Cell Stem Cell

ISSCR: Meeting Report

Stem Cells Down Under—ISSCR 2007

Stuart H. Orkin1,2,3,4,* and Martin Pera5
1Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children’s Hospital Boston
2Harvard Medical School
3Howard Hughes Medical Institute
4Harvard Stem Cell Institute

Boston, MA 02115, USA

5Center for Stem Cell and Regenerative Medicine, University of Southern California, Los Angeles, CA 90033, USA

*Correspondence: stuart_orkin@dfci.harvard.edu
DOI 10.1016/j.stem.2007.08.007

Cairns, Queensland, Australia provided the venue for the 5th annual meeting of the International
Society for Stem Cell Research (ISSCR), June 17–20, 2007. Consonant with the young society’s mis-
sion to serve the international stem cell community, this meeting was the first held outside North
America. The meeting drew attendees from 44 countries, with excellent representation from the
Asia/Pacific region. The more than 120 presentations and 1000 posters covered virtually all aspects
of the stem cell field and provided a snapshot of current areas of investigation. Here we review
some of the newest findings in an effort to convey the energy and excitement of the meeting and the
tempo of stem cell science.

Sources and Properties of Stem Cells
A remarkable aspect of the field is the continued discovery
of new types of multipotent stem cells and diverse ways to
generate such cells. Simple notions of embryonic versus
adult stem cells, often distinguished more for political
than scientific reasons, are blurred by recent findings.
The widely heralded conversion of adult mouse fibroblasts
to embryonic stem cell (ESC)-like cells (iPS cells) by a com-
bination of four transcription factors (Oct3/4, Sox2, Klf4,
and c-Myc), first reported by Takahashi and Yamanaka
(2006), has been confirmed and improved upon by isola-
tion of cells expressing endogenous Oct3/4 or Nanog
(Okita et al., 2007; Wernig et al., 2007; Maherali et al.,
2007). Yamanaka (Kyoto University) and Jaenisch (Massa-
chusetts Institute of Technology) reviewed their recent
demonstrations that iPS cells, reprogrammed in this man-
ner, are virtually indistinguishable from traditional mouse
ESCs (mESCs) and also germline competent. A striking
aspect of the reprogramming process is its slow tempo.
Greater than 2 weeks in culture is necessary to achieve
maximal reprogramming (0.5% of cells). One important
goal of the field—that is, reprogramming of an adult so-
matic cell to an embryonic, pluripotent state without the
use of oocytes or cell fusion—has been achieved. Several
questions immediately come to mind. How general is the
‘‘four-factor combination’’? Will this set of factors repro-
gram other types of somatic cells to an ESC state or will
different combinations be required depending on the host
cell’s transcriptional and epigenetic milieu? Given the
highly integrated transcriptional network in ESCs, might
other combinations of factors also reprogram somatic
cells to the same extent or more efficiently? What are
the precise steps that take place during the slow reprog-
ramming process? Finally, will the four-factor combination
reprogram somatic cells of other species, most notably
those derived from humans? The pace of current work
suggests that answers to these, and other, questions will
be forthcoming.
The inclusion of c-Myc, a bona fide oncoprotein, in the
reprogramming cocktail, along with the integration of the
retroviral constructs employed in the protocols into multi-
ple sites in the genome, ensures for the time being that
alternative methods for reprogramming need to be con-
sidered (Okita et al., 2007), particularly for generation of
human ESCs (hESCs) that might be employed in therapy.
Eggan (Harvard University) described his success in
nuclear transplantation (NT) into zygotes, as opposed to
unfertilized oocytes (Egli et al., 2007). With the availability
of numerous frozen zygotes from assisted reproduction
efforts, the modified method should facilitate generation
of disease-specific or genetically tailored hESC lines and
obviate the need for oocyte donations for these purposes.
Parthenogenetic ESCs (pESCs) offer yet another source of
histocompatible, pluripotent cells. Previously, Daley and
colleagues described efficient generation of pESCs by
direct activation of unfertilized oocytes (Kim et al.,
2007b). Using recombination signatures to distinguish
pESCs from ESCs derived from NT embryos, Daley
(Children’s Hospital Boston) reported that Hwang’s dis-
paraged first somatic cell nuclear transfer (SCNT)-hES1
cell line (Hwang et al., 2004) was, indeed, a parthenote
(Kim et al., 2007c). McLaughlin (University of Pennsylva-
nia) discussed the potential of pESCs for cellular therapy.
Mouse pESCs transduced with retrovirus expressing the
homeobox gene HoxB4 to enhance hematopoietic cell
maturation were cultured in vitro prior to transplantation
into immunocompromised gc/Rag2 double knockout
mice. Hematopoietic reconstitution was efficient and

