Exiting the ground state: the broad spectrum of cell fates accessible from naïve human pluripotent stem cells

Naïve human pluripotent stem cells (hPSCs) represent an in vitro analog of the pre-implantation epiblast - the founder tissue of the embryo proper. A widely held assumption, based on prior studies in the mouse system, was that naïve hPSCs are restricted in their differentiation potential toward more mature stages of epiblast development, as a prelude to gastrulation. However, over the past 5 years, a growing body of literature has demonstrated that naïve hPSCs have an expanded lineage potential toward a broad range of embryonic and extraembryonic fates and can even be used as a starting point for generating 8-cell-like cells. The most emphatic demonstration of the broad lineage potential of naïve hPSCs is their remarkable capacity to self-organize into blastocyst-like structures ("blastoids") that model all three lineages of the pre-implantation embryo and can be cultured to post-implantation stages. Here, we discuss the broad spectrum of cell fates accessible from naïve hPSCs and the signaling pathways that guide the exit from the ground state of human pluripotency.