Although DNA methylation has been studied extensively,
hypomethylation patterns cannot be designated as sole master switches for
controlling gene expression and the maintenance of pluripotency in mESC.
However, an increase in DNA methylation has been noted in selected CpG islands,
in a few hESC lines during long-term passages (Allegrucci
C et al., 2007).
Comparison of promoter DNA methylation in mESCs with histone modifications,
binding of transcription factors such as Oct4, Nanog, and polycomb group of proteins on gene promoters, has been
performed to analyse if epigenetic regulators act independently or in concert
with each other. Consequently, it was found that promoter DNA methylation is
the only marker found on more than 30% of genes, many of which are silenced in
mESCs (Meissner A et al., 2008). Genome-wide analysis of
DNA methylation of promoters in mESCs and pMEFs (primary mouse embryonic
fibroblasts) showed differences in methylation involving 69 gene promoters
predicted to be hypomethylated in ESCs, and methylated in pMEFs (Farthing CR et al., 2008).
These studies suggest that methylation patterns in ESCs may be distinctly
different from differentiated somatic cells. Some of the interactions
described in the above section are unique to ESCs and are possibly instrumental
in maintaining the stem cell state. Of the cytoplasmic signals, the
Activin/Nodal/FGF2 pathways are thought to maintain hESCs, while LIF/STAT3 is
necessary for mESCs. Epigenetically the repression of gene promoters related to
differentiation in spite of the chromosomes being largely euchromatic seems to
be a characteristic. This along with expression of relatively high levels of
proteins related to pluripotence including Oct4, c-Myc and Nanog are hallmarks
of the undifferentiated state of ESCs.
III. Lessons from somatic stem cells
Unlike embryonic stem cells,
somatic stem cells are restricted in their potential and reside in tissues of
developing or mature organs. Among the best studied of the SSCs are
hematopoietic stem cells (HSCs), neural stem cells (NSCs), and mesenchymal stem
cells (MSCs). While HSCs reside in bone marrow NSCs as the name suggests, reside
largely in the nervous system. Stem cells may also be identified in other
tissues including epidermis, intestine, breast, and retinal tissue, and potentially
in muscle and pancreas.
As discussed in the previous
section ESCs retain the potential to differentiate into most, if not all, the
tissues which constitute the adult organism, hence pluripotent. SSCs on the
other hand are multipotent and have restricted differentiation potential. They
usually retain the capacity to differentiate into some, or all, of the cell
types, which constitute the tissue that they reside within. Typically they
reside in 'niches' within the tissue which provide the necessary environment to
maintain a regulated number of stem cells in a state of quiescence, and which
can be effectively mobilized when appropriately stimulated. Unraveling the
factors and mechanisms which maintain niches will allow us to configure
appropriate culture conditions and further the practical use of these cells. When
one considers the various biological events, which might contribute to the
multipotentiality of SSCs, they might include maintenance of quiescence, which
could promote the maintenance of a stable stem-like phenotype in a mature
tissue, cell proliferation, cell survival, and inhibition of commitment and
differentiation.
The niche that SSCs reside in is
largely comprised of some relevant cell types native to the region and their
intrinsic and secreted principles, the blood vessels which carry soluble
factors, and the extra cellular matrix which possibly contains immobilized cues
(Alvarez-Buylla A and Lim DA, 2004, Kiel MJ and Morrison SJ,
2008). While
there is a possibility that there are two niches for HSCs, one osteoblastic and
the other vascular, it is also possible that these two niches actually serve to
maintain distinct functions of the HSCs during its life as a stem cell. The
osteoblastic niche may serve to maintain the cell at its peak of quiescence,
while the vascular niches might play a greater role during proliferation and
mobilization of these cells as and when required. The Tie-2 receptor along with
its ligand angiopoietin is thought to be one of the major regulators of
quiescence of HSCs (Arai F and Suda T, 2007, Fukuhara S et al., 2008). This receptor has intrinsic
tyrosine kinase activity and functions through the PI3kinase pathway to
maintain p21 levels thus maintaining quiescence. Osteopontin also serves to inhibit differentiation in the
niche (Nilsson SK et al., 2005, Stier S et al., 2005). The mammalian target of rapamycin
(mTOR) pathway could mediate HSC quiescence and maintenance by regulating
reactive oxygen species (Chen C et al., 2008). Wnt and Jagged are
expressed on osteoblasts and react with their respective receptors Frizzled and
Notch on HSCs and are involved in controlling the maintenance of HSCs (Fleming HE et al., 2008, Li L et al., 1998). Interestingly Notch 1 is
down-regulated in HSCs lacking Smad 4, which could be a possible mechanism by
which smad4 is one of the factors involved in the maintenance and self-renewal
of HSCs (Karlsson G et al., 2007). The calcium calmodulin
dependent kinase (CaM Kinase) present in HSCs appears to participate in their
maintenance by regulating bcl-2 levels through phosphorylation of CREB and CBP (Kitsos CM et al., 2005). Other molecules which
regulate the niche include sonic hedgehog (Shh), CXCR4/CXCL12, and SCF/c-Kit (Kiel MJ and Morrison SJ, 2008).
While the NSC niche is in the
process of being defined (Riquelme PA et al., 2008), the molecules that seem
to be required for maintaining a pool of stem cells include Shh, Notch, Wnt,
and FGF. GFAP positive neural stem
cells were reduced in the sub-ventricular zone of Gli deficient animals,
suggesting that Shh regulated the number of stem cells in vivo. In addition, the number of dividing cells as determined by
BrdU staining, was also decreased (Palma V and Ruiz i Altaba A, 2004). Basic FGF (bFGF) is
sufficient as a mitogen in monolayer cultures of NSCs, and is used in
combination with EGF for neurosphere cultures (Johe KK et al., 1996, Reynolds BA and Weiss S, 1996). Both signal through the
Ras/MAPK pathway, although EGF activates several other pathways in these cells
including PI3kinase. In addition to these growth factor mediated effects, the
polycomb protein Bmi1 is thought to function in the regulation of both the HSC
and NSC population in the adult (Molofsky AV et al., 2003, Park IK et al., 2003). Recently Wnts have been
shown to be relevant to the self renewal of stem cells in the brain (Kalani MY et al., 2008). Notch could mediate
possible density-related effects in NSC cultures (Kamakura S et al., 2004), while both Notch and BMPs
cause differentiation effects, the latter of which are rather complex and yield
three fates depending on the culture conditions: neurons, glia and smooth
muscle (Rajan P et al., 2003). Manipulation of
differentiation signals could also promote the maintenance of multipotency. Signals
which activate neurogenin appear to cause neuronal fate choice, while we and
others have shown that the activation of STAT3 is required for glial
differentiation (Bonni A et al., 1997, Rajan P and McKay RD, 1998, Sun Y et
al., 2001).
