Role of Gap Junctions in Embryonic and Somatic Stem Cells
Raymond C. B. Wong & Martin F. Pera & Alice Pébay
Published online: 14 August 2008
# Humana Press 2008
Abstract Stem cells provide an invaluable tool to develop
cell replacement therapies for a range of serious disorders
caused by cell damage or degeneration. Much research in
the field is focused on the identification of signals that
either maintain stem cell pluripotency or direct their
differentiation. Understanding how stem cells communicate
within their microenvironment is essential to achieve their
therapeutic potentials. Gap junctional intercellular commu-
nication (GJIC) has been described in embryonic stem cells
(ES cells) and various somatic stem cells. GJIC has been
implicated in regulating different biological events in many
stem cells, including cell proliferation, differentiation and
apoptosis. This review summarizes the current understand-
ing of gap junctions in both embryonic and somatic stem
cells, as well as their potential role in growth control and
Gapjunctional intercellular communication
Bone morphogenetic protein
Embryonic stem cells
Hematopoietic stem cells
Mesenchymal stem cells
Gap junctional intercellular communication
Human embryonic stem cells
Mouse embryonic stem cells
Platelet-derived growth factor
In the past years, stem cell biology has emerged as one of
the most active areas in biomedical research. Stem cells
possess two remarkable characteristics: they are capable of
self-renewal, while retaining the ability to differentiate into
mature daughter cells . Two categories of stem cells are
discussed here, embryonic stem cells (ES cells) and somatic
stem cells. ES cells are derived from the inner cell mass of
the blastocyst stage of embryo [30, 69, 96, 111]. ES cells
are pluripotent: they can give rise to most, if not all, tissue
types of the body . On the other hand, somatic stem
cells persist in various niches throughout postnatal life and
are critical to maintaining tissue homeostasis by replacing
cell losses due to turnover, damage, and degeneration .
Generally somatic stem cells are restricted to differentiation
into lineage(s) that comprise the tissue of origin. However,
in some cases somatic stem cells can differentiate into
multiple lineages, showing more developmental potential
than previously thought [92, 119]. This multi- or pluri-
potent developmental potential of stem cells has spurred
Stem Cell Rev (2008) 4:283–292
R. C. B. Wong (*)
Department of Biological Chemistry,
University of California Irvine,
Irvine, CA, USA
M. F. Pera
Eli and Edythe Broad Center for Regenerative Medicine and Stem
Cell Research, Keck School of Medicine,
University of Southern California,
Los Angeles, CA, USA
Centre for Neuroscience and Department of Pharmacology,
The University of Melbourne,
great interest in their potential implications in cell replace-
The microenvironment that stem cells reside in is critical
to their maintenance, and communications between neigh-
bouring cells play an important part in determining cell fate.
While most studies of the stem cell niche focus on
paracrine or juxtacrine cell interactions, intercellular com-
munication through gap junctions represents an under-
studied area. This review aims to summarize the current
understanding of gap junctions in both somatic stem cells
and ES cells.
The term ‘gap junction’ comes from histological studies
performed in the 1960s, where a distinct ‘gap’ between two
plasma membranes was observed by electron microscopy
. Gap junctions are hydrophilic channels made up of
two hemichannels termed connexons, each of them local-
ized in the membrane of adjacent cells. In turn, each
connexon consists of six integral membrane proteins termed
connexins [53, 104] Connexons can be assembled from
either a single type of connexins (homomeric) or multiple
types of connexins (heteromeric). Subsequently, the gap
junction can be either homotypic, consisting of two
identical homomeric connexons, or heterotypic, consisting
of two different heteromeric or homomeric composition
(Fig. 1). For a detailed discussion on connexin trafficking
and gap junction assembly, please refer to an excellent
review by Martin et al. .
Connexin genes belong to a highly conserved multigene
family [103, 125]. To date, 21 connexins have been
identified in human and 20 in the mouse. Connexins
generally consist of four transmembrane regions, two
extracellular loops and three intracellular domains .
The extracellular and transmembrane domains are con-
served among connexin family members, whereas their
intracellular sequences are more diverse . The cyto-
plasmic C-terminal tail contains multiple serine and
tyrosine residues which allow phosphorylation of connex-
ins, resulting in regulation of molecular diffusion through
gap junctions . The interaction of other cellular proteins
with connexins is the subject of an exhaustive review .
Connexins can be regulated at the transcriptional, transla-
tional and post-translational levels. This in turn can affect
biogenesis, assembly, intracellular transport, docking, chan-
nel gating, internalization and degradation of gap junctions
[56, 57, 79, 84, 103].
Traditionally, connexins are believed to be the only
proteins capable of forming gap junctions in vertebrates,
while innexins form gap junctions in invertebrates .
Recently three innexin orthologs, termed pannexins
PANX1, PANX2 and PANX3, have been described in the
mouse and human [86, 87]. At least one pannexin, PANX1
is able to form functional gap junctions in mammalian cells,
rendering pannexin as the second class of gap junction
proteins in vertebrates [43, 55]. However, it remains
controversial whether pannexins play an overlapping role
with connexins in mediating gap junctional intercellular
Gap Junctional Intercellular Communication
Gap junctions are the only intercellular junctions that allow
direct transfer of signaling molecules and metabolites to
adjacent cells [1, 53]. Atomic force microscopy studies
have demonstrated that gap junctions can exist in an
‘opened’ conformation that allows molecular diffusion
through their pore, or a ‘closed’ conformation that restricts
molecular diffusion . Moreover, gap junctions made up
from different connexins can have different pore sizes,
giving rise to different permeability for the transfer of
Fig. 1 Organisation of connexins into gap junctions and molecules
capable of diffusing through gap junctions
284Stem Cell Rev (2008) 4:283–292
molecules . However, it is generally accepted that only
molecules less than 1–1.5 kDa with a maximum diameter of
∼1.5 nm can diffuse through gap junctions in the ‘opened’
state [22, 31].
Gap junctional intercellular communication (GJIC) refers
to the diffusion of intracellular molecules through gap
junctions to the neighboring cell. Molecular movement
through the gap junctions is believed to occur by passive
diffusion. As illustrated in Fig. 1, numerous cytoplasmic
molecules can diffuse through gap junction channels,
including small ions (Na+, K+, Ca2+, H+, Cl−), second
messengers (cyclic nucleotides, inositol triphosphate), amino
acids (glycine, glutamate), metabolites (glucose, glutathione,
adenosine, AMP, ADP, ATP), short interfering RNA and
peptides involved in cross-presentation of major histocom-
patibility complex class I molecules [1, 52, 80, 115]. GJIC is
involved in various cellular mechanisms, including intercel-
lular buffering of cytoplasmic ions, electrical synchroniza-
tion, control of cell migration, cell proliferation, cell
differentiation, metabolism, apoptosis and carcinogenesis
[22, 52, 75, 88, 112, 121].
