Embryonic stem cells (ESCs) are a unique tool for genetic perturbation of mammalian cellular and organismal processes additionally in humans offer unprecedented opportunities for disease modeling and cell therapy. Furthermore, ESCs are a powerful system for exploring the fundamental biology of pluripotency. Indeed understanding the control of self-renewal and differentiation is key to realizing the potential of ESCs. Building on previous observations, we found that mouse ESCs can be derived and maintained with high efficiency through insulation from differentiation cues combined with consolidation of an innate cell proliferation program. This finding of a pluripotent ground state has led to conceptual and practical advances, including the establishment of germline-competent ESCs from recalcitrant mouse strains and for the first time from the rat. Here, we summarize historical and recent progress in defining the signaling environment that supports self-renewal. We compare the contrasting requirements of two types of pluripotent stem cell, naive ESCs and primed post-implantation epiblast stem cells (EpiSCs), and consider the outstanding challenge of generating naive pluripotent stem cells from different mammals.Research in the Q.-L.Y. laboratory is supported by the NIH (R01 OD010926), the California Institute for Regener ative Medicine (RN2-00938, RS1-00327, and RT3-07949), and the Yong Chen Foundation of the Zhongmei Group. A.S. is a Medical Research Council Professor and receives research funding from the Medical Research Council (MR/P00072X/1) and the Biotechnology and Biological Sciences Research Council of the United Kingdom (BB/P009867/1), and from the European Commission (PluriMes Project no. 602423)