Cell Stem Cell 1, September 2007 ª2007 Elsevier Inc. 271


ISSCR: Meeting Report
sustained, suggesting that pathenogenetic tissues may be
a suitable source for transplantable cells. Finally, sper-
matogonial stem cells, a rare subpopulation of germ cells
in the adult testis, display many properties in common with
ESCs and are capable of differentiation into a range of
adult cell types, including spermatozoa that can fertilize
eggs after intracytoplasmic sperm injection (Engel,
University of Goettingen).
In a last-minute addition to the program, S. Mitalipov
(Oregon Health and Science University) reported the
most stunning achievement announced at the meeting:
the generation of two macaque monkey ESC lines from
cloned nuclear transplantation-derived monkey embryos.
A modified SCNT technique, which avoided the use of
DNA binding dyes and ultraviolet light exposure, may
have contributed to the success of the procedure, and nu-
clear remodeling induced by the cytoplast is a key step in
the process.
Various adult stem cells with diverse developmental po-
tentials have been described in recent years. Some of
these, such as multipotent adult progenitor cells (MAPCs)
from the bone marrow (Jiang et al., 2002), have proven dif-
ficult to culture, and hence, their characterization and
therapeutic potential remain ill defined. Miller (Hospital
for Sick Children) reported her findings on a fascinating
multipotent progenitor cell, termed SKPs (for skin-derived
progenitors), that can be readily isolated and expanded
and then differentiated into mesodermal and neural cell
types. SKPs, which are grown as neurosphere-like cells
from skin of mouse or human origin, have properties of
neural crest cells and appear to be bipotent for Schwann
cell and hair follicle fates. Recent data implicate the neural
crest as a source of mesenchymal stem cells (Takashima
et al., 2007), and the widespread distribution of the de-
scendants of this multipotent embryonic lineage may ac-
count for a number of observations of adult tissue cell
plasticity. In poster form, Sparling (University of British
Columbia), in collaboration with Miller, presented prelimi-
nary data suggesting that SKPs may facilitate repair and
functional recovery of spinal cord after injury. Work of this
type suggests that we should remain open minded as to po-
tential sources of stem or progenitor cells for tissue repair.
Stem Cell Differentiation
Another sphere of intense activity centers on the differenti-
ation of ESCs into cells committed to specific lineages.
Keller (University Health Network) reviewed his laboratory’s
approach, which relies on careful temporal analysis of
in vitro differentiation coupled with use of mESCs harboring
markers (such as GFP, inactive CD4) targeted to critical in-
dicator loci for mesoderm (Brachyury) or endoderm (Foxa2).
An important realization to emerge from these studies is that
an early wave of mesoderm development leads to hemato-
poietic commitment, whereas a later wave generates car-
diac progenitors. The balance between mesoderm and en-
doderm commitment appears to be controlled by the levels
of activin and BMP-4, whereas induction of cardiogenic
mesoderm is driven by Notch signaling. D’Amour (Novocell
Inc.) and others provided strong evidence for the induction
272 Cell Stem Cell 1, September 2007 ª2007 Elsevier Inc.
Cell Stem Cell
of definitive endoderm in hESC cultures by high doses of
activin, and efforts to derive mature endodermal tissues, in-
cluding fully functional islet cells, from these progenitors are
well underway in many laboratories.
Keller and his colleagues also reported translation of
their mouse in vitro methods to differentiation of hESCs.
Importantly, they find striking similarities between the
sequence of events for mESCs and hESCs. For example,
human hemangioblasts express Flk-1/KDR and generate
blast colonies that give rise to both hematopoietic and
vascular progenitors, findings echoed by S.-J. Lu
(Advanced Cell Technology, Inc.). In complementary stud-
ies, Davis (Elefanty/Stanley lab, Monash University) pre-
sented elegant work in which GFP sequences were tar-
geted by homologous recombination to the MIXL1 gene
in hESCs to mark emerging primitive streak-like cells. Iso-
lation of GFP+ cells from differentiating hESC cultures en-
riched for hematopoietic blast colony activity. The exten-
sive similarities in in vitro differentiation of mESCs and