The functional state of GJIC can be determined
experimentally by demonstrating gap junction-mediated
transfer of either small biochemical dyes (e.g. Lucifer
yellow, 6-carboxyfluorescein) or ions between adjacent
cells (microelectrode impalements to detect electrical
voltage across adjacent cells). It is important to recognize
that GJIC should not be considered a simple all-or-none
phenomenon. In some situations, gap junctions can close to
a pore size that allows ions to pass through but not
relatively larger biochemical dyes [54, 63]. Furthermore,
different connexins can form gap junctions with dramati-
cally different permeability and selectivity to specific
molecules. For example, gap junctions comprised of Cx43
mediate transfer of glucose metabolites much better than
Cx32 channels, while Cx32 channels transfer adenosine
with greater efficiency than Cx43 channels . The basis of
this selectivity of molecular transfers is thought to be
related to the ability of different connexins to assemble
channels with different sizes, charges and binding affinities
to specific molecules . Gap junctions made of multiple
types of connexins (heterotypic or heteromeric) can have
different permeability and selectivity to diffused molecules
compared to homotypic gap junctions, in a manner that is
not yet fully understood.
Finally, recent evidence has also suggested that unpaired
connexon hemichannels can also mediate intercellular com-
municationwithoutforminggapjunctions[25, 31, 36]. Under
resting conditions, connexon hemichannels in the plasma
membrane are closed. However, in certain situations,
connexon can be stimulated to open and release intracellular
signalling molecules. Please refer to Goodenough and Paul
for an extensive review on this topic .
Gap Junctions in Growth Control
Gap junctions have an important role in cellular growth
control. Early studies led to a simple view that up-
regulation of GJIC inhibits cellular proliferation, while
down-regulation of GJIC stimulates proliferation [68, 114].
The diffusion of putative growth inhibitory factors through
the gap junction is thought to cause this effect .
Previous studies showed that GJIC become undetectable
as the cells enter mitosis [34, 106]. Decreasing GJIC is also
observed during normal cell cycle transit and is disrupted
during neoplastic growth . In the 1960’s, some pioneer-
ing works from Loewenstein and Kanno demonstrated that
rat hepatomas do not communicate via gap junctions [66,
67], contrary to normal hepatocytes which possess functional
GJIC . This work led to the hypothesis that gap junctions
are involved in growth control, where deficiency in GJIC
results in the deregulated growth of cancer cells . This
hypothesis is supported by the fact that GJIC deficiency is
described in many cancer cell types as opposed to their
normal counterpart [75, 76, 121]. Other evidences supportive
of this hypothesis in cancer cells include the following:
I. In many types of tumour cells, GJIC is not functional as
a result of deficient in connexin expression, or inability
to assemble functional gap junctions into the membrane
II. Cx32−/−knockout mice have a higher incidence of liver
cancer and leukemia, and Cx43+/−knockout mice have
a higher susceptibility to lung cancer [3, 38, 39, 110].
III. Tumour-promoting agents (e.g. phorbol 12-myristate
13-acetate) and oncogenes (e.g. Src) can regulate gap
junctional communication, further suggesting a role of
GJIC in carcinogenesis [33, 130].
IV. A direct relationship between gap junction expression
and the malignant phenotype is demonstrated by a
number of transfection studies, where transfection of
cancer cells with certain connexins is followed by the
subsequent restoration of GJIC and growth suppres-
sion [121, 130]. In addition, isolated HeLa clones with
Cx43 expression and GJIC restoration exhibit marked
decrease in cellular growth and tumorigenicity com-
pared to normal HeLa that lack Cx43 and GJIC .
Thus, early studies of gap junctions in cancer cells
supported a view where down-regulation of GJIC promotes
cell proliferation, while up-regulation of GJIC inhibits cell
proliferation . This view is almost certainly an
oversimplification, since cell proliferation and functional
GJIC are correlated in some cell types. Certain cancer cells
possess functional GJIC, such as embryonal carcinoma
cells and rat bladder carcinoma cells [4, 6, 51]. Moreover,
ES cells and early embryonic cells which proliferate rapidly
also form functional GJIC. Increasing evidence also hints
Stem Cell Rev (2008) 4:283–292285285
that tumour suppression by connexin transfection may act
via a GJIC-independent pathway . It appears that the
relationship between the functional state of GJIC and cell
proliferation may be more complicated than previously
thought. Nevertheless, the data do indicate that gap
junctions serve as a powerful regulator of growth control
in a cell type-dependent fashion.
Gap Junctions in Mediating Cellular Differentiation
in the Early Embryo
The early mouse embryo provides an excellent model to
study the role of gap junctions in mediating cellular
differentiation. The pre-implantation embryo expresses
multiple connexin transcripts, including Cx30, Cx30.3,
Cx31, Cx31.1, Cx36, Cx40, Cx43, Cx45 and Cx57, but
not Cx26 and Cx32 [21, 42, 81]. In the human blastocyst,
Cx26, Cx31, Cx43 and Cx45 transcripts are detected,
however connexin expression patterns can be inconsistent
between different embryos [12, 37].
GJIC between blastomeres appears from the eight-cell
stage during compaction in the mouse , or much
later at day 5–6 blastocyst stage in human . At the
blastocyst stage of the mouse embryo, GJIC was observed
between cells within the inner cell mass . Upon in
vitro implantation of mouse blastocysts (equivalent to
embryonic day 6.5, E6.5), dye coupling is progressively
lost between the inner cell mass and the trophectoderm, but
ionic coupling remains between these two populations .
By the egg cylinder stage (E7.5), ionic coupling also
ceases and GJIC is completely lost between the cells that
originate from the inner cell mass (ectoderm, endoderm,
mesoderm and extraembryonic endoderm) and those orig-
inate from the trophectoderm (extraembryonic ectoderm
and ectoplacental cone), thus giving rise to two different
‘communication compartments’ [45, 46]. Such changes in
GJIC are consistent with the spatial re-organisation of
connexin expression. For example, Cx43 and Cx31 are
expressed in both the inner cell mass and trophectoderm in
the pre-implantation mouse embryo, but Cx43 expression
becomes restricted to derivatives of the inner cell mass
while Cx31 expression is confined to derivatives of
trophectoderm after implantation (E6.5)  Since Cx43
and Cx31 are not able to form functional heterotypic gap
junctions , their distribution patterns effectively divide
the derivatives of the inner cell mass and trophectoderm
into two communication compartments. Further subdivision
into smaller communication compartments occurs within
both the embryo proper and extra-embryonic tissues, with
each germ layer comprising a separate communication
compartment [45, 46]. Curiously, in some cases, ionic
coupling may persist between some germ layers [45, 46]. In
summary, the current theory is that during early post-
implantation development, GJIC is maintained within cells
of the same lineage but lost between tissues whose fate
diverges [62, 122]. Thus the formation of gap junction
communication compartments is proposed to mediate
specific intercellular signalings between cells with similar
Despite many attempts to dissect the functional signifi-
cances of GJIC during pre-implantation embryo develop-
ment, to date whether GJIC is a functional requirement
remains controversial . Inhibition of GJIC by antibodies
targeting multiple connexins [5, 58] or antisense RNA 
prevents compaction and further development in mouse
embryos. However, pharmacological inhibition of GJIC
using α-glycyrrhetinic acid (α-GA) does not affect devel-
opment of the blastocyst, suggesting GJIC may be
dispensable during pre-implantation development in mouse
[42, 118]. More studies are needed to elucidate the role of
gap junctions in the early embryo development. In
particular, knockout study of multiple connexins will help
address this question in the future.
