The selection arena in early human blastocysts resolves the pluripotent inner cell mass

Abstract

Is the human early embryo unique in lacking an inner cell-mass (ICM) and having parallel development? We reanalyse single-cell transcriptomic data and stain human embryos in situ to reveal both classical step-wise development and a transcriptomically homologous ICM. This apparent classicism obscures phylogenetic singularity: unlike mice, human epiblast has self-renewal hallmarks and we have abundant blastocyst non-committed cells (NCCs), part of an apoptosis-mediated purging process. The transcriptomes of the pluripotent cells are fast evolving, in large part owing to endogenous retrovirus H (ERVH) activity, rendering all primate embryos unique. Each species is characterised by the ERVHs that are active and the neighbour genes whose expression are modulated. ERVH is associated with recent major gene expression gain and loss events of pluripotency{-}associated genes. Not least through lack of HERVH expression, the current portfolio of naive cultures, putative in vitro mimics of pluripotent cells, are both developmentally and phylogenetically "confused". O_LIAnalysis of single cell transcriptomics and in situ stainings uncover, and enable characterization of, human inner cell mass (ICM) C_LIO_LICell purging via apoptosis defines a phylogenetically restricted class of blastocyst non-committed cells (NCCs), whereas HERVs in conjunction with host defence mark the committed cells of ICM C_LIO_LIFast transcriptome evolution is particular to the pluripotent epiblast and is mostly due to the primate-specific transposable element, HERVH C_LIO_LICurrent naive cultures dont reflect human uniqueness being phylogenetically and developmentally "confused". C_LI