Biomedical Engineering Reference
In-Depth Information
suggests that the canonical wnt/b-catenin pathway in hESCs has a biphasic role
in controlling self-renewal and differentiation dependent on a specific threshold
of b-catenin activity.
Although other growth factors have been reported to have a positive effect
on hESCs including IGF-1, heregulin (Wang et al., 2007a), pleotrophin (Soh
et al., 2007), shingosin-1-phosphate (S1P) (Avery et al., 2008), PDGF (Pebay
et al., 2005), and neurotrophin (Pyle et al., 2006), the pathways involved have
not been fully explained.
3 ''Core'' Transcription Factors
Studies of the past few years have revealed the central role of transcription
factor networks in the maintenance of ESCs pluripotency and self-renewal.
Recently Yamanaka's group demonstrated that the stem cell state can be
imposed on somatic cells by forced expression of four transcription factors
(Oct4, Sox2, Klf4, and c-myc) (Takahashi and Yamanaka, 2006). Many other
groups followed this finding (Yamanaka, 2008). Surprisingly, the same set of
transcription factors reprogram both mouse and human somatic cells, despite
differences in growth factor requirements of their respective ESCs (Park et al.,
2008a,b; Takahashi et al., 2007a,b). iPS cells (induced pluripotent stem cell)
demonstrate that transcription factors indeed rule pluripotency. Oct4, Sox2,
and Nanog have been considered ''core'' transcription factors for pluripotency
and self-renewal of ESCs. First we review these ''core'' factors and then describe
the extended network surrounding the ''core'' factors and their relation with the
extrinsic network.
Oct4 was first identified as a gene exclusively expressed in pluripotent and
totipotent lineages (Okamoto et al., 1990; Scholer et al., 1989). Oct4 is a
transcription factor belonging to the POU (Pit-Oct-Unc) family that regulates
the expression of target genes by binding to the octamer motif ATGCAAAT
within their promoter or enhancer regions (Herr and Cleary, 1995). Oocyte
contains Oct4 maternal transcript and protein until fertilization (Pesce et al.,
1998). Significant, but relatively low, levels of OCT4 protein are also found in
all cytoplasm of 2- and 4-cell embryos. Zygotic expression of Oct4 is activated
from the 4-cell stage with the strong nuclear localization in all blastomeres
throughout the morula stage (Palmieri et al., 1994; Scholer et al., 1990). Oct4
expression is restricted to the ICM at the blastocyst stage and later on to the
germ cell lineage (Pesce and Scholer, 2000). Oct4 is also expressed in germ cell-
related tumors (Cheng et al., 2007). Recently, reports described Oct4 expression
in adult stem cells. However, this finding may be confounded by the existence of
Oct4 pseudogenes (Liedtke et al., 2007). Because of its unique restricted expres-
sion pattern and chromosome localization within t-complex on chromosome 17
(Yeom et al., 1991), Oct4 was a candidate of some of embryonic t-lethal
mutations. As expected, Oct4-deficient embryos have an early embryonic lethal
