Cell type and cell signalling innovations underlying mammalian pregnancy.

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.