Fig 7. The eutherian mammal decidual cell type evolved from a cellular stress response.

(A) Phylogeny showing the three major mammalian clades. Embedded in the species tree, the cell type tree for ESF and DSC cell types is drawn. Paleo-ESF is an ancestral cell type to crown group neo-ESF, such as human HsESF, which arose after the split of metatherian (marsupials) and eutherian (placental) mammals. The eutherian neo-ESF is defined by its ability to differentiate into DSC, which is the sister cell type to eutherian neo-ESF. (B) Proposed model of the evolution of eutherian DSC from a paleo-ESF ancestral cell type. Paleo-ESF underwent a stress response during the short gestational period in which fetal–maternal interactions lead the proinflammatory, stress-induced parturition seen in crown marsupials. The ancestral stem eutherian rewired the stress-related regulatory modules to stabilize an alternative gene regulatory state and control the expression of effector genes, which allow fetal implantation and invasive placentation, long gestation, and anti-inflammatory phenotypes typical of crown eutherian mammals. DSC, decidual stromal cell; ESF, endometrial stromal fibroblast; HsESF, human endometrial stromal fibroblast.