Partial embryo loss caused by disruption of the placental hormone CTRP6 coincides with dNK cell abnormalities during pregnancy

The proper embryo maintenance depends on tight maternal-fetal communications. C1q/TNF-related protein 6 (<i>C1qtnf6</i>)-encoding a hormone-like CTRP6 protein-exhibits placenta-enriched expression and its deficiency causes partial fetal loss. Here, we demonstrate that abundant <i>C1qtnf6</i> expression is distinctive for hemochorial placentae, which have deep uterine invasion. <i>C1qtnf6</i> is most highly expressed in human extravillous trophoblasts and mouse spiral artery-associated trophoblast giant cells, which are functionally analogous cells that invade uterines. The partial embryo loss is mainly due to impaired CTRP6 production by placenta, and key natural killer effectors in maternal-fetal interface (MFI) are impaired by C1qtnf6-deficiency. C1qtnf6-deficiency simultaneously impairs the amount and effector production of decidual NK (dNK) cells, yet the placental structure and spiral artery remodeling appear normal. CTRP6 injection rescues the dNK cell abnormality and alleviates embryo loss. Overall, the partial embryo loss by CTRP6-deficiency coincides with dNK cell abnormality, which highlights the importance of MFI immune microenvironment for embryo maintenance.