Gap Junctions in Embryonic Stem Cells
ES cells are traditionally derived from the inner cell mass of
the blastocyst stage of embryo [30, 69, 96, 111]. Since then,
recent reports have demonstrated successful derivation of
ES cells from different stages of embryo, including single
blastomere from eight–ten cell stage , morula and late
stage embryo [107, 108]. ES cells are pluripotent and
capable of proliferating indefinitely in vitro, thus potentially
serve as an unlimited source of healthy tissue for cell
replacement therapy .
Mouse Embryonic Stem Cells
Similar to cells from the inner cell mass, undifferentiated
mouse ES cells (mESC) express transcripts of Cx43 and
Cx45 and display functional GJIC [81, 85]. Furthermore, it
was recently shown that pannexin-1 and five additional
connexin transcripts are present in mESC: Cx26, Cx30.3,
Cx31, Cx32 and Cx37. Curiously, only Cx31, Cx43 and
Cx45 proteins were detected in mESC , suggesting
that a regulatory system may exists in mESC to suppress
translation of many connexin isoforms.
Several studies have attempted to study the function of
gap junctions in mESC by knocking out or knocking down
specific connexins. Cell proliferation of Cx43-knock down
mESC is reduced significantly, but cell survival remains
unchanged upon Cx43 knockdown [112, 129]. Moreover,
Cx43 knock-down mESC exhibit down-regulation of
several stem cell markers as well as up-regulation of
286Stem Cell Rev (2008) 4:283–292
differentiation markers . Interestingly, these mESC are
also unable to form embryoid bodies . This suggests
that GJIC is essential for the regulation of mESC to
maintain undifferentiated as well as initiating differentia-
tion. In addition, gene expression profiling indicates that
Cx43-null mESC undergoing neural differentiation exhibit
a deficiency in oligodendrocyte differentiation and an
increase in astrocyte differentiation . Although more
detailed studies are needed to confirm these data, this study
is the first to indicate an essential role of gap junction for
proper neuroectodermal specification. Together, these
results indicate an essential role of gap junction in mESC
In contrast, Cx45-null mESC are morphologically
similar to the wildtype and can readily differentiate into
cells of the three germ layers following embryoid body
formation . One explanation for this lack of phenotype
is that Cx43 is still expressed in Cx45-null mESC and may
compensate for the loss of Cx45 . Interestingly, when
Cx45-null mESC were injected into the blastocyst, they
failed to form chimeric mice or post-implantation embryos.
Subsequent studies of chimeric blastocysts cultured in vitro
showed that Cx45-null mESC were unable to incorporate
into the recipient inner cell mass . Cx45+/−heterozy-
gous mutant mESC also show a decreased efficiency in
forming chimeric mice . From this study, it is proposed
that Cx45 may play a distinct role in the incorporation of
ES cells into inner cell mass by mediating intercellular
Human Embryonic Stem Cells
Many transcriptome studies of human embryonic stem cells
(hESC) are now available. These studies initially aimed to
search for ‘stemness’ genes in hESC, and interestingly their
results hinted at a role of gap junctions in maintaining
hESC pluripotency. Multiple studies have demonstrated
that Cx43 is enriched in undifferentiated hESC when
compared to embryoid bodies [10, 61] or a pooled sample
of adult human tissues [11, 98]. Moreover, the pluripotent
factors Oct4, sox2 and nanog can co-occupy the upstream
region of Cx43 to activate its expression, suggesting its role
in the maintenance of hESC pluripotency . Other
microarray analysis have also shown that Cx43 and Cx45
mRNA are both highly enriched in hESC compared to a
range of somatic tissues or spontaneously differentiated
hESC [7, 105]. Interestingly, Cx45 is up-regulated in
hESC compare to human embryonal carcinoma cells
. Furthermore, Enver et al. showed that Cx45 is also
up-regulated in SSEA-3 positive undifferentiated hESC
compare to its SSEA-3 negative differentiated counterpart
. Finally, Assou et al. summarized 38 previous reports
of microarray studies in hESC and devised a ‘consensus
list’ of undifferentiated hESC markers, including Cx43 and
Cx45 . Together, these transcriptome studies hinted an
understudied role of connexins in the maintenance of hESC
Our previous study demonstrated that hESC express at
least two connexins, Cx43 and Cx45 , a result
consistent with others . Two phosphorylated forms of
Cx43 were observed in undifferentiated hESC, although the
role of connexin phosphorylation in regulating GJIC is not
clear . Moreover, a recent study demonstrated the
mRNA expression of an additional 16 connexin types in
hESC, including Cx25, Cx26, Cx30, Cx30.2, Cx30.3,
Cx31, Cx31.1, Cx31.9, Cx32, Cx36, Cx37, Cx40, Cx46,
Cx47, Cx59 and Cx62 . It appears that hESC express
almost all transcripts of human connexin isoforms, except
Cx40.1 and Cx50 . Furthermore, GJIC was observed in
undifferentiated hESC, as determined by dye coupling [15,
128, 132] and ionic coupling . Our previous studies
showed that such GJIC can be inhibited by BMP
stimulation, protein kinase C activation and Erk1/2 inhibi-
tion [127, 128]. However, exogenous calcium does not
modulate GJIC in hESC. In addition, hESC cultured in
serum-containing, serum-free or feeder-free conditions
possess similar gap junction properties . Together,
these studies suggest that functional GJIC is a common
characteristic of hESC maintained in different culture
conditions [127, 128]. We also showed that hESC do not
communicate with mouse embryonic fibroblast feeder cells
through gap junctions, a result consistent with studies in
mESC . Finally, the functional role of gap junctions in
hESC was studied using the gap junction blocker α-GA.
