JAK/STAT3 signalling is sufficient and dominant over antagonistic cues for the establishment of naive pluripotency

Induced pluripotency depends on cooperativity between expression of defined factors and the culture environment. The latter also determines the pluripotent cell state, that is, naïve or primed. LIF-JAK/STAT3 signalling was recently shown to be a limiting factor for reprogramming to naïve pluripotency. Here we show that sufficient activation of JAK/STAT3 overcomes the reprogramming block of cell intermediates and enables somatic cell reprogramming in absence of otherwise essential pluripotency medium requisites. Activation of FGF-ERK signalling, which promotes exit of naïve pluripotent cells from self-renewal, does not prevent JAK/STAT3 induced post-implantation epiblast-derived stem cell conversion into naïve pluripotency. Moreover, even in the presence of FGF plus Activin, which instructs and maintains the primed state, JAK/STAT3 enforces naïve pluripotency in epiblast stem cells. We conclude that JAK/STAT3 signalling can be sufficient and dominant over antagonistic cues to enable the induction of a naïve pluripotent state. Culture conditions are critical for the successful induction of pluripotent stem cells and define whether cells are primed or naïve. Here, activation of JAK/STAT3 signalling is shown to be sufficient and dominant over antagonistic cues to enable the induction of a naïve pluripotent state in stem cells.