An international research team led by scientists from the University of Vienna has uncovered new insights into how specialized cell types and communication networks at the interface between mother and fetus evolved over millions of years. These discoveries shed light on one of nature's most remarkable innovations – the ability to sustain a successful pregnancy. The findings have just been published in Nature Ecology & Evolution.

Pregnancy that lasts long enough to support full fetal development is a hallmark evolutionary breakthrough of placental mammals – a group that includes humans. At the center of this is the fetal-maternal interface: the site in the womb where a baby's placenta meets the mother's uterus, and where two genetically distinct organisms – mother and fetus – are in intimate contact and constant interaction. This interface has to strike a delicate balance: intimate enough to exchange nutrients and signals, but protected enough to prevent the maternal immune system from rejecting the genetically "foreign" fetus.

To uncover the origins and mechanisms behind this intricate structure, the team analyzed single-cell transcriptomes – snapshots of active genes in individual cells – from six mammalian species representing key branches of the mammalian evolutionary tree. These included mice and guinea pigs (rodents), macaques and humans (primates), and two more unusual mammals: the tenrec (an early placental mammal) and the opossum (a marsupial that split off from placental mammals before they evolved complex placentas).

A Cellular "Atlas of Mammal Pregnancy"

By analyzing cells at the fetal-maternal interface, the researchers were able to trace the evolutionary origin and diversification of the key cell types involved. Their focus was on two main players: placenta cells, which originate from the fetus and invade maternal tissue, and uterine stromal cells, which are of maternal origin and respond to this invasion.

Using molecular biology tools, the team identified distinct genetic signatures – patterns of gene activity unique to specific cell types and their specialized functions. Notably, they discovered a genetic signature associated with the invasive behavior of fetal placenta cells that has been conserved in mammals for over 100 million years. This finding challenges the traditional view that invasive placenta cells are unique to humans, and reveals instead that they are a deeply conserved feature of mammalian evolution. During this time, the maternal cells weren't static, either. Placental mammals, but not marsupials, were found to have acquired new forms of hormone production, a pivotal step toward prolonged pregnancies and complex gestation, and a sign that the fetus and the mother could be driving each other's evolution.

Cellular Dialogue: Between Cooperation and Conflict

To better understand how the fetal-maternal interface functions, the study tested two influential theories about the evolution of cellular communication between mother and fetus.

The first, the "Disambiguation Hypothesis," predicts that over evolutionary time, hormonal signals became clearly assigned to either the fetus or the mother – a possible safeguard to ensure clarity and prevent manipulation. The results confirmed this idea: certain signals, including WNT proteins, immune modulators, and steroid hormones, could be clearly traced back to one source tissue.

The second, the "Escalation Hypothesis" (or "genomic Conflict"), suggests an evolutionary arms race between maternal and fetal genes – with, for example, the fetus boosting growth signals while the maternal side tries to dampen them. This pattern was observed in a small number of genes, notably IGF2, which regulates growth. On the whole, evidence pointed to fine-tuned cooperative signaling.

"These findings suggest that evolution may have favored more coordination between mother and fetus than previously assumed," says Daniel J. Stadtmauer, lead author of the study and now a researcher at the Department of Evolutionary Biology, University of Vienna. "The so-called mother-fetus power struggle appears to be limited to specific genetic regions. Rather than asking whether pregnancy as a whole is conflict or cooperation, a more useful question may be: where is the conflict?"

Single-Cell Analysis: A Key to Evolutionary Discovery

The team's discoveries were made possible by combining two powerful tools: single-cell transcriptomics – which captures the activity of genes in individual cells – and evolutionary modeling techniques that help scientists reconstruct how traits might have looked in long-extinct ancestors. By applying these methods to cell types and their gene activity, the researchers could simulate how cells communicate in different species, and even glimpse how this dialogue has evolved over millions of years.

"Our approach opens a new window into the evolution of complex biological systems – from individual cells to entire tissues," says Silvia Basanta, co–first author and researcher at the University of Vienna. The study not only sheds light on how pregnancy evolved, but also offers a new framework for tracking evolutionary innovations at the cellular level – insights that could one day improve how we understand, diagnose, or treat pregnancy-related complications.

The research was conducted in the labs of Mihaela Pavličev at the Department of Evolutionary Biology, University of Vienna, and Günter Wagner at Yale University. Wagner is Professor Emeritus at Yale and a Senior Research Fellow at the University of Vienna. The study was supported by the John Templeton Foundation and the Austrian Science Fund (FWF).