We utilized a serum-free culture system for hESC previ-
ously established in our laboratory using S1P and PDGF
. In hESC cultured in S1P and PDGF, inhibition of
GJIC by α-GA resulted in reduced colony growth and
increased apoptosis . This result indicates an impor-
tant role of gap junctions in the maintenance of hESC.
However, it must be noted that α-GA had no significant
effect on hESC cultured in fetal calf serum, suggesting that
under certain conditions the effect of GJIC inhibition may
be compensated by other unidentified signals.
Future studies that utilise RNAi techniques to knock-
down specific connexins will be helpful in determining the
role of specific connexins in regulating cell pluripotency,
proliferation and survival in hESC. Research in this area
will prove useful in maintaining hESC in an undifferentiated
state or enhancing hESC differentiation along specific
lineage. In addition, hESC survive poorly as single cell,
which is vital to many genetic modification procedures. It is
speculated that cell–cell interaction between hESC is
important to their survival, thus a better understanding of
the role of gap junctions may lead to improved methodology
for cloning of hESC.
Stem Cell Rev (2008) 4:283–292287287
Gap Junctions in Somatic Stem Cells
In contrast to ES cells, a hallmark feature of somatic stem
cells is that they exist in specific niches where they remain
in a quiescence state . Somatic stem cells can undergo
symmetric division to self-renew, or asymmetric division
to generate a differentiated daughter cell . GJIC is
often important in regulating the cell fates of somatic stem
cells, a phenomenon possibly conserved from lower
organism to mammalians. For example, Ovieda et al.
recently demonstrated that the inhibition of GJIC in somatic
stem cells prevents regeneration of the planarian flatworm,
suggesting a conserved role of gap junctions in regulating
stem cell fate . Here we will discuss the current
understanding of gap junctions in a number of somatic
Hematopoietic Stem Cells
Hematopoietic stem cells (HSC) are the most extensively
studied somatic stem cell population in both humans and
mice . HSC are capable of giving rise to all blood cell
types, including red blood cells, B lymphocytes, T
lymphocytes, neutrophils, natural killer cells, basophils,
eosinophils, monocytes, macrophages and platelets .
During adulthood, HSC reside primarily within niches in
bone marrow, where cell–cell communication with the
surrounding stromal cells is critical for regulating HSC
maintenance . In particular, it has been proposed that
GJIC may be involved in this process [94, 100]. Recent
studies suggested that Cx32 is vital to HSC differentiation.
Cx32 expression can be readily detected in Lin−c-kit+HSC-
enriched cells . Interestingly, Cx32 knockout mice
exhibit more undifferentiated HSC and fewer progenitor
cells, suggesting a role of Cx32 in maturation of HSC to
progenitor cells [38, 39]. In addition, Cx43 is also
implicated in hematopoiesis. During the quiescent state,
undifferentiated HSC (Lin−, Sca1+, C-kit+) do not express
Cx43 mRNA . However, Cx43 expression can be
massively up-regulated in adult mouse bone marrow upon
forced stem cell division . Cx43 deficient mice also
demonstrate clear defects in blood cell formation .
However, it is not clear whether this effect is mediated by
functional gap junctions or by connexon hemichannels.
Moreover, it remains unclear whether GJIC among HSC or
between HSC and stromal cells is important in defining the
stem cell niche. Thus, further research is needed to provide
a definitive role of GJIC in HSC.
Mesenchymal Stem Cells
Mesenchymal stem cells (MSC) have been isolated from
various tissues, including bone, umbilical cord blood and
adipose [8, 123]. They can readily differentiate into adipose
tissue, tendon, cartilage and bone . Human MSC
express Cx40, Cx43 and Cx45, and can communicate
among themselves via gap junctions [59, 116]. However, a
rare population of MSC was shown to be deficient in GJIC
. The exact identity of this MSC population remains
unknown. Moreover, human MSC were demonstrated to
form Cx43-mediated GJIC with umbilical vein endothelial
cells, where this communication is important for osteogenic
differentiation of MSC .
Neural Stem Cells
Neural stem cells exist in the developing or adult nervous
system and can differentiate into all neural cell types,
including neurons, astrocytes and oligodendrocytes .
Neural stem cells isolated from the rat developing brain
express Cx43 and Cx45 and are capable of forming GJIC,
where GJIC is essential for survival and proliferation in
these cells . Moreover, Cx43 and Cx32 levels were
observed to increase temporarily during differentiation in
these cells . Future studies on human neural stem
cells will help address whether this role of gap junctions is
conserved among species. Similarly in mouse fetal neural
progenitors, the closure of gap junctions decreases cell
proliferation and diminishes cell survival [17, 24]. On the
other hand, overexpression of Cx43 stimulates cell
proliferation in these cells . In addition, neural
progenitors from other species have been demonstrated
to express connexin and communicate via GJIC, possibly
suggesting a conserved role of gap junction in neural stem
cell biology. The astroglial progenitor cell line TB2,
isolated from the fish brain, expresses Cx43 and Cx35
. In the turtle, the spinal cord neural progenitors
express Cx43 and are electrically and metabolically
coupled via gap junctions . Together, it appears that
gap junctions are critical to maintaining neural stem cell
homeostasis, both in self-renewal and early stages of
Other Somatic Stem Cells
Although GJIC seems to play a role in regulating many
somatic stem cell types, gap junctions are absent in some
somatic stem cells. This included two somatic stem cells
that give rise to the epithelium, keratinocyte stem cells 
and corneal epithelial stem cells , both of which lack
connexins and functional GJIC. A number of presumptive
somatic stem cells were also demonstrated to lack func-
tional GJIC, including pancreatic ductal epithelial stem
cells , neural–glial stem cells , bovine mammary
gland progenitor cells , human breast epithelial stem
cells  and human kidney epithelial stem cells .
288 Stem Cell Rev (2008) 4:283–292
However, in some cases the identification of the cell
populations studied as stem cells is questionable, and
further characterization is needed to confirm their potential
for self renewal and differentiation. Altogether, it appears
that intercellular communication via gap junctions is not a
universal feature of all somatic stem cells. Although the
function of gap junctions seems to be highly dependent on
the cell type, previous reports demonstrated that functional
GJIC plays a critical role in regulating the cell fates of
many somatic stem cells.
