An integrated atlas of human placental development delineates essential regulators of trophoblast stem cells
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ABSTRACT: The trophoblast lineage safeguards fetal development by mediating embryo implantation, immune tolerance, nutritional supply and gas exchange. Human trophoblast stem cells (hTSCs) provide a platform to study lineage specification of placental tissues; however, the regulatory network controlling self-renewal remains elusive. Here, we present a single-cell atlas of human trophoblast development from zygote to mid-gestation together with single-cell profiling of hTSCs. We determine the transcriptional networks of trophoblast lineages in vivo and leverage probabilistic modelling to identify a role for MAPK signalling in trophoblast differentiation. Placenta- and blastoid-derived hTSCs consistently map between late trophectoderm and early cytotrophoblast, in contrast to blastoid-trophoblast, which correspond to trophectoderm. We functionally assess the requirement of the predicted cytotrophoblast network in an siRNA-screen and reveal 15 essential regulators for hTSC self-renewal, including MAZ, NFE2L3, TFAP2C, NR2F2 and CTNNB1. Our human trophoblast atlas provides a powerful analytical resource to delineate trophoblast cell fate acquisition, to elucidate transcription factors required for hTSC self-renewal and to gauge the developmental stage of in vitro cultured cells.
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Funder: Centre for Trophoblast Research, University of Cambridge
Funder: Cambridge Philosophical Society
Funder: Pathological Society of Great Britain and Ireland; Id: http://dx.doi.org/10.13039/501100000672
Funder: Royal Society; Id: http://dx.doi.org/10.13039/501100000288
Funder: University of Cambridge; Id: http://dx.doi.org/10.13039/501100000735
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1477-9129