Acknowledgements: This publication is part of the Human Cell Atlas. The authors thank the Sanger Cellular Generation and Phenotyping (CGaP) Core Facility and the Sanger Core Sequencing pipeline for support with sample processing and sequencing library preparation; A. Surani for supplying the TSC lines; H. Okae and T. Arima for sharing permission; R. Argelaguet, V. Kleshchevnikov, S. van Dongen, M. Prete and S. Murray for insightful comments and web portal support; T. Porter and the Cellular Genetics wet lab team for experimental support; A. Garcia for graphical images; and A. Maartens for editing. Placental material was provided by the Joint MRC–Human Cell Atlas (MR/S036350/1). The authors are grateful to patients for donating tissue for research. We thank D. Moore and M. Maquinana and staff at Addenbrooke’s Hospital, Cambridge, UK. Supported by Wellcome Sanger core funding (WT206194 and 220540/Z/20/A) and the Wellcome Trust grant ‘Wellcome Strategic Support Science award’ (grant no. 211276/Z/18/Z). M.Y.T. held the Royal Society Dorothy Hodgkin Fellowship (DH160216) and Research Grant for Research Fellows (RGF\R1\180028) during this study and is also supported by funding from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (Grant agreement 853546). A.M. is in receipt of a Wellcome Trust Investigator Award (200841/Z/16/Z).The relationship between the human placenta—the extraembryonic organ made by the fetus, and the decidua—the mucosal layer of the uterus, is essential to nurture and protect the fetus during pregnancy. Extravillous trophoblast cells (EVTs) derived from placental villi infiltrate the decidua, transforming the maternal arteries into high-conductance vessels1. Defects in trophoblast invasion and arterial transformation established during early pregnancy underlie common pregnancy disorders such as pre-eclampsia2. Here we have generated a spatially resolved multiomics single-cell atlas of the entire human maternal–fetal interface including the myometrium, which enables us to resolve the full trajectory of trophoblast differentiation. We have used this cellular map to infer the possible transcription factors mediating EVT invasion and show that they are preserved in in vitro models of EVT differentiation from primary trophoblast organoids3, 4 and trophoblast stem cells5. We define the transcriptomes of the final cell states of trophoblast invasion: placental bed giant cells (fused multinucleated EVTs) and endovascular EVTs (which form plugs inside the maternal arteries). We predict the cell–cell communication events contributing to trophoblast invasion and placental bed giant cell formation, and model the dual role of interstitial EVTs and endovascular EVTs in mediating arterial transformation during early pregnancy. Together, our data provide a comprehensive analysis of postimplantation trophoblast differentiation that can be used to inform the design of experimental models of the human placenta in early pregnancy