As the reader can appreciate, the role of gap junctions in
stem cells requires further research and remains an
important research question. Emerging evidence suggests
that gap junctions seem to play an important role in
regulating the cell fate of ES cells, neural stem cells,
mesenchymal stem cells and possibly hematopoietic stem
cells. However, the precise role of gap junctions appears to
be highly dependent on the type of stem cells. This is not
surprising, given the biological differences between somatic
stem cells and ES cells. To date, several key questions
remain to be addressed: Is GJIC a defining feature of the
stem cell niche that maintains homeostasis of somatic stem
cells? During commitment and differentiation, do stem cells
form ‘communication compartments’ where GJIC is re-
stricted to only cells with similar cell fate? If so, what is the
role of the specific connexin isoforms? Does the formation
of communication compartment enhance cellular commit-
ment and differentiation? Which intracellular molecules
that diffuse through gap junction are responsible for such
effects? One interesting candidate is microRNA that
diffuses through gap junctions , given the increasing
appreciation of the important role of microRNA in directing
stem cell fate . Indeed, recently it was demonstrated in
hESC that siRNA are able to move through gap junctions to
affect gene expression of the neighbouring cells . The
identification of molecules that mediate intercellular com-
munication through gap junctions will be an important step
towards the elucidation of regulatory mechanisms of stem
cell survival, differentiation and proliferation. Studies on
gap junctions in stem cells can potentially lead to the
development of novel methods in expanding stem cells in
vitro, directing their differentiation into functional mature
cells or cancer treatment that target particular cancer stem
Institute of Regenerative Medicine, the University of Melbourne and
the National Health and Medical Research Council of Australia
This work was supported by the California
important molecules between cells through gap junction channels.
Current Medicinal Chemistry, 10(19), 2045–2058.
2. Assou, S., Lecarrour, T., et al. (2007). A meta-analysis of human
embryonic stem cells transcriptome integrated into a web-based
expression atlas. Stem Cells, 25, 961–973.
3. Avanzo, J. L., Mesnil, M., et al. (2004). Increased susceptibility
to urethane-induced lung tumors in mice with decreased
expression of connexin43. Carcinogenesis, 25(10), 1973–1982.
4. Bani-Yaghoub, M., Bechberger, J. F., et al. (1997). Reduction of
connexin43 expression and dye-coupling during neuronal differ-
entiation of human NTera2/clone D1 cells. Journal of Neurosci-
ence Research, 49(1), 19–31.
5. Becker, D. L., Evans, W. H., et al. (1995). Functional analysis of
amino acid sequences in connexin43 involved in intercellular
communication through gap junctions. Journal of Cell Science,
108(Pt 4), 1455–1467.
6. Belliveau, D. J., Bechberger, J. F., et al. (1997). Differential
expression of gap junctions in neurons and astrocytes derived
from P19 embryonal carcinoma cells. Developmental Genetics,
7. Beqqali, A., Kloots, J., et al. (2006). Genome-wide transcrip-
tional profiling of human embryonic stem cells differentiating to
cardiomyocytes. Stem Cells, 24(8), 1956–1967.
8. Bernacki, S. H., Wall, M. E., et al. (2008). Isolation of human
mesenchymal stem cells from bone and adipose tissue. Methods
in Cell Biology, 86, 257–278.
9. Bevilacqua, A., Loch-Caruso, R., et al. (1989). Abnormal
development and dye coupling produced by antisense RNA to
gap junction protein in mouse preimplantation embryos. Pro-
ceedings of National Academy of Sciences of United States of
America, 86(14), 5444–5448.
10. Bhattacharya, B., Cai, J., et al. (2005). Comparison of the gene
expression profile of undifferentiated human embryonic stem cell
lines and differentiating embryoid bodies. BMC Developmental
Biology, 5, 22.
11. Bhattacharya, B., Miura, T., et al. (2004). Gene expression in
human embryonic stem cell lines: unique molecular signature.
Blood, 103(8), 2956–2964.
12. Bloor, D. J., Wilson, Y., et al. (2004). Expression of connexins in
human preimplantation embryos in vitro. Reproductive Biology
and Endocrinology, 2, 25.
13. Boyer, L. A., Lee, T. I., et al. (2005). Core transcriptional
regulatory circuitry in human embryonic stem cells. Cell, 122(6),
14. Cai, J., Cheng, A., et al. (2004). Membrane properties of rat
embryonic multipotent neural stem cells. Journal of Neurochem-
istry, 88(1), 212–226.
15. Carpenter, M. K., Rosler, E. S., et al. (2004). Properties of four
human embryonic stem cell lines maintained in a feeder-free
culture system. Developmental Dynamics, 229(2), 243–258.
16. Chang, C. C., Trosko, J. E., et al. (1987). Contact insensitivity of
a subpopulation of normal human fetal kidney epithelial cells
and of human carcinoma cell lines. Cancer Research, 47(6),
17. Cheng,A.,Tang,H.,etal.(2004).Gap junctionalcommunicationis
required to maintain mouse cortical neural progenitor cells in a
proliferative state. Developments in Biologicals, 272(1), 203–216.
18. Chung, Y., Klimanskaya, I., et al. (2008). Human embryonic
stem cell lines generated without embryo destruction. Cell Stem
Cell, 2(2), 113–117.
19. Dahl, E., Winterhager, E., et al. (1996). Expression of the gap
junction proteins connexin31 and connexin43 correlates with
Stem Cell Rev (2008) 4:283–292289289
communication compartments in extraembryonic tissues and in
the gastrulating mouse embryo, respectively. Journal of Cell
Science, 109(Pt 1), 191–197.
20. Dale, B., Gualtieri, R., et al. (1991). Intercellular communication
in the early human embryo. Molecular Reproduction and
Development, 29(1), 22–28.
21. Davies, T. C., Barr, K. J., et al. (1996). Multiple members of the
connexin gene family participate in preimplantation development
of the mouse. Developmental Genetics, 18(3), 234–243.
22. De Maio, A., Vega, V., et al. (2002). Gap junctions, homeostasis,
and injury. Journal of Cellular Physiology, 191(3), 269–282.
23. Dowling-Warriner, C. V., & Trosko, J. E. (2000). Induction of gap
junctional intercellular communication, connexin43 expression, and
subsequent differentiation in human fetal neuronal cells by stimula-
tion of the cyclic AMP pathway. Neuroscience, 95(3), 859–868.
24. Duval, N., Gomes, D., et al. (2002). Cell coupling and Cx43
expression in embryonic mouse neural progenitor cells. Journal
of Cell Science, 115(Pt 16), 3241–3251.
25. Ebihara,L.(2003).Newrolesforconnexons.News in Physiological
Sciences, 18, 100–103.
junction protein connexin45-deficient embryonic stem cell-derived
cardiac myocytes. The Anatomical Record. Part A, Discoveries in
Molecular, Cellular, and Evolutionary Biology, 280(2), 973–979.
27. Elfgang, C., Eckert, R., et al. (1995). Specific permeability and
selective formation of gap junction channels in connexin-trans-
fected HeLa cells. Journal of Cell Biology, 129(3), 805–817.
