IHH, SHH, and primary cilia mediate epithelial-stromal cross-talk during decidualization in mice

The establishment of pregnancy depends on interactions between the epithelial and stromal cells of the endometrium that drive the decidual reaction that remodels the stroma and enables embryo implantation. Decidualization in mice also depends on ovarian Hormones and the presence of a blastocyst. Hedgehog signaling is transduced by primary cilia in many tissues and is involved in epithelial-stromal cross-talk during decidualization. We found that primary cilia on mouse uterine stromal cells increased in number and length during early pregnancy and were required for decidualization. In vitro and in vivo, progesterone promoted stromal ciliogenesis and the production of Indian Hedgehog (IHH) in the epithelium and Sonic Hedgehog (SHH) in the stroma. Blastocyst-derived TNF-α also induced epithelial IHH, which stimulated the production of SHH in the stroma through a mechanism that may involve the release of arachidonic acid from epithelial cells. In the stroma, SHH activated canonical Hedgehog signaling through primary cilia and promoted decidualization through a mechanism that depended on interleukin-11 (IL-11) and primary cilia. Our findings identify a primary cilia-dependent network that controls endometrial decidualization and suggest primary cilia as a candidate therapeutic target for endometrial diseases.