hESCs in these careful studies provides encouragement
that the lessons learned from mESCs can, indeed, be
transferred to the human system.
Perhaps due to differences between how mESCs and
hESCs are generally cultured, experience to date in ge-
netic modification of hESCs has been limited. Irion (Keller
lab, University Health Network) reported identification of
the human homolog of the mouse Rosa26 locus, a ubiqui-
tously expressed gene that has served as an excellent tar-
get for introduction of exogenous cDNAs. A cre-inducible
red fluorescent protein sequence was introduced into the
human Rosa26 locus, as were modified loxP sites that per-
mit recombination-mediated cassette exchange (RMCE).
The creation of a cell line suitable for RMCE will allow effi-
cient introduction of foreign sequences for overexpres-
sion or gene silencing in hESCs.
In contrast to the hematopoietic system where numer-
ous cell-surface markers and antibodies have been char-
acterized for prospective isolation of hematopoietic stem
cells (HSCs) and intermediate progenitors, similar re-
agents are largely lacking for other tissues. This limitation
has often led to the reliance of investigators on markers
such as Sca-1, c-kit, and the side-population phenotype
for characterization of stem/progenitor cells of other tis-
sues, rather than more specific surface markers. Grompe
and Dorrell (Oregon Health and Science University) de-
scribed efforts to close this gap by generating panels of
surface-reactive monoclonal antibodies for prospective
isolation of pancreatic cell subsets and for liver colony-
forming cells. Many of the reagents marked ductal cell
subpopulations in both tissues. Using a GFP reporter
driven by the telomerase promoter to identify putative
stem cell populations, Carlone (Children’s Hospital,
Boston) showed that during exendin-induced b cell neo-
genesis, ductal cells, but not islet cells, expressed GFP,
suggestive of their potential role as facultative stem cells
in this tissue. Deng (Peking University) presented data
showing that long-term label retaining cells appear to be
present in pancreatic ducts. The vexing issue of the cells
responsible for pancreatic regeneration thus seems likely
Cell Stem Cell
ISSCR: Meeting Report
to generate continued discussion. Gadue (Mount Sinai
School of Medicine) also reported generating antibodies
to Foxa2+/Foxa3+ ESCs that distinguished endodermal
progenitors from ESC-derived ectoderm or mesoderm.
In a systematic effort to identify lineage-specific precur-
sors with antibodies, Drukker (Stanford University School
of Medicine) reported a large-scale FACS analysis of
hESC-derived precursors with a panel of 500 commer-
cially available monoclonal antibodies. Among this collec-
tion, CD30 was detected as an ESC-specific antigen, a
finding in agreement with findings reported by Pera (Uni-
versity of Southern California), who reported signaling
through the NF-kB pathway. An important goal going for-
ward will be the availability of antibody cocktails suitable
for isolation of various tissue stem and progenitor cell pop-
ulations. Community resources of this kind will greatly fa-
cilitate basic studies of differentiation as well as prepara-
tion of defined cellular populations for tissue repair.
Several presentations focused on cardiac and skeletal
muscle stem and progenitor cells. Harvey (Victor Change
Cardiac Research Insitute) reported the isolation of a pro-
genitor population in the adult mouse heart that expresses
PDGFRa and is capable of both self-renewal and multiline-
age differentiation into cardiomyocytes and other mesoder-
mal derivatives. Mummery (Hubrecht Institute) described
gene expression during cardiomyocyte differentiation of
hESCs and identified several new genes with potential roles
in the generation of congenital heart defects in humans. The
survival of the satellite cell, a myogenic progenitor in skele-
tal muscle, is dependent upon Pax-7; deletion of this gene
leads to gradual depletion of this population (Buckingham,
Institut Pasteur). Pax-7 and Pax-3 function together to
specify the skeletal muscle lineage.
Mechanisms of Pluripotency and Self-Renewal:
Transcriptional and Epigenetic
Although the phenomenon of reprogramming is estab-
lished, there is yet much to be learned regarding mecha-
nisms responsible for orchestrating pluripotency. The re-