Activation of STAT3, and glial differentiation, could be brought about by JAK
downstream of CNTF/LIF, mTOR downstream of BMP, and possibly MAPK downstream of
CNTF and EGF. Other studies have
shown that p300 works cooperatively with STAT3 and Smad to cause glial differentiation
under BMP treatment (Nakashima K et al., 1999). While several of the
signaling studies have been performed on rodent systems for ease of work, some
of these have been verified in human cells, particularly when there is
relevance to cancer. Some of these pathways and their interactions have been
recently reviewed (Rajan P and Snyder E, 2009).
MSCs were originally isolated and
cultured from bone marrow, and are fibroblastic cells which have the potential
for differentiation into adipocytic, chondrocytic and osteoblastic lineages,
and also into muscle and tendons (Pittenger MF et al., 1999). MSC-like cells have
subsequently been cultured from adipose tissue, umbilical cord, Wharton's jelly
and placenta. They are arguably the stem cells which are the easiest to culture
and manipulate, and several cell surface markers are used in the
characterization of these cells (Majumdar MK et al., 1998). Stro1 is sometimes used
as a prospective marker for these cells, although it is not unique to them, and
recently other markers have been suggested for MSCs (Roche S et al., 2009, Simmons PJ et al., 1994). Although serum is the
most commonly used culture additive, bFGF, LIF, HGF, Wnt, EGF and PDGF
contribute to the maintenance of MSCs (Kolf CM et al., 2007).
Alternative approaches are
yielding some windows into the complex methods, which are operational in SSCs
and stem cells in general. Systems biology has proved to be an excellent tool
for generating hypotheses relating to molecules which may be associated with,
or characteristic of, a particular fate or event (Muller FJ et al., 2008, Ulloa-Montoya F et al., 2007). Some such studies have
implicated molecules such as Gata2 as being instrumental in de-differentiation
of mature somatic cells into a SSC like state (Huang TS et al., 2008). Other molecules which are
associated with the somatic stem cell state include Angiopoietin1, Kit, Sox9,
Timp3, and several genes which are also present in ESCs (Forsberg EC et al., 2005, Huang TS et al., 2008). Creative methods to
activate specific receptor and downstream kinases have yielded interesting
insights. Dimerisation of the thrombopoietin receptor, mpl1, by an artificial
crosslinking method causes HSCs to proliferate for appreciable longer periods
than is achieved in culture with known means, and certainly more than is
obtained with receptor dimerisation with the natural ligand (Abdel-Azim H et al., 2008). The factors and active
principles which maintain other stem cells including epidermal, intestinal and
breast are in the process of being defined (Blanpain C and Fuchs E, 2009, Sato T et al., 2009, Scoville
DH et al., 2008). Recently transcription factors such as
Achaete-Scute have been implicated in intestinal stem cell maintenance (van der Flier LG et al., 2009).
While Oct 4, Nanog, Sox2, and
other genes are largely associated with the pluripotent state of ESCs, they
have also been seen to be expressed in NSCs, MSCs and HSCs to varying degrees.
One study showed that the lack of Oct4 does not compromise the maintenance of
somatic stem cells (Lengner CJ et al., 2007, Lengner CJ et al., 2008), while others showed that
the suppression of Oct4 is a step in the generation of a NSC like cell from
ESCs (Akamatsu W et al., 2009). Sox2 is a marker for NSCs
and is thought to regulate the proliferation and maintenance of NSCs, and their
differentiation into neurons (Episkopou V, 2005).
Thus, to recapitulate the above
discussion of SSCs, the developmentally important molecules Shh, Notch, Wnt/b
catenin, and the BMP family of receptors/ligands are important for maintaining
self-renewal and the multipotency phenotype. In the case of NSCs and MSCs
extensive culture work has revealed several soluble growth factors, which may
be used to manipulate the stem-like, and differentiation end points. Due to
limitations in the culture methods of HSCs the bulk of the experimental work is
performed in in vivo models.
IV. Conclusions and projections
A circumspect study of the signals
which mediate pluripotency and multipotency in ESCs and HSCs respectively could
permit the design of reagents and protocols which will result in the stable
differentiation of SSCs and mature cells from ESCs, and perhaps all other
desired combinations. Figure 1 and Figure 2 summarize some of our thoughts
on the salient cellular signals and events, which maintain the pluripotent
state of mouse and human ESCs. It has recently been possible to
de-differentiate cells which are thought to be of mature origin to cells which
are reminiscent of ESCs by the induced expression of the transcription factors
Oct4, Myc and Klf4 in combination with
other transcription factors. It is possible that other procedures could use
signaling intermediates and activated cytoplasmic and nuclear proteins.
The relatively recent progress in
the creation of induced pluripotent stem cells (iPSCs) (Takahashi K et al., 2007, Takahashi K and Yamanaka S, 2006), and to a lesser extent
nuclear reprogramming by cell fusion (Cowan CA et al., 2005), has challenged several of
our notions regarding pluripotent, differentiating and mature differentiated
states. It appears from the cell fusion studies that principles present in the
cytoplasm of the ESC can reprogram the mature differentiated nucleus into an
undifferentiated 'pluripotent' one (Cowan CA et al., 2005). The surprising
observation that the simple overexpression of about four genes, which are
usually expressed in ESCs, has the capacity to reprogram a 'mature' cell has
elicited great interest. The genes usually used for the induction of
pluripotency are Oct4, Klf4, Sox2 and Myc, in the absence or presence of other
genes such as Large-T and Nanog (Park IH et al., 2008, Yu J et al., 2007). The frequency with which
iPS occurs is low, and it must be mentioned that the exact nature of the
'mature' cell which is being de-differentiated is not entirely clear. iPS seems
to be much more efficient when performed in cells which are more stem-like than
mature (Aasen T et al., 2008). Several refinements are
now being rapidly reported where iPSCs are being generated with varying
efficiencies using small molecules (Shi Y et al., 2008), micro RNAs (Judson RL et al., 2009), protein transductions (Zhou H et al., 2009), plasmid transfections (Okita K et al., 2008), adenoviral vectors (Stadtfeld M et al., 2008), transposons (Woltjen K et al., 2009) and other cell signaling
manipulations (Feng B et al., 2009) instead of the original retro/lentiviral
transductions. HDAC inhibitors such as valproate have been shown to greatly
increase the efficiency of iPSC generation even with just 2 of the original
reprogramming genes (Huangfu D et al., 2008), suggesting the
involvement of epigenetic modifications in the regulation and/or maintenance of
pluripotence. Lluis et al have shown
that cyclic activation of Wnt/β catenin signaling can enhance the
reprogramming of somatic cells upon fusion with ESCs, whereby the
differentiated cells undergo the process of dedifferentiation (Lluis F et al., 2008). These supposedly 'safer' methods of generation could be an
advance to potentially using these cells in autologous and allogeneic cellular
transplantation therapies, as they are not induced to pluripotence with the aid
of lentiviruses. While the promise of these cells in regenerative medicine
still remains to be realized, their power in the establishment of in vitro models of disease and in
screening models is obvious.
