Kinetics and molecular hallmarks of the acquisition of developmental pluripotency during cellular reprogramming [ATAC-Seq]

The ability of induced pluripotent stem cells (iPSCs) to differentiate into all adult cell types makes them attractive for basic research and regenerative medicine applications, but it remains unknown when and how this hallmark of the pluripotent state is established. Here, we pinpoint the acquisition of developmental pluripotency in a suitable reprogramming system and show that nascent iPSCs abruptly and without extensive maturation period in culture become capable of generating all tissues upon injection into preimplantation embryos. Strikingly, the developmental potential of nascent iPSCs is comparable to or even surpasses that of high-quality established pluripotent cells. Further functional assays as well as genome-wide transcriptional and chromatin analyses suggest that cells acquiring developmental pluripotency exhibit a unique combination of molecular and functional properties that distinguish them from canonical pluripotency states. These include reduced clonal self-renewal potential and the elevated expression of transcriptional regulators of postimplantation development. Our observations close an important gap in our understanding of induced pluripotency and provide an improved roadmap of cellular reprogramming with ramifications for the biomedical use of iPSCs. ATAC-seq cells at four stages (MEF, Stage 1 or day 6, Stage 2 or day 6+4 and established iPSCs) in triplicate. Cells (except MEFs) were sorted for Oct4-GFP+