cent description of postimplantation epiblast-derived
stem cells (EpiSCs) isolated from the mouse (Brons
et al., 2007; Tesar et al., 2007), which are representative
of a somewhat later developmental stage than mESCs
yet more closely resemble hESCs in signaling properties,
suggests that there are different degrees of pluripotency.
Attention in the field initially focused on single transcrip-
tion factors, such as Oct3/4, Sox2, and Nanog. More re-
cently, the involvement of numerous factors in maintaining
a transcriptional network supporting pluripotency of
mESCs has been more fully appreciated (Ivanova et al.,
2006; Wang et al., 2006). With the availability of methods
that now permit genome-wide analysis, investigators are
also interrogating transcription factor binding and chro-
matin modification on a broad level in ESCs and differen-
tiated progeny. Within the past 2 years, several notable
findings have been described (Bernstein et al., 2006;
Boyer et al., 2005, 2006; Lee et al., 2006), yet the involve-
ment of each mechanistically in the establishment/mainte-
nance of pluripotency requires further substantiation.
Among those most widely discussed observations are
the binding of Polycomb complex 2 (PcG2) members
(with the corresponding histone mark H3K27me3), such
as Ezh2, Suz12, and Eed, to differentiation-associated
genes in ESCs and the existence of a class of genes
with ‘‘bivalent marks’’ (H3K4me3 and H3K27me3), indica-
tive of a ‘‘poised’’ state. The contribution of PcG repres-
sion to the maintenance of pluripotency (Boyer et al.,
2006) has pervaded recent thinking in the field, despite ev-
idence indicating that pluripotency transcription factors,
such as Oct3/4 and Nanog, operate in part by antagoniz-
ing expression of lineage-promoting genes, such as
GATA-4/6 and Cdx2 (Niwa, 2007). Boyer (Young labora-
tory, Massachusetts Institute of Technology) reviewed
prior findings on the binding and potential roles of PcG
proteins in mouse and human ESCs and provided new
data revealing coassembly of a histone variant, H2AZ,
with PcG proteins at the promoters of PcG-responsive
genes. The association is lost on differentiation. Hence,
multiple pathways converge on PcG-bound genes. Berg-
man (Hebrew University Medical School) illustrated how
assessment of the chromatin status of the Oct3/4 locus
during ESC differentiation provides a unique window into
the multistep program of gene inactivation, which is ac-
companied by histone H3 methylation (H3K9) mediated
by the SET-containing protein G9a and followed by heter-
ochromatinization by HP1 and de novo DNA methylation
by Dnmt3a/3b. These epigenetic changes need to be
reversed during cellular reprogramming.
Young (Massachusetts Institute of Technology) added
a new wrinkle with the report that the majority of genes
in hESCs display the H3K4me3 mark, even though only
about 30% express transcripts. These data suggest that
genes fall into three categories: productive, nonproduc-
tive but poised, and inactive (Guenther et al., 2007). These
findings may not be unique to ESCs but rather describe
a state in which many genes are ready to be expressed
once elongation is permitted. Perhaps the signature of
H3K4me3 facilitates cellular reprogramming. In contrast,
some loci, most notably the olfactory receptor genes,
are not marked in this manner and are presumably subject
to other regulatory mechanisms.
Building on prior work describing a protein interaction
network associated with pluripotency of mESCs (Wang
et al., 2006), Orkin (Harvard Medical School) described
global promoter occupancy by multiple transcription fac-
tors that identifies sets of genes bound simultaneously
by multiple (up to nine) factors. These targets may contrib-
ute uniquely to maintenance of pluripotency, but func-
tional studies are required to address this possibility. In
parallel, he presented studies of mESCs harboring inacti-
vating mutations in PcG components that point to critical
involvement of PcG complexes in orchestrating differenti-
ation of mESCs, as opposed to maintaining pluripotency.
Self-renewal is a defining property of all stem cells. Van
Lohuizen (Netherlands Cancer Institute) described the
critical role of the PcG1 complex component Bmi-1 in
regulating self-renewal of diverse cell types. Prior work
established Bmi-1’s involvement in self-renewal of
Cell Stem Cell 1, September 2007 ª2007 Elsevier Inc. 273