While the initial stimulus for
iPSC formation is the forced expression of Oct4, Myc, Klf4, and other selected
genes, the eventual transformation of the cell to its stem-like state is due to
reprogramming of the nuclear architecture such that the cell starts to express
endogenous Oct4, Myc, Nanog, etc. The exact mechanism by which Oct4, Myc, etc.
brings about these epigenetic modifications to the cell, such that it is
reprogrammed, is under study (Figure 2).
While it has been recently possible to de-differentiate cells which are thought
to be of mature origin to cells which are reminiscent of ESCs, the conversion
of mature cells to SSCs remains to be achieved (Figure 3). One may also use the knowledge reviewed here to stably
cause the differentiation of an ESC to an HSC or NSC (Bajpai R et al., 2009, Matsumoto K et al., 2009). This has been achieved by
the selective addition of various growth factors and manipulation of tissue
culture conditions. It may also be achieved by other more direct means
including the manipulation of levels and interactions of specific transcription
factors (as implied in the Gata2 study (Huang TS et al., 2008), or by directing the
epigenetic modification of specific promoters to achieve the MSC, NSC or a
pre-insulin producing b-cell state. Such manipulations would be of immense
use in regenerative medicine, perhaps in the generation of specific cell types
for regenerative medicine and for the generation of in vitro experimental models.
The recent literature would appear
to suggest that differentiation of cells towards the mature end phenotype is
not a one way phenomenon, and that the appropriate stimuli will cause ESCs,
SSCs and mature differentiated cells to flip between states (Figure 3). As a case in point, iPSCs
derived from skin fibroblasts have been differentiated into cells of the
central nervous system (Dimos JT et al., 2008). While all these
experiments have been performed in vitro, the possibilities of these types of
dynamic shifts in a general sense, and in vivo, remain to be detected. The idea
represented in Figure 3 begs the
question of whether the fully differentiated status of mature cellular
phenotypes is actively maintained in the adult organism, as are stem cells.
Figure 3: Are all
cells in a dynamic equilibrium with respect to their 'fate choice' decisions?
The current status of ESC generation and
differentiation suggests that ESCs, SSCs and mature differentiated cells may be
inter-convertible given the correct stimuli. Somatic stem cells such as neural
stem cells and keratinocyte precursors have been used successfully for iPSC
generation. Mouse embryo fibroblast cultures, which are used for iPSC
generation, are a heterogeneous population of cells, which may well contain MSC
like cells. Adult fibroblasts and blood have also been used with varying levels
of success for iPSC. By all
recognizable criteria, iPSCs closely resemble ESCs. ESCs have been differentiated into NSC and HSCs. Of the
other options possible in the continuum shown in the figure, ESCs and SSCs have
been differentiated into the several types of mature cells. The successful
de-differentiation of mature cells into their respective SSCs could be possible
if the correct cohort of cytoplasmic, nuclear, and epigenetic signals were
expressed in sufficient quantities, and with correct timing.
Acknowledgements
We gratefully acknowledge the
financial support of the Department of Biotechnology of the Ministry of Science
and Technology, India. We thank Dr. R.V. Shaji for commenting on the
manuscript.
References
Aasen T, Raya A, Barrero MJ,
Garreta E, Consiglio A, Gonzalez F, Vassena R, Bilic J, Pekarik V, Tiscornia G,
Edel M, Boue S, and Belmonte JC (2008)
Efficient and rapid generation of induced pluripotent stem cells from human
keratinocytes. Nat Biotechnol
26(11), 1276-1284.
Abdel-Azim H, Zhu Y, Hollis R,
Wang X, Ge S, Hao QL, Smbatyan G, Kohn DB, Rosol M, and Crooks GM (2008) Expansion of multipotent and
lymphoid-committed human progenitors through intracellular dimerization of Mpl.
Blood 111(8), 4064-4074.
Akamatsu W, DeVeale B, Okano H,
Cooney AJ, and van der Kooy D (2009)
Suppression of Oct4 by germ cell nuclear factor restricts pluripotency and
promotes neural stem cell development in the early neural lineage. J Neurosci 29(7), 2113-2124.
Aksoy I, Sakabedoyan C, Bourillot
PY, Malashicheva AB, Mancip J, Knoblauch K, Afanassieff M, and Savatier P (2007) Self-renewal of murine embryonic stem
cells is supported by the serine/threonine kinases Pim-1 and Pim-3. Stem Cells 25(12), 2996-3004.
Allegrucci C, Wu YZ, Thurston A,
Denning CN, Priddle H, Mummery CL, Ward-van Oostwaard D, Andrews PW, Stojkovic
M, Smith N, Parkin T, Jones ME, Warren G, Yu L, Brena RM, Plass C, and Young LE
(2007) Restriction landmark genome
scanning identifies culture-induced DNA methylation instability in the human
embryonic stem cell epigenome. Hum Mol
Genet 16(10), 1253-1268.
Alvarez-Buylla A, and Lim DA (2004) For the long run: maintaining
germinal niches in the adult brain. Neuron
41(5), 683-686.
Anneren C, Cowan CA, and Melton DA
(2004) The Src family of tyrosine
kinases is important for embryonic stem cell self-renewal. J Biol Chem 279(30), 31590-31598.
Arai F, and Suda T (2007) Maintenance of quiescent
hematopoietic stem cells in the osteoblastic niche. Ann N Y Acad Sci 110641-53.
Armstrong L, Hughes O, Yung S,
Hyslop L, Stewart R, Wappler I, Peters H, Walter T, Stojkovic P, Evans J,
Stojkovic M, and Lako M (2006) The
role of PI3K/AKT, MAPK/ERK and NFkappabeta signalling in the maintenance of
human embryonic stem cell pluripotency and viability highlighted by
transcriptional profiling and functional analysis. Hum Mol Genet 15(11), 1894-1913.
Bajpai R, Coppola G, Kaul M,
Talantova M, Cimadamore F, Nilbratt M, Geschwind DH, Lipton SA, and Terskikh AV
(2009) Molecular stages of rapid and
uniform neuralization of human embryonic stem cells. Cell Death Differ.
