A spatially resolved timeline of the human maternal–fetal interface

• Published in: Nature (London) Vol. 619; no. 7970; pp. 595 - 605
• Main Authors: Greenbaum, Shirley, Averbukh, Inna, Soon, Erin, Rizzuto, Gabrielle, Baranski, Alex, Greenwald, Noah F., Kagel, Adam, Bosse, Marc, Jaswa, Eleni G., Khair, Zumana, Kwok, Shirley, Warshawsky, Shiri, Piyadasa, Hadeesha, Goldston, Mako, Spence, Angie, Miller, Geneva, Schwartz, Morgan, Graf, Will, Van Valen, David, Winn, Virginia D., Hollmann, Travis, Keren, Leeat, van de Rijn, Matt, Angelo, Michael
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.07.2023; Nature Publishing Group
• Subjects: 13/51; 38/39; 631/136; 631/250; 631/443/494; 82; 82/1; 82/58; Angiogenesis; Antibodies; Arteries; Arteries - physiology; Blood vessels; CD163 antigen; Cell activation; Cells; Datasets as Topic; Decidua; Decidua - blood supply; Decidua - cytology; Decidua - immunology; Decidua - physiology; Endothelium; Female; Fetuses; Galectin-9; Gene Expression Profiling; Gestational Age; Humanities and Social Sciences; Humans; Immune system; Immunoregulation; Ion beams; Maternal-Fetal Exchange - genetics; Maternal-Fetal Exchange - immunology; Maternal-Fetal Exchange - physiology; Metabolism; Microenvironments; multidisciplinary; Obstetrics; Pregnancy; Pregnancy Trimester, First - genetics; Pregnancy Trimester, First - metabolism; Pregnancy Trimester, First - physiology; Proteomics; Science; Science (multidisciplinary); Smooth muscle; Stromal cells; Time Factors; Transcriptomics; Trophoblasts - cytology; Trophoblasts - immunology; Trophoblasts - physiology; Uterus; Uterus - blood supply; Uterus - cytology; Uterus - immunology; Uterus - physiology; Veins & arteries
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-023-06298-9

Beginning in the first trimester, fetally derived extravillous trophoblasts (EVTs) invade the uterus and remodel its spiral arteries, transforming them into large, dilated blood vessels. Several mechanisms have been proposed to explain how EVTs coordinate with the maternal decidua to promote a tissue microenvironment conducive to spiral artery remodelling (SAR) 1 – 3 . However, it remains a matter of debate regarding which immune and stromal cells participate in these interactions and how this evolves with respect to gestational age. Here we used a multiomics approach, combining the strengths of spatial proteomics and transcriptomics, to construct a spatiotemporal atlas of the human maternal–fetal interface in the first half of pregnancy. We used multiplexed ion beam imaging by time-of-flight and a 37-plex antibody panel to analyse around 500,000 cells and 588 arteries within intact decidua from 66 individuals between 6 and 20 weeks of gestation, integrating this dataset with co-registered transcriptomics profiles. Gestational age substantially influenced the frequency of maternal immune and stromal cells, with tolerogenic subsets expressing CD206, CD163, TIM-3, galectin-9 and IDO-1 becoming increasingly enriched and colocalized at later time points. By contrast, SAR progression preferentially correlated with EVT invasion and was transcriptionally defined by 78 gene ontology pathways exhibiting distinct monotonic and biphasic trends. Last, we developed an integrated model of SAR whereby invasion is accompanied by the upregulation of pro-angiogenic, immunoregulatory EVT programmes that promote interactions with the vascular endothelium while avoiding the activation of maternal immune cells. A multiomics approach is used to produce a spatiotemporal atlas of the human maternal–fetal interface in the first half of pregnancy, revealing relationships among gestational age, extravillous trophoblasts and spiral artery remodelling.