ISSCR: Meeting Report
hematopoietic and neural stem cells. Van Lohuizen has
now implicated Bmi-1 in ductal outgrowth in the mammary
gland, consistent with a role in mammary stem cells. Re-
markably, Bmi-1 appears to serve important functions in
all stem cells thus far examined. Although Bmi-1 acts in
part through repression of Ink4/Arf, this mechanism is un-
likely to account for its broad involvement. Further work
elucidating Bmi-1 action should illuminate general as-
pects of stem cell self-renewal.
Rather than remaining phenotypically stable throughout
life, stem cells may exhibit intrinsic differences at different
developmental stages. How such differences are
programmed has remained largely obscure. Morrison
(University of Michigan) reported that fetal and adult
HSCs, which differ in their cycling properties among others,
are distinguished by expression of Sox17 (Kim et al., 2007a).
Conditional loss of Sox17 selectively impairs fetal and
neonatal HSCs. Interestingly, Sox17 is also important in
differentiation of other tissues. Hence, important functional
differences between stem cells at different times in develop-
ment may be determined by single transcription factors that
may participate in fate decisions in other contexts.
An epigenetic mechanism proposed to be unique to
stem cells—preservation of the ‘‘immortal strand’’—
came under attack at the meeting in a presentation by
M. Kiel (Morrison laboratory, University of Michigan). The
immortal strand theory posits that stem cells asymmetri-
cally segregate chromosomes during self-renewing divi-
sions to preserve the older (immortal) DNA strand in
daughter stem cells, whereas younger strands are segre-
gated to differentiating cells. The longstanding contro-
versy over this theory has been revitalized by recent find-
ings (Conboy et al., 2007; Rando, 2007; Lansdorp, 2007).
Data obtained by pulse labeling hematopoietic cells in vivo
and following retention of label in HSCs were incompatible
with the immortal strand theory, suggesting that this epige-
netic mechanism, if operative, is not a general property of
stem cells.
Niche Contributions to Stem Cell Functions
Stem cells do not exist alone but live in complex environ-
ments, presumably tailored to control quiescence, prolif-
eration, and differentiation. The niches in which stem cells
reside are poorly characterized in vertebrates compared
to what has been learned in more primitive animal models.
For example, as Yamashita (University of Michigan)
reviewed, the Drosophila male germline stem cells are
anchored to hub cells. Furthermore, the mitotic spindle
is oriented perpendicular to the hub cell, such that on di-
vision one cell remains attached to the hub and the other
is displaced from the niche (Yamashita et al., 2007).
In vertebrates niche control of stem cell function is less
well defined. Within the bone marrow, different cellular
constituents, such as osteoblasts and vascular cells,
have been singled out as critical for HSC interactions. Arai
(Suda laboratory, Keio University) presented evidence that
homotypic N-cadherin-mediated interactions between
HSCs and osteoblasts may control stem cell quiescence,
in large part through b-catenin and presumably Wnt
274 Cell Stem Cell 1, September 2007 ª2007 Elsevier Inc.
Cell Stem Cell
signaling. Nilsson (Australia Stem Cell Centre) presented
evidence pointing to the involvement of another protein,
CD44, on both hematopoietic cells and cells in the micro-
environment as important for retention of HSCs within the
endosteal niche. Yet another molecule present on HSCs,
the sialomucin endolyn (CD164), was suggested to be
critical in modulating interaction with the marrow
environment (Watt, University of Oxford). Walkley (Orkin
laboratory, Dana-Farber Cancer Institute) suggested
a more complex situation in the marrow microenviron-
ment, as revealed through study of cell-selective inactiva-
tion of the retinoblastoma protein Rb. In this instance, Rb
acts as an extrinsic regulator of HSC through its mainte-
nance of the competence of the marrow niche to support
HSCs; Rb function is required in both in hematopoietic-
and nonhematopoietic-derived cells (Walkley et al.,
2007). Defining the contribution of individual marrow com-
ponents to niche function is a challenge for the field.
Signals from the microenvironment must be received by
stem cells for proper self-renewal and differentiation.
Goetz (GSF Institute of Stem Cell Research) reported a re-
quirement for a complex containing CDC42 and the parti-
tioning complex (Par) both for self-renewal of neural stem
