PMID- 30487605 OWN - NLM STAT- MEDLINE DCOM- 20190617 LR - 20240328 IS - 1476-4687 (Electronic) IS - 0028-0836 (Print) IS - 0028-0836 (Linking) VI - 564 IP - 7735 DP - 2018 Dec TI - Trophoblast organoids as a model for maternal-fetal interactions during human placentation. PG - 263-267 LID - 10.1038/s41586-018-0753-3 [doi] AB - 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 models(1). 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 arteries(2). 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 criteria(3). 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. FAU - Turco, Margherita Y AU - Turco MY AD - Department of Pathology, University of Cambridge, Cambridge, UK. myt25@cam.ac.uk. AD - Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK. myt25@cam.ac.uk. AD - Centre for Trophoblast Research, University of Cambridge, Cambridge, UK. myt25@cam.ac.uk. FAU - Gardner, Lucy AU - Gardner L AD - Department of Pathology, University of Cambridge, Cambridge, UK. AD - Centre for Trophoblast Research, University of Cambridge, Cambridge, UK. FAU - Kay, Richard G AU - Kay RG AD - Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK. FAU - Hamilton, Russell S AU - Hamilton RS AD - Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK. AD - Centre for Trophoblast Research, University of Cambridge, Cambridge, UK. FAU - Prater, Malwina AU - Prater M AD - Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK. AD - Centre for Trophoblast Research, University of Cambridge, Cambridge, UK. FAU - Hollinshead, Michael S AU - Hollinshead MS AD - Department of Pathology, University of Cambridge, Cambridge, UK. FAU - McWhinnie, Alasdair AU - McWhinnie A AD - Anthony Nolan Research Institute, Royal Free Hospital, London, UK. FAU - Esposito, Laura AU - Esposito L AD - Department of Pathology, University of Cambridge, Cambridge, UK. FAU - Fernando, Ridma AU - Fernando R AD - Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK. AD - Centre for Trophoblast Research, University of Cambridge, Cambridge, UK. FAU - Skelton, Helen AU - Skelton H AD - Department of Pathology, University of Cambridge, Cambridge, UK. FAU - Reimann, Frank AU - Reimann F AD - Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK. FAU - Gribble, Fiona M AU - Gribble FM AD - Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK. FAU - Sharkey, Andrew AU - Sharkey A AD - Department of Pathology, University of Cambridge, Cambridge, UK. AD - Centre for Trophoblast Research, University of Cambridge, Cambridge, UK. FAU - Marsh, Steven G E AU - Marsh SGE AD - Anthony Nolan Research Institute, Royal Free Hospital, London, UK. AD - UCL Cancer Institute, Royal Free Campus, London, UK. FAU - O'Rahilly, Stephen AU - O'Rahilly S AD - Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK. FAU - Hemberger, Myriam AU - Hemberger M AD - Centre for Trophoblast Research, University of Cambridge, Cambridge, UK. AD - Epigenetics Programme, The Babraham Institute, Cambridge, UK. FAU - Burton, Graham J AU - Burton GJ AD - Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK. gjb2@cam.ac.uk. AD - Centre for Trophoblast Research, University of Cambridge, Cambridge, UK. gjb2@cam.ac.uk. FAU - Moffett, Ashley AU - Moffett A AD - Department of Pathology, University of Cambridge, Cambridge, UK. am485@cam.ac.uk. AD - Centre for Trophoblast Research, University of Cambridge, Cambridge, UK. am485@cam.ac.uk. LA - eng GR - MR/L020041/1/MRC_/Medical Research Council/United Kingdom GR - 106262/WT_/Wellcome Trust/United Kingdom GR - 200841/WT_/Wellcome Trust/United Kingdom GR - MR/M009041/1/MRC_/Medical Research Council/United Kingdom GR - MC_UU_00014/5/MRC_/Medical Research Council/United Kingdom GR - MC_UU_12012/1/MRC_/Medical Research Council/United Kingdom GR - WT_/Wellcome Trust/United Kingdom GR - MC_UU_12012/3/MRC_/Medical Research Council/United Kingdom GR - MC_UU_00014/3/MRC_/Medical Research Council/United Kingdom GR - 106263/WT_/Wellcome Trust/United Kingdom GR - MR/M024873/1/MRC_/Medical Research Council/United Kingdom GR - MR/P001092/1/MRC_/Medical Research Council/United Kingdom GR - 200841/Z/16/Z/WT_/Wellcome Trust/United Kingdom GR - MC_UU_12012/5/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181128 PL - England TA - Nature JT - Nature JID - 0410462 RN - 0 (Chorionic Gonadotropin) RN - 0 (GDF15 protein, human) RN - 0 (Growth Differentiation Factor 15) RN - 0 (HLA Antigens) RN - 0 (Pregnancy-Specific beta 1-Glycoproteins) SB - IM CIN - Nat Methods. 2019 Feb;16(2):144. PMID: 30700892 MH - Cell Differentiation MH - Cell Movement MH - Chorionic Gonadotropin/metabolism MH - DNA Methylation MH - Decidua/cytology MH - Female MH - Growth Differentiation Factor 15/metabolism MH - HLA Antigens/metabolism MH - Humans MH - *Maternal-Fetal Relations MH - *Models, Biological MH - Organoids/*cytology/metabolism/*physiology MH - *Placentation MH - Pregnancy MH - Pregnancy-Specific beta 1-Glycoproteins/metabolism MH - *Tissue Culture Techniques MH - Transcriptome/genetics MH - Trophoblasts/*cytology/metabolism/*physiology PMC - PMC7220805 MID - EMS80369 COIS- Competing interests The authors declare no competing interests. EDAT- 2018/11/30 06:00 MHDA- 2019/06/18 06:00 PMCR- 2020/05/13 CRDT- 2018/11/30 06:00 PHST- 2018/04/03 00:00 [received] PHST- 2018/10/31 00:00 [accepted] PHST- 2018/11/30 06:00 [pubmed] PHST- 2019/06/18 06:00 [medline] PHST- 2018/11/30 06:00 [entrez] PHST- 2020/05/13 00:00 [pmc-release] AID - 10.1038/s41586-018-0753-3 [pii] AID - 10.1038/s41586-018-0753-3 [doi] PST - ppublish SO - Nature. 2018 Dec;564(7735):263-267. doi: 10.1038/s41586-018-0753-3. Epub 2018 Nov 28.