although the existence of cancer stem cells is
now generally accepted for both blood and solid
tissue tumours, the definitive identification ofmarkers for cancer stem cells is still in its
infancy. Several genes and signalling pathways
that are known to regulate tissue and embryonicstem cells, such as BMI1 and the SHH, Notch andWnt/β-catenin pathways, are deregulated incancer. Surface markers can be used inconjunction with assays such as self renewal
in vitro or transplantation in vivo to identify
potential tumour stem cells, although inisolation they are not definitive. The six yellow
boxes show some of these attributes and thetumours with which they have been associated.
They are not intended to show definitive cancer
stem-cell markers.

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