Trophoblast organoids as a model for maternal–fetal interactions during human placentation

Margherita Y. Turco (), Lucy Gardner, Richard G. Kay, Russell S. Hamilton, Malwina Prater, Michael S. Hollinshead, Alasdair McWhinnie, Laura Esposito, Ridma Fernando, Helen Skelton, Frank Reimann, Fiona M. Gribble, Andrew Sharkey, Steven G. E. Marsh, Stephen O’Rahilly, Myriam Hemberger, Graham J. Burton () and Ashley Moffett ()
Additional contact information
Margherita Y. Turco: University of Cambridge
Lucy Gardner: University of Cambridge
Richard G. Kay: Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital
Russell S. Hamilton: University of Cambridge
Malwina Prater: University of Cambridge
Michael S. Hollinshead: University of Cambridge
Alasdair McWhinnie: Anthony Nolan Research Institute, Royal Free Hospital
Laura Esposito: University of Cambridge
Ridma Fernando: University of Cambridge
Helen Skelton: University of Cambridge
Frank Reimann: Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital
Fiona M. Gribble: Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital
Andrew Sharkey: University of Cambridge
Steven G. E. Marsh: Anthony Nolan Research Institute, Royal Free Hospital
Stephen O’Rahilly: Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital
Myriam Hemberger: University of Cambridge
Graham J. Burton: University of Cambridge
Ashley Moffett: University of Cambridge

Nature, 2018, vol. 564, issue 7735, 263-267

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41586-018-0753-3

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