Bendall SC, Stewart MH, Menendez
P, George D, Vijayaragavan K, Werbowetski-Ogilvie T, Ramos-Mejia V, Rouleau A,
Yang J, Bosse M, Lajoie G, and Bhatia M (2007)
IGF and FGF cooperatively establish the regulatory stem cell niche of
pluripotent human cells in vitro. Nature
448(7157), 1015-1021.
Bernstein BE, Kamal M, Lindblad-Toh
K, Bekiranov S, Bailey DK, Huebert DJ, McMahon S, Karlsson EK, Kulbokas EJ,
3rd, Gingeras TR, Schreiber SL, and Lander ES (2005) Genomic maps and comparative analysis of histone
modifications in human and mouse. Cell
120(2), 169-181.
Bestor T, Laudano A, Mattaliano R,
and Ingram V (1988) Cloning and
sequencing of a cDNA encoding DNA methyltransferase of mouse cells. The
carboxyl-terminal domain of the mammalian enzymes is related to bacterial
restriction methyltransferases. J Mol
Biol 203(4), 971-983.
Blake RA, Broome MA, Liu X, Wu J,
Gishizky M, Sun L, and Courtneidge SA (2000)
SU6656, a selective src family kinase inhibitor, used to probe growth factor
signaling. Mol Cell Biol 20(23),
9018-9027.
Blanpain C, and Fuchs E (2009) Epidermal homeostasis: a
balancing act of stem cells in the skin. Nat
Rev Mol Cell Biol 10(3), 207-217.
Bonni A, Sun Y, Nadal-Vicens M,
Bhatt A, Frank DA, Rozovsky I, Stahl N, Yancopoulos GD, and Greenberg ME (1997) Regulation of gliogenesis in the
central nervous system by the JAK-STAT signaling pathway. Science 278(5337), 477-483.
Boyer LA, Lee TI, Cole MF,
Johnstone SE, Levine SS, Zucker JP, Guenther MG, Kumar RM, Murray HL, Jenner
RG, Gifford DK, Melton DA, Jaenisch R, and Young RA (2005) Core transcriptional regulatory circuitry in human embryonic
stem cells. Cell 122(6), 947-956.
Boyer LA, Plath K, Zeitlinger J,
Brambrink T, Medeiros LA, Lee TI, Levine SS, Wernig M, Tajonar A, Ray MK, Bell
GW, Otte AP, Vidal M, Gifford DK, Young RA, and Jaenisch R (2006) Polycomb complexes repress
developmental regulators in murine embryonic stem cells. Nature 441(7091), 349-353.
Burdon T, Stracey C, Chambers I,
Nichols J, and Smith A (1999)
Suppression of SHP-2 and ERK signalling promotes self-renewal of mouse
embryonic stem cells. Dev Biol
210(1), 30-43.
Cao R, and Zhang Y (2004) The functions of
E(Z)/EZH2-mediated methylation of lysine 27 in histone H3. Curr Opin Genet Dev 14(2), 155-164.
Cartwright P, McLean C, Sheppard
A, Rivett D, Jones K, and Dalton S (2005)
LIF/STAT3 controls ES cell self-renewal and pluripotency by a Myc-dependent
mechanism. Development 132(5),
885-896.
Cavalli G, and Paro R (1999) Epigenetic inheritance of active
chromatin after removal of the main transactivator. Science 286(5441), 955-958.
Chambers I, and Smith A (2004) Self-renewal of teratocarcinoma
and embryonic stem cells. Oncogene
23(43), 7150-7160.
Chen C, Liu Y, Liu R, Ikenoue T,
Guan KL, Liu Y, and Zheng P (2008)
TSC-mTOR maintains quiescence and function of hematopoietic stem cells by
repressing mitochondrial biogenesis and reactive oxygen species. J Exp Med 205(10), 2397-2408.
Chen X, Xu H, Yuan P, Fang F, Huss
M, Vega VB, Wong E, Orlov YL, Zhang W, Jiang J, Loh YH, Yeo HC, Yeo ZX, Narang
V, Govindarajan KR, Leong B, Shahab A, Ruan Y, Bourque G, Sung WK, Clarke ND,
Wei CL, and Ng HH (2008) Integration
of external signaling pathways with the core transcriptional network in
embryonic stem cells. Cell 133(6),
1106-1117.
Christensen J, Agger K, Cloos PA,
Pasini D, Rose S, Sennels L, Rappsilber J, Hansen KH, Salcini AE, and Helin K (2007) RBP2 belongs to a family of
demethylases, specific for tri-and dimethylated lysine 4 on histone 3. Cell 128(6), 1063-1076.
Cowan CA, Atienza J, Melton DA,
and Eggan K (2005) Nuclear
reprogramming of somatic cells after fusion with human embryonic stem cells. Science 309(5739), 1369-1373.
Daheron L, Opitz SL, Zaehres H,
Lensch MW, Andrews PW, Itskovitz-Eldor J, and Daley GQ (2004) LIF/STAT3 signaling fails to maintain self-renewal of human
embryonic stem cells. Stem Cells
22(5), 770-778.
Dey BK, Stalker L, Schnerch A,
Bhatia M, Taylor-Papidimitriou J, and Wynder C (2008) The histone demethylase KDM5b/JARID1b plays a role in cell
fate decisions by blocking terminal differentiation. Mol Cell Biol 28(17), 5312-5327.
Dimos JT, Rodolfa KT, Niakan KK,
Weisenthal LM, Mitsumoto H, Chung W, Croft GF, Saphier G, Leibel R, Goland R,
Wichterle H, Henderson CE, and Eggan K (2008)
Induced pluripotent stem cells generated from patients with ALS can be
differentiated into motor neurons. Science
321(5893), 1218-1221.
Dvorak P, Dvorakova D, and Hampl A
(2006) Fibroblast growth factor
signaling in embryonic and cancer stem cells. FEBS Lett 580(12), 2869-2874.
Dvorak P, Dvorakova D, Koskova S,
Vodinska M, Najvirtova M, Krekac D, and Hampl A (2005) Expression and potential role of fibroblast growth factor 2
and its receptors in human embryonic stem cells. Stem Cells 23(8), 1200-1211.
Episkopou V (2005) SOX2 functions in adult neural stem cells. Trends Neurosci 28(5), 219-221.
Evans MJ, and Kaufman MH (1981) Establishment in culture of
pluripotential cells from mouse embryos. Nature
292(5819), 154-156.
