At the frontier between two lives—the evolutionary origins of pregnancy

Amazing stuff!

"... 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. ...

Pregnancy that lasts long enough to support full fetal development is a hallmark evolutionary breakthrough of placental mammals ... 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). ...

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 more than 100 million years. ...

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 ..."

From the abstract:

"How fetal and maternal cell types have co-evolved to enable mammalian placentation poses a unique evolutionary puzzle.

Here we integrate and compare single-cell transcriptomes from six species bracketing therian mammal diversity: opossum (a marsupial), Malagasy common tenrec (an afrotherian), mouse and guinea pig (rodents), and macaque and human (primates).

We identify a conserved transcriptomic signature of invasive trophoblast across eutherians, probably representing a cell type family that radiated with the evolution of haemochorial placentation.

In the maternal stroma, comparative analysis reveals that the endocrine decidual cell evolved from an immunomodulatory predecidual cell type retained in Tenrec and resembling early human decidua.

Fetal and maternal cell signalling shows a pronounced tendency towards disambiguation—the exclusive expression of ligands by only one partner—although few ligand–receptor pairs follow an escalatory arms race dynamic. Finally, we reconstruct the uteroplacental cell–cell communication networks of extinct mammalian ancestors, identifying signalling innovations and widespread integration of fetal trophoblast and maternal decidual cells into signalling networks. Together, these results reveal a dynamic history of cell type innovation and co-evolution at the fetal–maternal interface."

At the frontier between two lives—the evolutionary origins of pregnancy

At the Frontier Between Two Lives – The Evolutionary Origins of Pregnancy (original press release)

Cell type and cell signalling innovations underlying mammalian pregnancy (open access)

Fig. 1: Single-cell transcriptomic atlases of six mammalian species spanning the diversification of viviparity.