28. Engel, A., & Muller, D. J. (2000). Observing single biomole-
cules at work with the atomic force microscope. Nature
Structural Biology, 7(9), 715–718.
29. Enver, T., Soneji, S., et al. (2005). Cellular differentiation
hierarchies in normal and culture-adapted human embryonic
stem cells. Human Molecular Genetics, 14(21), 3129–3140.
30. Evans, M. J., & Kaufman, M. H. (1981). Establishment in
culture of pluripotential cells from mouse embryos. Nature, 292
31. Evans, W. H., De Vuyst, E., et al. (2006). The gap junction
cellular internet: connexin hemichannels enter the signalling
limelight. Biochemical Journal, 397(1), 1–14.
32. Gage, F. H. (2000). Mammalian neural stem cells. Science, 287
33. Giepmans, B. N. (2004). Gap junctions and connexin-interacting
proteins. Cardiovascular Research, 62(2), 233–245.
34. Goodall, H., & Maro, B. (1986). Major loss of junctional
coupling during mitosis in early mouse embryos. Journal of Cell
Biology, 102(2), 568–575.
35. Goodenough, D. A., Goliger, J. A., et al. (1996). Connexins,
connexons, and intercellular communication. Annual Reviews of
Biochemical, 65, 475–502.
36. Goodenough, D. A., & Paul, D. L. (2003). Beyond the gap:
functions of unpaired connexon channels. Nature Reviews.
Molecular Cell Biology, 4(4), 285–294.
37. Hardy, K., Warner, A., et al. (1996). Expression of intercellular
junctions during preimplantation development of the human
embryo. Molecular Human Reproduction, 2(8), 621–632.
38. Hirabayashi, Y., Yoon, B. I., et al. (2007a). Membrane channel
connexin 32 maintains Lin(-)/c-kit(+) hematopoietic progenitor
cell compartment: analysis of the cell cycle. Journal of
Membrane Biology, 217(1–3), 105–113.
39. Hirabayashi, Y., Yoon, B. I., et al. (2007b). Protective role of
connexin 32 in steady-state hematopoiesis, regeneration state,
and leukemogenesis. Experimental Biology and Medicine (May-
wood), 232(5), 700–712.
40. Holland, M. S., Tai, M. H., et al. (2003). Isolation and
differentiation of bovine mammary gland progenitor cell popula-
tions. American Journal of Veterinary Research, 64(4), 396–403.
41. Houghton, F. D. (2005). Role of gap junctions during early
embryo development. Reproduction, 129(2), 129–135.
42. Houghton, F. D., Barr, K. J., et al. (2002). Functional
significance of gap junctional coupling in preimplantation
development. Biology of Reproduction, 66(5), 1403–1412.
43. Huang, Y. J., Maruyama, Y., et al. (2007). The role of pannexin 1
hemichannels in ATP release and cell–cell communication in
mouse taste buds. Proceedings of National Academy of Sciences
of the United State of America, 104(15), 6436–6441.
44. Huettner, J. E., Lu, A., et al. (2006). Gap junctions and connexon
hemichannels in human embryonic stem cells. Stem Cells, 24(7),
45. Kalimi, G. H., & Lo, C. W. (1988). Communication compart-
ments in the gastrulating mouse embryo. Journal of Cell Biology,
46. Kalimi, G. H., & Lo, C. W. (1989). Gap junctional communi-
cation in the extraembryonic tissues of the gastrulating mouse
embryo. Journal of Cell Biology, 109(6 Pt 1), 3015–3026.
47. Kao, C. Y., Nomata, K., et al. (1995). Two types of normal
human breast epithelial cells derived from reduction mammo-
plasty: phenotypic characterization and response to SV40
transfection. Carcinogenesis, 16(3), 531–538.
48. Kiel, M. J., He, S., et al. (2007). Haematopoietic stem cells do
not asymmetrically segregate chromosomes or retain BrdU.
Nature, 449(7159), 238–242.
49. King, T. J., Fukushima, L. H., et al. (2000). Correlation between
growth control, neoplastic potential and endogenous connexin43
expression in HeLa cell lines: implications for tumor progres-
sion. Carcinogenesis, 21(2), 311–315.
50. Knoblich, J. A. (2008). Mechanisms of asymmetric stem cell
division. Cell, 132(4), 583–597.
51. Krutovskikh, V. A., Yamasaki, H., et al. (1998). Inhibition of
intrinsic gap-junction intercellular communication and enhance-
ment of tumorigenicity of the rat bladder carcinoma cell line
BC31 by a dominant-negative connexin 43 mutant. Molecular
Carcinogenesis, 23(4), 254–261.
52. Krysko, D. V., Leybaert, L., et al. (2005). Gap junctions and the
propagation of cell survival and cell death signals. Apoptosis, 10
53. Kumar, N. M., & Gilula, N. B. (1996). The gap junction
communication channel. Cell, 84(3), 381–388.
54. Kwak, B. R., & Jongsma, H. J. (1996). Regulation of cardiac gap
junction channel permeability and conductance by several
phosphorylating conditions. Molecular and Cellular Biochemis-
try, 157(1–2), 93–99.
55. Lai, C. P., Bechberger, J. F., et al. (2007). Tumor-suppressive
effects of pannexin 1 in C6 glioma cells. Cancer Research, 67
56. Laird, D. W. (2005). Connexin phosphorylation as a regulatory
event linked to gap junction internalization and degradation.
Biochimica et Biophysica Acta, 1711(2), 172–182.
57. Lampe, P. D., & Lau, A. F. (2004). The effects of connexin
phosphorylation on gap junctional communication. International
Journal of Biochemistry & Cell Biology, 36(7), 1171–1186.
58. Lee, S., Gilula, N. B., et al. (1987). Gap junctional communi-
cation and compaction during preimplantation stages of mouse
development. Cell, 51(5), 851–860.
59. Lin, T. M., Chang, H. W., et al. (2007). Isolation and
identification of mesenchymal stem cells from human lipoma
tissue. Biochemical and Biophysical Research Communications,
60. Litvin, O., Tiunova, A., et al. (2006). What is hidden in the
pannexin treasure trove: the sneak peek and the guesswork.
Journal of Cellular and Molecular Medicine, 10(3), 613–634.
61. Liu, Y., Shin, S., et al. (2006). Genome wide profiling of human
embryonic stem cells (hESCs), their derivatives and embryonal
290Stem Cell Rev (2008) 4:283–292
carcinoma cells to develop base profiles of U.S. Federal
government approved hESC lines. BMC Developmental Biology,
62. Lo, C. W. (1996). The role of gap junction membrane channels
in development. Journal of Bioenergetics and Biomembranes, 28
63. Lo, C. W., & Gilula, N. B. (1979a). Gap junctional communication
in the post-implantation mouse embryo. Cell, 18(2), 411–422.
