and extra-embryonic cell lineages, and resembled the properties of mouse embryonic stem cells (mESCs); and (2) a “primed” state, which was FGF2-dependent, reminiscent of “epiblast” identity, and resembled human embryonic stem cells (hESCs) (reviewed by Stadtfeld and Hochedlinger, 2010). In mice, it is well established that inhibition of ERK1/ERK2 and GSK3β (2i/LIF) is necessary to maintain the naive state (Marks et al., 2012, Ying et al., 2008); withdrawal of 2i/LIF is sufficient to drift naive cells to the primed state (Brons et al., 2007). Recently, several groups have described culture conditions for maintaining transgene-independent hESCs that share various properties with mESCs (Chan et al., 2013, Gafni et al., 2013, Marinho et al., 2015, Valamehr et al., 2014, Ware et al., 2014). Most compellingly, Hanna and colleagues reported that 2i/LIF, together with EGF, FGF2, JNKi, ROCKi, and p38I, not only converted primed hESCs to the naive state but also conferred competence to form cross-species chimeric mouse embryos (Gafni et al., 2013). While culture of mouse cells in 2i/LIF can convert cells from the primed into the naive ground state, this is not sufficient to convert primed human cells into a naive state. A number of different protocols have been published using
