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

Abstract

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.

Basic Research Advances in China on Embryo Implantation, Placentation, and Parturition

“…1). Li et al 50 found that blastocyst-derived TNFα induces epithelial IHH, which stimulates expression of SHH in the stroma and thereby augments decidualization. Chen et al 51 further discovered that TNFα produced by the embryo promotes release of arachidonic acid from the epithelium to ignite fibroblast activation and decidualization through PGI2 and PPARδ.…”

“…1). Li et al 50 . found that blastocyst-derived TNFα induces epithelial IHH, which stimulates expression of SHH in the stroma and thereby augments decidualization.…”

Structure, function, and research progress of primary cilia in reproductive physiology and reproductive diseases

“…Research has demonstrated the presence of primary cilia in human endometrial stromal cells. Within stromal cells, Sonic Hedgehog (SHH) stimulates the canonical Hedgehog (Hh) signaling pathway via primary cilia and facilitates decidualization through mechanisms implicating interleukin-11 (IL-11) and primary cilia ( Li et al, 2023 ). Mounting evidence suggests that impaired decidualization is closely associated with Recurrent Implantation Failure (RIF).…”