Recent insights into the naive state of human pluripotency and its applications

The past decade has seen significant interest in the isolation of pluripotent stem cells corresponding to various stages of mammalian embryonic development. Two distinct and well-defined pluripotent states can be derived from mouse embryos: naive pluripotent cells with properties of pre-implantation epiblast, and primed pluripotent cells, resembling post-implantation epiblast. Prompted by the successful interconversion between these two stem cell states in the mouse system, several groups have devised strategies for inducing a naive state of pluripotency in human pluripotent stem cells. Here, we review recent insights into the naive state of human pluripotency, focusing on two methods that confer defining transcriptomic and epigenomic signatures of the pre-implantation embryo. The isolation of naive human pluripotent stem cells offers a window into early developmental mechanisms that cannot be adequately modeled in primed cells, such as X chromosome reactivation, metabolic reprogramming, and the regulation of hominid-specific transposable elements. We outline key unresolved questions regarding naive human pluripotency, including its extrinsic and intrinsic control mechanisms, potential for embryonic and extraembryonic differentiation, and general utility as a model system for human development and disease.