The placenta is the extraembryonic organ that supports the fetus during intrauterine life. Although placental dysfunction results in major disorders of pregnancy with immediate and lifelong consequences for the mother and child, our knowledge of the human placenta is limited owing to a lack of functional experimental models1. After implantation, the trophectoderm of the blastocyst rapidly proliferates and generates the trophoblast, the unique cell type of the placenta. In vivo, proliferative villous cytotrophoblast cells differentiate into two main sub-populations: syncytiotrophoblast, the multinucleated epithelium of the villi responsible for nutrient exchange and hormone production, and extravillous trophoblast cells, which anchor the placenta to the maternal decidua and transform the maternal spiral arteries2. Here we describe the generation of long-term, genetically stable organoid cultures of trophoblast that can differentiate into both syncytiotrophoblast and extravillous trophoblast. We used human leukocyte antigen (HLA) typing to confirm that the organoids were derived from the fetus, and verified their identities against four trophoblast-specific criteria3. The cultures organize into villous-like structures, and we detected the secretion of placental-specific peptides and hormones, including human chorionic gonadotropin (hCG), growth differentiation factor 15 (GDF15) and pregnancy-specific glycoprotein (PSG) by mass spectrometry. The organoids also differentiate into HLA-G+ extravillous trophoblast cells, which vigorously invade in three-dimensional cultures. Analysis of the methylome reveals that the organoids closely resemble normal first trimester placentas. This organoid model will be transformative for studying human placental development and for investigating trophoblast interactions with the local and systemic maternal environment.
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Microarray data for Fig. 2 and Extended Data Figs. 4 and 5 have been deposited in the ArrayExpress database at EMBL-EBI under accession number E-MTAB-6683. Illumina EPIC methylation array data for Fig. 2 and Extended Data Fig. 5 have been deposited in the ArrayExpress database at EMBL-EBI under accession number E-MTAB-7204. The mass spectrometry proteomics data for Extended Data Table 3 and Supplementary Table 2 have been deposited to the ProteomeXchange Consortium via the PRIDE36 partner repository (https://www.ebi.ac.uk/pride/archive/) with the dataset identifier PXD009118 and 10.6019/PXD009118. All other data that support the findings of this study are available from the corresponding authors upon reasonable request.
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The authors are grateful to patients for donating tissue for research. We thank D. Moore and staff at the Addenbrooke’s Hospital, Cambridge; J. Bauer, E. Clemente, E. Farnell, C. Reitter from Cambridge Genomic Services, Department of Pathology; K. Burling and Core Biochemical Assay Laboratory staff at NIHR Cambridge Biomedical Research Centre; I. Simonic; and T. Cindrova-Davies, H. W. Yung, B. D. Simons, B. K. Koo, M. Huch, Y. W. Loke and all members of the Moffett and Burton laboratories. This work was funded by Centre for Trophoblast Research, University of Cambridge and Medical Research Council (MR/L020041/1). A. Moffett holds a Wellcome Trust investigator award (200841/Z/16/Z). M.Y.T. received funding from EU Seventh Framework Programme for research, technological development and demonstration (PIEF-GA-2013-629785) and now holds a Royal Society Dorothy Hodgkin Fellowship. F.R. and F.M.G. hold Wellcome Trust joint investigator awards (106262/Z/14/Z and 106263/Z/14/Z), and funding from MRC-Metabolic Diseases Unit (MRC_MC_UU_12012/3), NIHR-Cambridge BRC and AZ/MedImmune.
Nature thanks M. Roberts and the anonymous reviewer(s) for their contribution to the peer review of this work.
Extended data figures and tables
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Nature Reviews Genetics (2019)