Farthing CR, Ficz G, Ng RK, Chan
CF, Andrews S, Dean W, Hemberger M, and Reik W (2008) Global mapping of DNA methylation in mouse promoters reveals
epigenetic reprogramming of pluripotency genes. PLoS Genet 4(6), e1000116.
Fazzio TG, Huff JT, and Panning B
(2008) An RNAi screen of chromatin
proteins identifies Tip60-p400 as a regulator of embryonic stem cell identity. Cell 134(1), 162-174.
Feng B, Jiang J, Kraus P, Ng JH,
Heng JC, Chan YS, Yaw LP, Zhang W, Loh YH, Han J, Vega VB, Cacheux-Rataboul V,
Lim B, Lufkin T, and Ng HH (2009)
Reprogramming of fibroblasts into induced pluripotent stem cells with orphan
nuclear receptor Esrrb. Nat Cell Biol
11(2), 197-203.
Fleming HE, Janzen V, Lo Celso C,
Guo J, Leahy KM, Kronenberg HM, and Scadden DT (2008) Wnt signaling in the niche enforces hematopoietic stem cell
quiescence and is necessary to preserve self-renewal in vivo. Cell Stem Cell 2(3), 274-283.
Forsberg EC, Prohaska SS, Katzman
S, Heffner GC, Stuart JM, and Weissman IL (2005)
Differential expression of novel potential regulators in hematopoietic stem
cells. PLoS Genet 1(3), e28.
Fukuhara S, Sako K, Minami T, Noda
K, Kim HZ, Kodama T, Shibuya M, Takakura N, Koh GY, and Mochizuki N (2008) Differential function of Tie2 at
cell-cell contacts and cell-substratum contacts regulated by angiopoietin-1. Nat Cell Biol 10(5), 513-526.
Ginis I, Luo Y, Miura T, Thies S,
Brandenberger R, Gerecht-Nir S, Amit M, Hoke A, Carpenter MK, Itskovitz-Eldor
J, and Rao MS (2004) Differences
between human and mouse embryonic stem cells. Dev Biol 269(2), 360-380.
Hall IM, Shankaranarayana GD, Noma
K, Ayoub N, Cohen A, and Grewal SI (2002)
Establishment and maintenance of a heterochromatin domain. Science 297(5590), 2232-2237.
Hooker CW, and Hurlin PJ (2006) Of Myc and Mnt. J Cell Sci 119(Pt 2), 208-216.
Huang TS, Hsieh JY, Wu YH, Jen CH,
Tsuang YH, Chiou SH, Partanen J, Anderson H, Jaatinen T, Yu YH, and Wang HW (2008) Functional network reconstruction
reveals somatic stemness genetic maps and dedifferentiation-like transcriptome
reprogramming induced by GATA2. Stem
Cells 26(5), 1186-1201.
Huangfu D, Maehr R, Guo W,
Eijkelenboom A, Snitow M, Chen AE, and Melton DA (2008) Induction of pluripotent stem cells by defined factors is
greatly improved by small-molecule compounds. Nat Biotechnol 26(7), 795-797.
Humphrey RK, Beattie GM, Lopez AD,
Bucay N, King CC, Firpo MT, Rose-John S, and Hayek A (2004) Maintenance of pluripotency in human embryonic stem cells is
STAT3 independent. Stem Cells 22(4),
522-530.
Ivanova N, Dobrin R, Lu R, Kotenko
I, Levorse J, DeCoste C, Schafer X, Lun Y, and Lemischka IR (2006) Dissecting self-renewal in stem
cells with RNA interference. Nature
442(7102), 533-538.
James D, Levine AJ, Besser D, and
Hemmati-Brivanlou A (2005)
TGFbeta/activin/nodal signaling is necessary for the maintenance of
pluripotency in human embryonic stem cells. Development 132(6), 1273-1282.
Jirmanova L, Afanassieff M,
Gobert-Gosse S, Markossian S, and Savatier P (2002) Differential contributions of ERK and PI3-kinase to the
regulation of cyclin D1 expression and to the control of the G1/S transition in
mouse embryonic stem cells. Oncogene
21(36), 5515-5528.
Johe KK, Hazel TG, Muller T,
Dugich-Djordjevic MM, and McKay RD (1996)
Single factors direct the differentiation of stem cells from the fetal and
adult central nervous system. Genes Dev
10(24), 3129-3140.
Judson RL, Babiarz JE, Venere M,
and Blelloch R (2009) Embryonic stem
cell-specific microRNAs promote induced pluripotency. Nat Biotechnol.
Kaji K, Caballero IM, MacLeod R,
Nichols J, Wilson VA, and Hendrich B (2006)
The NuRD component Mbd3 is required for pluripotency of embryonic stem cells. Nat Cell Biol 8(3), 285-292.
Kalani MY, Cheshier SH, Cord BJ,
Bababeygy SR, Vogel H, Weissman IL, Palmer TD, and Nusse R (2008) Wnt-mediated self-renewal of
neural stem/progenitor cells. Proc Natl
Acad Sci U S A 105(44), 16970-16975.
Kamakura S, Oishi K, Yoshimatsu T,
Nakafuku M, Masuyama N, and Gotoh Y (2004)
Hes binding to STAT3 mediates crosstalk between Notch and JAK-STAT signalling. Nat Cell Biol 6(6), 547-554.
Karlsson G, Blank U, Moody JL,
Ehinger M, Singbrant S, Deng CX, and Karlsson S (2007) Smad4 is critical for self-renewal of hematopoietic stem cells.
J Exp Med 204(3), 467-474.
Kiel MJ, and Morrison SJ (2008) Uncertainty in the niches that
maintain haematopoietic stem cells. Nat
Rev Immunol 8(4), 290-301.
Kimura H, Tada M, Nakatsuji N, and
Tada T (2004) Histone code
modifications on pluripotential nuclei of reprogrammed somatic cells. Mol Cell Biol 24(13), 5710-5720.
Kitsos CM, Sankar U, Illario M,
Colomer-Font JM, Duncan AW, Ribar TJ, Reya T, and Means AR (2005) Calmodulin-dependent protein
kinase IV regulates hematopoietic stem cell maintenance. J Biol Chem 280(39), 33101-33108.
Kolf CM, Cho E, and Tuan RS (2007) Mesenchymal stromal cells.
Biology of adult mesenchymal stem cells: regulation of niche, self-renewal and
differentiation. Arthritis Res Ther
9(1), 204.
Lee JH, Hart SR, and Skalnik DG (2004) Histone deacetylase activity is
required for embryonic stem cell differentiation. Genesis 38(1), 32-38.
