A few days after fertilisation mammalian embryos form a blastocyst comprised of three tissues; trophoblast and hypoblast are the forebears of extraembryonic structures, while naive epiblast cell are the pluripotent source of the embryo proper. Classical mouse embryological studies indicate that lineage potencies are determined concomitant with segregation of the three founder tissues. Textbook definitions of pluripotency thus exclude extraembryonic potential. Consistent with this paradigm, mouse embryonic stem cells are generally ineffective in producing trophoblast or hypoblast derivatives. However, we have discovered that human naïve pluripotent cells have high intrinsic competence for trophoblast formation. Furthermore, unlike in mouse, extraembryonic transcription factors are present in human epiblast in vivo. These findings challenge the dogma of early lineage restriction but may be compatible with the ancestral origin of pluripotency. We hypothesise that extraembryonic plasticity underlaid by entwined regulatory networks is the evolutionary template of pluripotency. Consequently, signal modulation to suppress extraembryonic specification may be crucial for capture of stem cells representative of naïve epiblast in most mammals. We will examine human and non-human primates, farm animals in which embryos undergo extended development before implantation, and a marsupial in which pluripotent cells are generated from the trophoblast. In a cross-disciplinary approach we will employ transcriptomics, embryo and stem cell experimentation, and formal computational modelling to uncover the core biological program moulded by evolution into different forms. We aim to establish hitherto elusive chimaera-competent embryonic stem cells from species of importance for research, biomedical applications and livestock improvement. We will obtain fresh insight into the molecular logic governing early development, lineage plasticity, pluripotent identity, and stem cell self-renewal.
