Sox2 modulation increases naïve pluripotency plasticity

Induced pluripotency provides a tool to explore the molecular mechanisms underlying the establishment, maintenance and differentiation of naïve pluripotent stem cells (nPSCs). Here, we report that self-renewal of nPSCs requires minimal Sox2 expression (Sox2-low). Sox2-low nPSCs do not show impaired neuroectoderm specification and differentiate efficiently in vitro into all embryonic germ lineages. Strikingly, Sox2-low cells also differentiate towards the trophoblast lineage both in vitro and in vivo . At the single-cell level self-renewing Sox2-low nPSCs exhibit a homogeneous naïve molecular signature. However, they also display a basal trophoblast molecular signature and decreased ability of Oct4 to bind naïve-associated regulatory sequences compared to control cells. These features underlie observed enhanced cell potency upon the removal of self-renewing cues. In sum, this work defines Sox2 as a restrictor of developmental potential and suggests perturbation of the naïve pluripotent network as an underlying cause of increased cell potency. Highlights Low Sox2 expression is sufficient for naïve pluripotent stem cell self-renewal Low Sox2 expression does not impair neurectoderm differentiation in vitro Low Sox2 expression impairs Oct4 genomic occupancy Low Sox2 expression increases naïve pluripotent cell plasticity in vitro and in vivo