Lee TI, Jenner RG, Boyer LA,
Guenther MG, Levine SS, Kumar RM, Chevalier B, Johnstone SE, Cole MF, Isono K,
Koseki H, Fuchikami T, Abe K, Murray HL, Zucker JP, Yuan B, Bell GW,
Herbolsheimer E, Hannett NM, Sun K, Odom DT, Otte AP, Volkert TL, Bartel DP,
Melton DA, Gifford DK, Jaenisch R, and Young RA (2006) Control of developmental regulators by Polycomb in human
embryonic stem cells. Cell 125(2), 301-313.
Lengner CJ, Camargo FD,
Hochedlinger K, Welstead GG, Zaidi S, Gokhale S, Scholer HR, Tomilin A, and
Jaenisch R (2007) Oct4 expression is
not required for mouse somatic stem cell self-renewal. Cell Stem Cell 1(4), 403-415.
Lengner CJ, Welstead GG, and
Jaenisch R (2008) The pluripotency
regulator Oct4: a role in somatic stem cells? Cell Cycle 7(6), 725-728.
Levine SS, King IF, and Kingston
RE (2004) Division of labor in
polycomb group repression. Trends
Biochem Sci 29(9), 478-485.
Li JY, Pu MT, Hirasawa R, Li BZ,
Huang YN, Zeng R, Jing NH, Chen T, Li E, Sasaki H, and Xu GL (2007) Synergistic function of DNA
methyltransferases Dnmt3a and Dnmt3b in the methylation of Oct4 and Nanog. Mol Cell Biol 27(24), 8748-8759.
Li L, Milner LA, Deng Y, Iwata M,
Banta A, Graf L, Marcovina S, Friedman C, Trask BJ, Hood L, and Torok-Storb B (1998) The human homolog of rat Jagged1
expressed by marrow stroma inhibits differentiation of 32D cells through
interaction with Notch1. Immunity
8(1), 43-55.
Li Y, McClintick J, Zhong L,
Edenberg HJ, Yoder MC, and Chan RJ (2005)
Murine embryonic stem cell differentiation is promoted by SOCS-3 and inhibited
by the zinc finger transcription factor Klf4. Blood 105(2), 635-637.
Lluis F, Pedone E, Pepe S, and
Cosma MP (2008) Periodic activation
of Wnt/beta-catenin signaling enhances somatic cell reprogramming mediated by
cell fusion. Cell Stem Cell 3(5),
493-507.
Loh YH, Wu Q, Chew JL, Vega VB,
Zhang W, Chen X, Bourque G, George J, Leong B, Liu J, Wong KY, Sung KW, Lee CW,
Zhao XD, Chiu KP, Lipovich L, Kuznetsov VA, Robson P, Stanton LW, Wei CL, Ruan
Y, Lim B, and Ng HH (2006) The Oct4
and Nanog transcription network regulates pluripotency in mouse embryonic stem
cells. Nat Genet 38(4), 431-440.
Loh YH, Zhang W, Chen X, George J,
and Ng HH (2007) Jmjd1a and Jmjd2c
histone H3 Lys 9 demethylases regulate self-renewal in embryonic stem cells. Genes Dev 21(20), 2545-2557.
Lu M, Glover CH, Tien AH,
Humphries RK, Piret JM, and Helgason CD (2007)
Involvement of tyrosine kinase signaling in maintaining murine embryonic stem
cell functionality. Exp Hematol
35(8), 1293-1302.
Majumdar MK, Thiede MA, Mosca JD,
Moorman M, and Gerson SL (1998)
Phenotypic and functional comparison of cultures of marrow-derived mesenchymal
stem cells (MSCs) and stromal cells. J
Cell Physiol 176(1), 57-66.
Matsumoto K, Isagawa T, Nishimura
T, Ogaeri T, Eto K, Miyazaki S, Miyazaki J, Aburatani H, Nakauchi H, and Ema H
(2009) Stepwise development of
hematopoietic stem cells from embryonic stem cells. PLoS ONE 4(3), e4820.
McNeish J (2004) Embryonic stem cells in drug discovery. Nat Rev Drug Discov 3(1), 70-80.
Meissner A, Mikkelsen TS, Gu H,
Wernig M, Hanna J, Sivachenko A, Zhang X, Bernstein BE, Nusbaum C, Jaffe DB,
Gnirke A, Jaenisch R, and Lander ES (2008)
Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454(7205), 766-770.
Meshorer E, and Misteli T (2006) Chromatin in pluripotent
embryonic stem cells and differentiation. Nat
Rev Mol Cell Biol 7(7), 540-546.
Meyn MA, 3rd, Schreiner SJ,
Dumitrescu TP, Nau GJ, and Smithgall TE (2005)
SRC family kinase activity is required for murine embryonic stem cell growth
and differentiation. Mol Pharmacol
68(5), 1320-1330.
Mitsui K, Tokuzawa Y, Itoh H,
Segawa K, Murakami M, Takahashi K, Maruyama M, Maeda M, and Yamanaka S (2003) The homeoprotein Nanog is
required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 113(5), 631-642.
Miyabayashi T, Teo JL, Yamamoto M,
McMillan M, Nguyen C, and Kahn M (2007)
Wnt/beta-catenin/CBP signaling maintains long-term murine embryonic stem cell
pluripotency. Proc Natl Acad Sci U S A
104(13), 5668-5673.
Molofsky AV, Pardal R, Iwashita T,
Park IK, Clarke MF, and Morrison SJ (2003)
Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor
proliferation. Nature 425(6961),
962-967.
Muller FJ, Laurent LC, Kostka D,
Ulitsky I, Williams R, Lu C, Park IH, Rao MS, Shamir R, Schwartz PH, Schmidt
NO, and Loring JF (2008) Regulatory
networks define phenotypic classes of human stem cell lines. Nature 455(7211), 401-405.
Nakashima K, Yanagisawa M, Arakawa
H, Kimura N, Hisatsune T, Kawabata M, Miyazono K, and Taga T (1999) Synergistic signaling in fetal
brain by STAT3-Smad1 complex bridged by p300. Science 284(5413), 479-482.
Nilsson SK, Johnston HM, Whitty GA,
Williams B, Webb RJ, Denhardt DT, Bertoncello I, Bendall LJ, Simmons PJ, and
Haylock DN (2005) Osteopontin, a key
component of the hematopoietic stem cell niche and regulator of primitive
hematopoietic progenitor cells. Blood
106(4), 1232-1239.
Niwa H, Miyazaki J, and Smith AG (2000) Quantitative expression of
Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells.
Nat Genet 24(4), 372-376.
Niwa H, Toyooka Y, Shimosato D,
Strumpf D, Takahashi K, Yagi R, and Rossant J (2005) Interaction between Oct3/4 and Cdx2 determines trophectoderm
differentiation. Cell 123(5),
917-929.
