Cornacchia, D. et al. Cell Stem Cell 25, 120–136 (2019).

Human pluripotent stem cells (hPSCs) can be described as naive or primed, corresponding to pre- or post-implantation epiblast tissue, respectively. These distinct states differ in their transcription factor profile, with genes such as KLF4, ESRRB, TFE3 and STELLA (DPPA3) being upregulated in naive hPSCs. However, the boundaries are fluid, and intermediate states are possible. Cornacchia et al. now report that such an intermediate state is induced when hPSCs are maintained in the chemically defined E8 culture medium. E8 hPSCs express some but not all of the markers of naive pluripotency, and they more closely resemble naive hPSCs than primed hPSCs. An important feature of the E8 medium is its lack of lipids, and the researchers found that it is indeed lipid deprivation that induces the naive-to-primed intermediate state. Furthermore, these cells are characterized by an inhibited ERK pathway, a feature they share with naive hPSCs. As E8 hPSCs represent an intermediate developmental stage between naive and primed hPSCs, they may help shed light on the cellular and molecular changes during the implantation process.