64. Lo, C. W., & Gilula, N. B. (1979b). Gap junctional communica-
tion in the preimplantation mouse embryo. Cell, 18(2), 399–409.
65. Loewenstein, W. R. (1979). Junctional intercellular communica-
tion and the control of growth. Biochimica et Biophysica Acta,
66. Loewenstein, W. R., & Kanno, Y. (1966). Intercellular commu-
nication and the control of tissue growth: lack of communication
between cancer cells. Nature, 209(5029), 1248–1249.
67. Loewenstein, W. R., & Kanno, Y. (1967). Intercellular commu-
nication and tissue growth. I. Cancerous growth. Journal of Cell
Biology, 33(2), 225–234.
68. Loewenstein, W. R., & Rose, B. (1992). The cell–cell channel in
the control of growth. Seminars in Cell & Biology, 3(1), 59–79.
69. Martin, G. R. (1981). Isolation of a pluripotent cell line from
early mouse embryos cultured in medium conditioned by
teratocarcinoma stem cells. Proceedings of National Academy
of Sciences of the United State of America, 78(12), 7634–7638.
70. Martin, P. E., & Evans, W. H. (2004). Incorporation of connexins
into plasma membranes and gap junctions. Cardiovascular
Research, 62(2), 378–387.
71. Matic, M., Evans, W. H., et al. (2002). Epidermal stem cells do
not communicate through gap junctions. Journal of Investigative
Dermatology, 118(1), 110–116.
72. Matic, M., Petrov, I. N., et al. (1997). Stem cells of the corneal
epithelium lack connexins and metabolite transfer capacity.
Differentiation, 61(4), 251–260.
73. McCulloch, E. A., & Till, J. E. (2005). Perspectives on the
properties of stem cells. Natural Medicines, 11(10), 1026–1028.
74. Melton, D. a., & Cowan, C. (2004). ‘Stemness’: Definitions,
criteria and standards. In R. Lanza, J. Gearhart, B. Hogan, D.
Melton, R. Pedersen, J. Thomson, & M. West (Eds.), Handbook
of stem cells, Vol. 1. Amsterdam: Elsevier.
75. Mesnil, M., Crespin, S., et al. (2005). Defective gap junctional
intercellular communication in the carcinogenic process. Biochi-
mica et Biophysica Acta, 1719(1–2), 125–145.
76. Mesnil, M., & Yamasaki, H. (2000). Bystander effect in herpes
simplex virus-thymidine kinase/ganciclovir cancer gene therapy:
role of gap-junctional intercellular communication. Cancer
Research, 60(15), 3989–3999.
77. Mimeault, M., & Batra, S. K. (2006). Concise review: recent
advances on the significance of stem cells in tissue regeneration
and cancer therapies. Stem Cells, 24(11), 2319–2345.
78. Montecino-Rodriguez, E., Leathers, H., et al. (2000). Expression
of connexin 43 (Cx43) is critical for normal hematopoiesis.
Blood, 96(3), 917–924.
79. Moreno, A. P. (2005). Connexin phosphorylation as a regulatory
event linked to channel gating. Biochimica et Biophysica Acta,
80. Neijssen, J., Herberts, C., et al. (2005). Cross-presentation by
intercellular peptide transfer through gap junctions. Nature, 434
81. Nishi, M., Kumar, N. M., et al. (1991). Developmental
regulation of gap junction gene expression during mouse
embryonic development. Developments in Biologicals, 146(1),
82. Orford, K. W., & Scadden, D. T. (2008). Deconstructing stem
cell self-renewal: genetic insights into cell-cycle regulation.
Nature Reviews. Genetics, 9(2), 115–128.
83. Oviedo, N. J., & Levin, M. (2007). smedinx-11 is a planarian
stem cell gap junction gene required for regeneration and
homeostasis. Development, 134(17), 3121–3131.
84. Oyamada, M., Oyamada, Y., et al. (2005). Regulation of connexin
expression. Biochimica et Biophysica Acta, 1719(1–2), 6–23.
85. Oyamada, Y., Komatsu, K., et al. (1996). Differential regulation
of gap junction protein (connexin) genes during cardiomyocytic
differentiation of mouse embryonic stem cells in vitro. Experi-
mental Cell Research, 229(2), 318–326.
86. Panchin, Y., Kelmanson, I., et al. (2000). A ubiquitous family of
putative gap junction molecules. Current Biology, 10(13), R473–
87. Panchin, Y. V. (2005). Evolution of gap junction proteins—the
pannexin alternative. Journal of Experimental Biology, 208(Pt 8),
88. Parekkadan, B., Berdichevsky, Y., et al. (2008). Cell–cell
interaction modulates neuroectodermal specification of embry-
onic stem cells. Neuroscience Letters, 438(2), 190–195.
89. Pebay, A., Wong, R. C., et al. (2005). Essential roles of
sphingosine-1-phosphate and platelet-derived growth factor in
the maintenance of human embryonic stem cells. Stem Cells, 23
90. Penn, R. D. (1966). Ionic communication between liver cells.
Journal of Cell Biology, 29(1), 171–174.
91. Pera, M. F., Reubinoff, B., et al. (2000). Human embryonic stem
cells. Journal of Cell Science, 113(Pt 1), 5–10.
92. Phinney, D. G., & Prockop, D. J. (2007). Concise review:
mesenchymal stem/multipotent stromal cells: the state of trans-
differentiation and modes of tissue repair—current views. Stem
Cells, 25(11), 2896–2902.
93. Pittenger, M. F., Mackay, A. M., et al. (1999). Multilineage
potential of adult human mesenchymal stem cells. Science, 284
94. Ploemacher, R. E., Mayen, A. E., et al. (2000). Hematopoiesis:
gap junction intercellular communication is likely to be involved
in regulation of stroma-dependent proliferation of hemopoietic
stem cells. Hematology, 5(2), 133–147.
95. Qin, H., Shao, Q., et al. (2002). Retroviral delivery of connexin
genes to human breast tumor cells inhibits in vivo tumor growth
by a mechanism that is independent of significant gap junctional
intercellular communication. Journal of Biological Chemistry,
96. Reubinoff, B. E., Pera, M. F., et al. (2000). Embryonic stem cell
lines from human blastocysts: somatic differentiation in vitro.
Nature Biotechnology, 18(4), 399–404.
97. Revel, J. P., & Karnovsky, M. J. (1967). Hexagonal array of
subunits in intercellular junctions of the mouse heart and liver.
Journal of Cell Biology, 33(3), C7–C12.