O'Carroll D, Erhardt S, Pagani M,
Barton SC, Surani MA, and Jenuwein T (2001)
The polycomb-group gene Ezh2 is required for early mouse development. Mol Cell Biol 21(13), 4330-4336.
Oda M, Yamagiwa A, Yamamoto S,
Nakayama T, Tsumura A, Sasaki H, Nakao K, Li E, and Okano M (2006) DNA methylation regulates
long-range gene silencing of an X-linked homeobox gene cluster in a
lineage-specific manner. Genes Dev
20(24), 3382-3394.
Okano M, Bell DW, Haber DA, and Li
E (1999) DNA methyltransferases
Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian
development. Cell 99(3), 247-257.
Okita K, Nakagawa M, Hyenjong H,
Ichisaka T, and Yamanaka S (2008)
Generation of mouse induced pluripotent stem cells without viral vectors. Science 322(5903), 949-953.
Palma V, and Ruiz i Altaba A (2004) Hedgehog-GLI signaling regulates
the behavior of cells with stem cell properties in the developing neocortex. Development 131(2), 337-345.
Palmqvist L, Glover CH, Hsu L, Lu
M, Bossen B, Piret JM, Humphries RK, and Helgason CD (2005) Correlation of murine embryonic stem cell gene expression
profiles with functional measures of pluripotency. Stem Cells 23(5), 663-680.
Park IH, Arora N, Huo H, Maherali
N, Ahfeldt T, Shimamura A, Lensch MW, Cowan C, Hochedlinger K, and Daley GQ (2008) Disease-specific induced
pluripotent stem cells. Cell 134(5),
877-886.
Park IK, Qian D, Kiel M, Becker
MW, Pihalja M, Weissman IL, Morrison SJ, and Clarke MF (2003) Bmi-1 is required for maintenance of adult self-renewing
haematopoietic stem cells. Nature
423(6937), 302-305.
Pasini D, Hansen KH, Christensen
J, Agger K, Cloos PA, and Helin K (2008)
Coordinated regulation of transcriptional repression by the RBP2 H3K4
demethylase and Polycomb-Repressive Complex 2. Genes Dev 22(10), 1345-1355.
Pittenger MF, Mackay AM, Beck SC,
Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, and Marshak
DR (1999) Multilineage potential of
adult human mesenchymal stem cells. Science
284(5411), 143-147.
Qi X, Li TG, Hao J, Hu J, Wang J,
Simmons H, Miura S, Mishina Y, and Zhao GQ (2004) BMP4 supports self-renewal of embryonic stem cells by
inhibiting mitogen-activated protein kinase pathways. Proc Natl Acad Sci U S A 101(16), 6027-6032.
Rajan P, and McKay RD (1998) Multiple routes to astrocytic
differentiation in the CNS. J Neurosci
18(10), 3620-3629.
Rajan P, Panchision DM, Newell LF,
and McKay RD (2003) BMPs signal
alternately through a SMAD or FRAP-STAT pathway to regulate fate choice in CNS
stem cells. J Cell Biol 161(5),
911-921.
Rajan P, and Snyder E (2009) Neural stem cells and their
manipulation. Methods Enzymol -
Reprinted in Best of Series Edition Essential Stem Cell Methods 23-51.
Ramalho-Santos M, Yoon S,
Matsuzaki Y, Mulligan RC, and Melton DA (2002)
"Stemness": transcriptional profiling of embryonic and adult stem
cells. Science 298(5593), 597-600.
Rao M (2004) Conserved and divergent paths that regulate self-renewal in
mouse and human embryonic stem cells. Dev
Biol 275(2), 269-286.
Reynolds BA, and Weiss S (1996) Clonal and population analyses
demonstrate that an EGF-responsive mammalian embryonic CNS precursor is a stem
cell. Dev Biol 175(1), 1-13.
Riquelme PA, Drapeau E, and
Doetsch F (2008) Brain
micro-ecologies: neural stem cell niches in the adult mammalian brain. Philos Trans R Soc Lond B Biol Sci
363(1489), 123-137.
Roche S, Delorme B, Oostendorp RA,
Barbet R, Caton D, Noel D, Boumediene K, Papadaki HA, Cousin B, Crozet C,
Milhavet O, Casteilla L, Hatzfeld J, Jorgensen C, Charbord P, and Lehmann S (2009) Comparative proteomic analysis of
human mesenchymal and embryonic stem cells: towards the definition of a
mesenchymal stem cell proteomic signature. Proteomics
9(2), 223-232.
Sato N, Meijer L, Skaltsounis L,
Greengard P, and Brivanlou AH (2004)
Maintenance of pluripotency in human and mouse embryonic stem cells through
activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med 10(1), 55-63.
Sato T, Vries RG, Snippert HJ, van
de Wetering M, Barker N, Stange DE, van Es JH, Abo A, Kujala P, Peters PJ, and
Clevers H (2009) Single Lgr5 stem
cells build crypt-villus structures in vitro without a mesenchymal niche. Nature.
Schubeler D, MacAlpine DM, Scalzo
D, Wirbelauer C, Kooperberg C, van Leeuwen F, Gottschling DE, O'Neill LP,
Turner BM, Delrow J, Bell SP, and Groudine M (2004) The histone modification pattern of active genes revealed
through genome-wide chromatin analysis of a higher eukaryote. Genes Dev 18(11), 1263-1271.
Schuldiner M, Yanuka O,
Itskovitz-Eldor J, Melton DA, and Benvenisty N (2000) Effects of eight growth factors on the differentiation of
cells derived from human embryonic stem cells. Proc Natl Acad Sci U S A 97(21), 11307-11312.
Scoville DH, Sato T, He XC, and Li
L (2008) Current view: intestinal
stem cells and signaling. Gastroenterology
134(3), 849-864.
Shi Y, Desponts C, Do JT, Hahm HS,
Scholer HR, and Ding S (2008)
Induction of pluripotent stem cells from mouse embryonic fibroblasts by Oct4
and Klf4 with small-molecule compounds. Cell
Stem Cell 3(5), 568-574.
Simmons PJ, Gronthos S, Zannettino
A, Ohta S, and Graves S (1994)
Isolation, characterization and functional activity of human marrow stromal
progenitors in hemopoiesis. Prog Clin
Biol Res 389271-280.
Smith AG, Heath JK, Donaldson DD,
Wong GG, Moreau J, Stahl M, and Rogers D (1988)
Inhibition of pluripotential embryonic stem cell differentiation by purified
polypeptides. Nature 336(6200),
688-690.
