The decidua is a hallmark of reproduction in many placental mammals. Differentiation of decidual stromal cells is known to be induced by progesterone and the cyclic AMP/protein kinase A (cAMP/PKA) pathway. Several candidates have been identified as the physiological stimulus for adenylyl cyclase activation, but their relative importance remains unclear. To bypass this uncertainty, the standard approach for in vitro experiments uses membrane-permeable cAMP and progestin. We phylogenetically infer that prostaglandin E₂ (PGE₂) likely was the signal that ancestrally induced decidualization in conjunction with progesterone. This suggests that PGE₂ and progestin should be able to activate the core gene regulatory network of decidual cells. To test this prediction, we performed a genome-wide study of gene expression in human endometrial fibroblasts decidualized with PGE₂ and progestin. Comparison to a cAMP-based protocol revealed shared activation of core decidual genes and decreased induction of senescence-associated genes. Single-cell transcriptomics of PGE₂-mediated decidualization revealed a distinct, early-activated state transitioning to a differentiated decidual state. PGE₂-mediated decidualization was found to depend upon progestin-dependent induction of PGE₂ receptor 2 (PTGER2) which in turn leads to PKA activation upon PGE₂ stimulation. Progesterone-dependent induction of PTGER2 is absent in opossum, an outgroup taxon of placental mammals which is incapable of decidualization. Together, these findings suggest that the origin of decidualization involved the evolution of progesterone-dependent activation of the PGE₂/PTGER2/PKA axis, facilitating entry into a PKA-dominant rather than AKT-dominant cellular state. We propose the use of PGE₂ for in vitro decidualization as an alternative to 8-Br-cAMP.

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.

Synopsis: Embryo implantation is a hallmark of the female reproductive biology of eutherian (placental) mammals and does not exist in a sustainable form in any other vertebrate group. Implantation is the initial process that leads to a sustained fetal-maternal unit engendering a complex functional relationship between the mother and the embryo/fetus. The nature of this relationship is often portrayed as one of conflict between an aggressive embryo and a passive or defensive maternal organism. Recent progress in elucidating the evolutionary origin of eutherian pregnancy leads to a different picture. The emerging scenario suggests that the very initial stages in the evolution of embryo implantation required evolutionary changes to the maternal physiology which modified an ancestral generic mucosal inflammation in response to the presence of the embryo into an active embedding process. This “female-first” evolutionary scenario also explains the role of endometrial receptivity in human pregnancy. On the marsupial side, where in most animals the fetal–maternal interaction is short and does not lead to a long term sustainable placentation, the relationship is mutual. In these mammals, uterine inflammation is followed by parturition in short order. The inflammatory signaling pathways, however, are cooperative, i.e., they are performed by both the fetus and the mother and therefore we call this relationship “cooperative inflammation.” Based on these discoveries we reconceive the narrative of the maternal–fetal relationship.

What the molecular mechanisms underlying the evolutionary origin of novel cell types are is a major unresolved question in biology. The uterine decidual cell is a novel cell type of placental mammals which serves as the interface between maternal and fetal tissues during pregnancy. In this paper, we investigate two models for the nature of the differentiation of decidual cells: first, that it represents a mesenchymal-epithelial transition (MET), and second, that it evolved from wound-induced fibroblast activation (WIFA). Immunocytochemistry and RNA-seq analysis of decidualizing human endometrial fibroblasts cast doubt on the MET hypothesis and instead demonstrate a similarity between decidualization and fibroblast activation, including a central role for TGFB1. Through single-cell RNA-seq, we found a transient myofibroblast-like cell population in the in vitro differentiation trajectory of human decidual cells and found that these cells represent a pre-decidual state approaching the inferred transcriptomic transition to decidual cells. We propose an evolutionary developmental model wherein the decidual cell is a novel cell type not equivalent to the myofibroblast, but the process of decidual differentiation itself evolved as an endometrial-specific modification to fibroblast activation in response to the wound caused by embryo implantation.

Evolutionary biologists have long been fascinated by pregnancy sickness, the heritable, stereotyped syndrome in early pregnancy that usually consists of benign nausea and vomiting and in around 1% of cases progresses to the pathological extreme hyperemesis gravidarum. Identification of the placental hormone GDF15 as a principal causal factor justifies reassessment of its proximate and ultimate causes. This Review synthesizes knowledge of pregnancy sickness at the four levels of analysis of classical ethology—mechanism, development, phylogeny, and adaptive function. Emerging insight into GDF15’s role in innate sickness behaviors suggests pregnancy sickness is a heightened state of pre-existing behavioral defenses triggered by placental production of an emetogenic hormone which may hold a different primary function. Comparison of transcriptomes reveals that placental GDF15 production rose 100- to 1000-fold to human-like levels in catarrhine primates, and is low or absent in New World monkeys, rodents, and other mammals, with the possible exception of elephants. This suggests that pregnancy sickness is phylogenetically restricted yet not human-specific, and associates with innovations in syncytiotrophoblast biology rather than diet. I re-evaluate leading adaptive hypotheses (prophylactic, metabolic rewiring, placental growth, and anti-rejection) and argue that the key to adjudicating among them hinges on whether GDF15 acts locally through non-canonical receptors and whether additional factors distinguish pregnancy sickness from sickness behavior. Finally, I evaluate explanations for the persistent risk of hyperemesis gravidarum in modern humans, including trade-offs, mismatch, and conflict. With recent advances, pregnancy sickness is not just a curiosity of human evolution, but a compelling opportunity to investigate the mechanistic bases of complex adaptive behaviors.