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An integrated atlas of human placental development delineates essential regulators of trophoblast stem cells.

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Chen, Yutong 
Siriwardena, Dylan 
Penfold, Christopher 
Pavlinek, Adam 
Boroviak, Thorsten E  ORCID logo


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.



Human development, Human trophoblast stem cells, Placenta development, Self-renewal, Trophoblast, Basic-Leucine Zipper Transcription Factors, Cell Differentiation, Female, Humans, Placenta, Placentation, Pregnancy, Stem Cells, Trophoblasts

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The Company of Biologists
Wellcome Trust (206684/Z/17/Z)
Royal Society (IEC\R3\183044)