98. Richards, M., Tan, S. P., et al. (2004). The transcriptome profile
of human embryonic stem cells as defined by SAGE. Stem Cells,
99. Rosendaal, M., Green, C. R., et al. (1994). Up-regulation of the
connexin43+ gap junction network in haemopoietic tissue before
thegrowthofstemcells.Journal of Cell Science, 107(Pt 1), 29–37.
100. Rosendaal, M., Mayen, A., et al. (1997). Does transmembrane
communication through gap junctions enable stem cells to
overcome stromal inhibition? Leukemia, 11(8), 1281–1289.
101. Ruch, R. J., & Trosko, J. E. (2001). Gap-junction communica-
tion in chemical carcinogenesis. Drug Metabolism Reviews, 33
102. Russo, R. E., Reali, C., et al. (2008). Connexin 43 delimits
functional domains of neurogenic precursors in the spinal cord.
Journal of Neuroscience, 28(13), 3298–3309.
103. Saez, J. C., Berthoud, V. M., et al. (2003). Plasma membrane
channels formed by connexins: Their regulation and functions.
Physiological Reviews, 83(4), 1359–1400.
Stem Cell Rev (2008) 4:283–292 291291
104. Sosinsky, G. E., & Nicholson, B. J. (2005). Structural organiza-
tion of gap junction channels. Biochimica et Biophysica Acta,
105. Sperger, J. M., Chen, X., et al. (2003). Gene expression patterns
in human embryonic stem cells and human pluripotent germ cell
tumors. Proceedings of National Academy of Sciences of the
United State of America, 100(23), 13350–13355.
106. Stein, L. S., Boonstra, J., et al. (1992). Reduced cell–cell
communication between mitotic and nonmitotic coupled cells.
Experimental Cell Research, 198(1), 1–7.
107. Stojkovic, M., Lako, M., et al. (2004). Derivation of human
embryonic stem cells from day-8 blastocysts recovered after
three-step in vitro culture. Stem Cells, 22(5), 790–797.
108. Strelchenko, N., Verlinsky, O., et al. (2004). Morula-derived
human embryonic stem cells. Reproductive Biomedicine Online,
109. Tai, M. H., Olson, L. K., et al. (2003). Characterization of gap
junctional intercellular communication in immortalized human
pancreatic ductal epithelial cells with stem cell characteristics.
Pancreas, 26(1), e18–e26.
110. Temme, A., Buchmann, A., et al. (1997). High incidence of
spontaneous and chemically induced liver tumors in mice
deficient for connexin32. Current Biology, 7(9), 713–716.
111. Thomson, J. A., Itskovitz-Eldor, J., et al. (1998). Embryonic stem
cell lines derived from human blastocysts. Science, 282(5391),
112. Todorova, M. G., Soria, B., et al. (2008). Gap junctional
intercellular communication is required to maintain embryonic
stem cells in a non-differentiated and proliferative state. Journal
of Cellular Physiology, 214(2), 354–362.
113. Traver, D. a. & Akashi, K. (2004). Common myeloid progeni-
tors. In Handbook of Stem Cells (M. a. T. 2005), Elsevier 1.
114. Trosko, J. E. (2003). Human stem cells as targets for the aging
and diseases of aging processes. Medical Hypotheses, 60(3),
115. Valiunas, V., Bukauskas, F. F., et al. (1997). Conductances and
selective permeability of connexin43 gap junction channels
examined in neonatal rat heart cells. Circulation Research, 80
116. Valiunas, V., Doronin, S., et al. (2004). Human mesenchymal
stem cells make cardiac connexins and form functional gap
junctions. Journal of Physiology, 555(Pt 3), 617–626.
117. Valiunas, V., Polosina, Y. Y., et al. (2005). Connexin-specific
cell-to-cell transfer of short interfering RNA by gap junctions.
Journal of Physiology, 568(Pt 2), 459–468.
118. Vance, M. M., & Wiley, L. M. (1999). Gap junction intercellular
communication mediates the competitive cell proliferation
disadvantage of irradiated mouse preimplantation embryos in
aggregation chimeras. Radiation Research, 152(5), 544–551.
119. Verfaillie, C. M., Pera, M. F., et al. (2002). Stem cells: hype and
reality. Hematology (American Society of Hematology. Education
120. Villars, F., Guillotin, B., et al. (2002). Effect of HUVEC on
human osteoprogenitor cell differentiation needs heterotypic gap
junction communication. American Journal of Physiology. Cell
Physiology, 282(4), C775–C785.
121. Vine, A. L., & Bertram, J. S. (2002). Cancer chemoprevention by
connexins. Cancer Metastasis Reviews, 21(3–4), 199–216.
122. Wei, C. J., Xu, X., et al. (2004). Connexins and cell signaling in
development and disease. Annual Review of Cell and Develop-
mental Biology, 20, 811–838.
123. Weiss, M. L., & Troyer, D. L. (2006). Stem cells in the umbilical
cord. Stem Cell Reviews, 2(2), 155–162.
124. Wen, C. M., Cheng, Y. H., et al. (2008). Isolation and
characterization of a neural progenitor cell line from tilapia
brain. Comparative Biochemistry and Physiology. Part A,
Molecular & Integrative Physiology, 149(2), 167–180.
125. Willecke, K., Eiberger, J., et al. (2002). Structural and functional
diversity of connexin genes in the mouse and human genome.
Biological Chemistry, 383(5), 725–737.
126. Wolvetang, E. J., Pera, M. F., et al. (2007). Gap junction
mediated transport of shRNA between human embryonic stem
cells. Biochemical and Biophysical Research Communications,
127. Wong, R. C., Dottori, M., et al. (2006). Gap junctions modulate
apoptosis and colony growth of human embryonic stem cells
maintained in a serum-free system. Biochemical and Biophysical
Research Communications, 344(1), 181–188.
128. Wong, R. C., Pebay, A., et al. (2004). Presence of functional gap
junctions in human embryonic stem cells. Stem Cells, 22(6),
129. Worsdorfer, P., Maxeiner, S., et al. (2008). Connexin expression
and functional analysis of gap junctional communication in
mouse embryonic stem cells. Stem Cells, 26(2), 431–439.
130. Yamasaki, H., Krutovskikh, V., et al. (1999). Role of connexin
(gap junction) genes in cell growth control and carcinogenesis.
Comptes Rendus de l’AcadeÂmie des Sciences III, 322(2–3),
131. Yang, S. R., Cho, S. D., et al. (2005). Role of gap junctional
intercellular communication (GJIC) through p38 and ERK1/2
pathway in the differentiation of rat neuronal stem cells. Journal
of Veterinary Medical Science, 67(3), 291–294.
132. Zhang, B., Pan, X., et al. (2006). MicroRNA: a new player in
stem cells. Journal of Cellular Physiology, 209(2), 266–269.
292Stem Cell Rev (2008) 4:283–292
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