cells and regulation of the critical neural fate determinant
Pax6. These neurogenic fate determinants can, however,
be overruled by the transcription factor Olig2 that is re-
pressed in the adult neurogenic niche by Smad4-medi-
ated BMP signaling. In the hematopoietic system, increas-
ing evidence suggests that BMP and Wnt act in concert to
direct formation of hemogenic mesoderm through activa-
tion of a Cdx-Hox transcription factor pathway (Lengerke,
Daley laboratory, Children’s Hospital Boston). Similarly,
activation of Wnt or BMP signaling promotes faster recov-
ery of hematopoietic progenitors after radiation injury
(Bowman, Zon laboratory, Children’s Hospital Boston).
Pharmacological stimulation of these pathways by small
molecules or drugs might be of particular use in augment-
ing the numbers of stem cells for bone marrow transplan-
tation. Indeed, as reported by Bowman, prostaglandin E2
increases HSC number and possibly function in both
zebrafish and the mouse (North et al., 2007). The balance
of BMP and Wnt signaling is also critical to the regulation
of stem cells in the hair follicle bulge region; ablation of
BMP signaling leads to elevated levels of Lef1 and b-
catenin, activation of quiescent stem cells, and their pro-
liferation to form tumor-like structures (Fuchs, Rockefeller
University) (Kobielak et al., 2007).
Therapeutic Developments
Many preclinical translational studies in a variety of dis-
ease or injury models have shown that the administration
of stem or progenitor cells results in benefit, but in most
studies, it is uncertain whether the improvement seen is
a result of functional integration of the graft into the dam-
aged host tissue or an indirect effect of survival or trophic
factors secreted from the grafted cells. In a spinal cord in-
jury model in the mouse, Anderson (University of California
Irvine) showed that human neural stem cells could form
myelinating oligodendrocytes and neurons that made
Cell Stem Cell
ISSCR: Meeting Report
synaptic connections with host cells. Inoculation in utero
of mesenchymal stem cells into oim mice, a model of os-
teogenesis imperfecta, increased bone strength and re-
duced spontaneous fracture rates, and descendants of
the grafted cells were found at areas of bone remodeling
and fracture repair (Fisk, Imperial College London).
Several groups reported early improvement of function
in animal models of myocardial infarction or pacemaker
dysfunction after administration of ES-cell derived cardio-
myocytes (Gold, Geron Corp.; Gepstein, Technion-Israel
Institute of Technology), but achievement of long-term
functional improvement attributable to integration of the
cells into host myocardium still presents challenges
(Mummery, Hubrecht Institute).
Final Comments
As befits an international meeting held ‘‘down under,’’
Metcalf (The Walter and Eliza Hall Institute of Medical Re-
search) mused on his nearly 50 years studying HSCs. He
cautioned those in attendance to remember that the facts
supporting many of the ‘‘accepted’’ concepts in the stem
cell field should be viewed with healthy skepticism. Do we
really know the developmental path followed by commit-
ted cells as they differentiate from HSCs? Is the full devel-
opmental potential of HSCs understood? To what extent
can differentiation be reversed?
These fundamental questions about the HSC, arguably
the best studied of all vertebrate stem cells, remain de-
spite half a century of research by many scientists, and
workers in other fields of stem cell biology will struggle
to grapple with similar issues. Nevertheless, as the Cairns
meeting showed, during the brief 5 year history of the
ISSCR, stem cell research has now become one of the
most rapidly growing areas of biomedical research inter-
nationally. A number of experimental challenges that
seemed insurmountable only a few years back, reprog-
ramming of somatic cells with defined factors being but
one example, have been met. The experience from de-
cades of molecular genetic studies of embryonic develop-
ment has proven remarkably useful in efforts to guide
hESCs toward desired fates. Application of genome-
wide approaches to stem cell transcription and epige-
netics has provided a blueprint of the networks that con-
trol pluripotency. And gradually, discoveries from basic
research are moving into the translational arena. It seems
quite unlikely that any of the attendants in Cairns could
predict with any accuracy the content of the program for
ISSCR 2012.
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