Metabolic plasticity complements the unique nature and demands of distinct pluripotency states

Pluripotency, the ability to differentiate into all somatic cell types, is a pertinent feature of embryonic stem cells (ESCs). However, during early ontogenesis, in vivo, this capacity only exists transiently (1,2). Within this window of development, extracellular signals governing embryogenesis grant pluripotency a dynamic nature, while molecular changes in cellular identity occur in preparation for further lineage specification (2). By precisely coordinating the cellular microenvironment and embryonic derivation stage, ESCs can be stabilized in distinct states of pluripotency, in vitro. Conventional derivation of human ESCs (hESCs) from the inner cell mass (ICM) of the pre-implantation blastocyst gives rise to stem cells, which are markedly different from mouse ESCs (mESCs). In vitro, hESCs originate from a post-ICM intermediate, a transient epiblast-like structure (3,4). As such, hESCs adopt the distinct primed state of pluripotency, sharing more similarities with mouse epiblast stem cells (mEpiSCs) derived from post-implantation stage embryos (5). Conversely, mESCs, adopt the naive state, which constitutes the functional in vitro equivalent of the pre-implantation epiblast (5).