title: The cellular origins and evolution of the maternal-fetal interface in mammals : Final report DFG Project number: 433034324
creator: Kaessmann, Henrik
creator: Anders, Simon
creator: Stegle, Oliver
subject: ddc-570
subject: 570 Life sciences
description: The placenta is a fascinating evolutionary innovation—an entirely new organ that arose in mammals to enable pregnancy and mediate physiological exchange between mother and fetus. Yet, how this organ originated, diversified, and is regulated at the cellular level across species remains poorly understood. In this project, we set out to explore the evolution and development of the placenta through a deep, comparative lens, using single-cell transcriptomic and epigenomic profiling across a diverse set of mammals.  We generated nearly 400,000 single-nucleus transcriptomes from the maternal and fetal components of the placenta in nine species: human, marmoset, mouse, rat, guinea pig, rabbit, sheep, horse, and opossum. These datasets span key stages of pregnancy and enabled the generation of high-resolution, cross-species cell atlases of the maternal-fetal interface. In parallel, we produced high-quality epigenomic data for the mouse placenta, to understand the gene regulatory architecture driving cell differentiation.  Our analyses revealed striking evolutionary innovations in murid rodents, such as the emergence of novel trophoblast cell (sub)types—including the split of syncytiotrophoblast into two layer-specific subtypes, sinusoidal giant cells, and spongiotrophoblasts—that are absent in humans, primates, and other mammals. Using gene expression similarity and phylogenetic mapping across six core species, we reconstructed the evolutionary history of trophoblast cell types, showing that new cell types emerged in the murid lineage ~27 million years ago, fundamentally reshaping the placental interface in rodents.  To investigate the regulatory mechanisms behind these changes, we developed novel methods to integrate the transcriptomic and epigenomic data, combining autoencoder-based neural networks, tailored statistical models, and custom strategies to overcome challenges posed by large developmental time gaps. This enabled us to trace the regulatory divergence between syncytiotrophoblast subtypes, highlighting transcription factors such as CREB5 and Jun-AP1 as key drivers of subtype specification. These TFs target genes involved in cytoskeletal remodeling, suggesting a functional link between gene regulation and the morphological adaptation of trophoblasts in fetal versus maternal regions of the placenta.  Our findings position the placenta as a unique outlier among mammalian organs—defined not by the conservation of ancestral cell types, but by remarkable cell-type innovation. This exceptional evolutionary plasticity makes it an ideal system for addressing one of the most fundamental questions in biology: how do new cell types evolve?
date: 2025
type: Other
type: info:eu-repo/semantics/report
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserver/37236/7/Kaessmann_DFG_Final_Report_Placenta_2025.pdf
identifier: DOI:10.11588/heidok.00037236
identifier: urn:nbn:de:bsz:16-heidok-372362
identifier:   Kaessmann, Henrik ; Anders, Simon ; Stegle, Oliver  (2025) The cellular origins and evolution of the maternal-fetal interface in mammals : Final report DFG Project number: 433034324.  [Other]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/37236/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng