This group identify a gene expression signature that distinguishes stabilisation competent and stabilisation incompetent

cells and show that stabilisation competent cells require Receptor Tyrosine Kinase Signaling Pathway transgene repression to enter this stage. Since the stabilisation stage is characterised by transgene independence, only cells that have activated endogenous pluripotency gene expression are able to maintain pluripotency at this late stage. Endogenous pluripotency gene expression is facilitated by demethylation of pluripotency gene promoters, thus explaining why various DNA and histone methyltransferase inhibitors have been shown to accelerate iPS cell reprogramming, amongst other small molecules (Table ​(Table2).2). This may also explain the ability of the H3K27 demethylase UTX to substitute for some of the original reprogramming factors[82]. The end-point of iPS cell reprogramming is a matter of some controversy. For example, the stabilisation stage of mouse iPS cell reprogramming involves X chromosome reactivation whereas human iPS cell reprogramming does not[83]. X chromosome inactivation is a process that occurs as female embryonic cells, which have 2 active X chromosomes, commit

to differentiation. This feature of human ES and human iPS cells, amongst others (reviewed in[84]), means that they represent the primed pluripotent state. Human iPS cells generated in the presence

of ACTIVIN/NODAL and FGF2 ligands are stabilised in this primed state whereas mouse iPS cells reprogrammed in the presence of LIF and BMP4 can be fully reprogrammed to the uncommitted naïve ground state (Figure ​(Figure2).2). Interestingly, human dermal fibroblasts (HDFs) have been shown to give rise to naïve human iPS cells when reprogrammed in the presence of LIF, FGF2 and TGFβ1 plus inhibitors of c-Jun NH2-terminal kinase, p38, MAPK and glycogen synthase kinase 3 (3i)[85], thus demonstrating that the cell signalling context is critical to the determination of naïve and primed pluripotency rather than the two states representing a species difference. The derivation of various novel stem cell lines, Entinostat including intermediate epiblast stem cells which exhibit dual responsiveness to LIF and ACTIVIN/NODAL signalling[86], has challenged the concept of 2 distinct pluripotent states, instead suggesting that a spectrum of pluripotency exists, an idea we develop in Hawkins et al[87]. Thorough investigation into this spectrum of pluripotency, and therefore the transition from pluripotent cells to differentiated cells, should accelerate the delineation of mechanisms occurring throughout the reverse process, from a somatic cell to an iPS cell. Figure 2 The core signalling networks that maintain pluripotency in (A) naive and (B) primed pluripotent cells.