Sperger JM, Chen X, Draper JS,
Antosiewicz JE, Chon CH, Jones SB, Brooks JD, Andrews PW, Brown PO, and Thomson
JA (2003) Gene expression patterns
in human embryonic stem cells and human pluripotent germ cell tumors. Proc Natl Acad Sci U S A 100(23),
13350-13355.
Stadtfeld M, Nagaya M, Utikal J,
Weir G, and Hochedlinger K (2008)
Induced pluripotent stem cells generated without viral integration. Science 322(5903), 945-949.
Stier S, Ko Y, Forkert R, Lutz C,
Neuhaus T, Grunewald E, Cheng T, Dombkowski D, Calvi LM, Rittling SR, and
Scadden DT (2005) Osteopontin is a hematopoietic
stem cell niche component that negatively regulates stem cell pool size. J Exp Med 201(11), 1781-1791.
Sun H, Lesche R, Li DM, Liliental
J, Zhang H, Gao J, Gavrilova N, Mueller B, Liu X, and Wu H (1999) PTEN modulates cell cycle
progression and cell survival by regulating phosphatidylinositol
3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway. Proc Natl Acad Sci U S A 96(11),
6199-6204.
Sun Y, Nadal-Vicens M, Misono S,
Lin MZ, Zubiaga A, Hua X, Fan G, and Greenberg ME (2001) Neurogenin promotes neurogenesis and inhibits glial
differentiation by independent mechanisms. Cell
104(3), 365-376.
Suzuki A, Raya A, Kawakami Y,
Morita M, Matsui T, Nakashima K, Gage FH, Rodriguez-Esteban C, and Belmonte JC
(2006) Maintenance of embryonic stem
cell pluripotency by Nanog-mediated reversal of mesoderm specification. Nat Clin Pract Cardiovasc Med 3 Suppl
1S114-122.
Suzuki A, Raya A, Kawakami Y,
Morita M, Matsui T, Nakashima K, Gage FH, Rodriguez-Esteban C, and Izpisua
Belmonte JC (2006) Nanog binds to
Smad1 and blocks bone morphogenetic protein-induced differentiation of
embryonic stem cells. Proc Natl Acad Sci
U S A 103(27), 10294-10299.
Takahashi A, Takahashi Y,
Matsumoto K, and Miyata K (1995)
Synergistic effects of insulin-like growth factor II (IGF-II) with leukemia
inhibiting factor (LIF) on establishment of rat pluripotential cell lines. J Vet Med Sci 57(3), 553-556.
Takahashi K, Tanabe K, Ohnuki M,
Narita M, Ichisaka T, Tomoda K, and Yamanaka S (2007) Induction of pluripotent stem cells from adult human
fibroblasts by defined factors. Cell
131(5), 861-872.
Takahashi K, and Yamanaka S (2006) Induction of pluripotent stem
cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4), 663-676.
Ulloa-Montoya F, Kidder BL,
Pauwelyn KA, Chase LG, Luttun A, Crabbe A, Geraerts M, Sharov AA, Piao Y, Ko
MS, Hu WS, and Verfaillie CM (2007)
Comparative transcriptome analysis of embryonic and adult stem cells with
extended and limited differentiation capacity. Genome Biol 8(8), R163.
Vallier L, Alexander M, and
Pedersen RA (2005) Activin/Nodal and
FGF pathways cooperate to maintain pluripotency of human embryonic stem cells. J Cell Sci 118(Pt 19), 4495-4509.
van der Flier LG, van Gijn ME,
Hatzis P, Kujala P, Haegebarth A, Stange DE, Begthel H, van den Born M, Guryev
V, Oving I, van Es JH, Barker N, Peters PJ, van de Wetering M, and Clevers H (2009) Transcription factor achaete
scute-like 2 controls intestinal stem cell fate. Cell 136(5), 903-912.
Watanabe S, Umehara H, Murayama K,
Okabe M, Kimura T, and Nakano T (2006)
Activation of Akt signaling is sufficient to maintain pluripotency in mouse and
primate embryonic stem cells. Oncogene
25(19), 2697-2707.
Welham MJ, Storm MP, Kingham E,
and Bone HK (2007) Phosphoinositide
3-kinases and regulation of embryonic stem cell fate. Biochem Soc Trans 35(Pt 2), 225-228.
Woltjen K, Michael IP, Mohseni P,
Desai R, Mileikovsky M, Hamalainen R, Cowling R, Wang W, Liu P, Gertsenstein M,
Kaji K, Sung HK, and Nagy A (2009)
piggyBac transposition reprograms fibroblasts to induced pluripotent stem
cells. Nature 458(7239), 766-770.
Xu C, Rosler E, Jiang J, Lebkowski
JS, Gold JD, O'Sullivan C, Delavan-Boorsma K, Mok M, Bronstein A, and Carpenter
MK (2005) Basic fibroblast growth
factor supports undifferentiated human embryonic stem cell growth without
conditioned medium. Stem Cells
23(3), 315-323.
Yamaguchi TP, Takada S, Yoshikawa
Y, Wu N, and McMahon AP (1999) T
(Brachyury) is a direct target of Wnt3a during paraxial mesoderm specification.
Genes Dev 13(24), 3185-3190.
Yang J, Chai L, Fowles TC, Alipio
Z, Xu D, Fink LM, Ward DC, and Ma Y (2008)
Genome-wide analysis reveals Sall4 to be a major regulator of pluripotency in
murine-embryonic stem cells. Proc Natl
Acad Sci U S A 105(50), 19756-19761.
Ying QL, Nichols J, Chambers I,
and Smith A (2003) BMP induction of
Id proteins suppresses differentiation and sustains embryonic stem cell
self-renewal in collaboration with STAT3. Cell
115(3), 281-292.
Yu J, Vodyanik MA, Smuga-Otto K,
Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V,
Stewart R, Slukvin, II, and Thomson JA (2007)
Induced pluripotent stem cell lines derived from human somatic cells. Science 318(5858), 1917-1920.
Yuan H, Corbi N, Basilico C, and
Dailey L (1995) Developmental-specific
activity of the FGF-4 enhancer requires
the synergistic action of Sox2 and
Oct-3. Genes Dev 9(21), 2635-2645.
Zhong X, and Jin Y (2009) Critical roles of coactivator
p300 in mouse embryonic stem cell differentiation and Nanog expression. J Biol Chem 284(14), 9168-9175.
Zhou H, Wu S, Joo JY, Zhu S, Han
DW, Lin T, Trauger S, Bien G, Yao S, Zhu Y, Siuzdak G, Scholer HR, Duan L, and
Ding S (2009) Generation of Induced
Pluripotent Stem Cells Using Recombinant Proteins. Cell Stem Cell.
