Origin of extra-embryonic mesenchyme points to evolutionary novelty in primate early development [scRNA-seq]

As ontogeny does not recapitulate phylogeny and little developmental restraint exists prior to gastrulation, early mammalian development differs significantly between species. A prime example is the temporal difference in the first emergence of extra-embryonic mesenchymal cells (ExMC) between mouse and human. Here, we report a fast and efficient in vitro cell model of human ExMC formation from induced pluripotent stem cells. This ExMC emerges from the apparent late blastocystic trophoblast. We define HAND1 as an essential regulator of ExMC specification, with HAND1 null cells reverting to the trophoblast lineage. Regulatory phenotyping defines primary target genes of, and primate-specific genomic regions bound by, HAND1. These data emphasize the nascent evolutionary innovation in early development relevant to human health but, through pleiotropy, also to later in life human biology. The novel findings that trophectoderm is a source of ExMC lineage and how recently evolved young transposable elements regulate this process emphasize the evolutionary novelties of our model to explore the primate embryogenesis.