Preconceptional immunomodulation partially corrects pregnancy associated abnormalities induced by endometriosis in a mice model, with a normalization of transcriptional alteration observed in the developing fetal maternal interface at the single cell level.

Abstract

Endometriosis is a chronic disease of gynaecological origin that affects approximately 10% of women worldwide and has a significant impact on patients lives. Women with endometriosis attempting to conceive may experience infertility and have a higher risk of obstetric complications. They are also more likely to miscarry and have placental defects during pregnancy. The impact of endometriosis on pregnancy remains unclear. Defects in implantation and placentation may be present, but these processes are difficult to study in human subjects. To address this issue, we used a surgically induced mouse model of endometriosis and examined pregnancy in the CBAxDBA crossbreed, which is commonly employed to study pregnancy immunology. We examined early (E9.5) and late (E18.5) gestational stages. In this model, we confirmed that the presence of endometriosis-like lesions resulted in fewer implantations and a higher proportion of fetal resorption, which is analogous to miscarriage. When an immune tolerance was induced previous to the endometriosis induction, we observed that endometriotic lesions were smaller, and gestational complications were mostly corrected. At early gestation (E9.5), fetal-maternal interfaces were retrieved to assess the potential impact of endometriosis and immunomodulation on placental development using single-cell RNA-sequencing. Our data show that most changes induced by endometriosis occur in decidual stromal cells, which originate from the endometrium. In these cells, we observed a consistent upregulation of Gata4, a transcription factor previously found to be elevated in the endometrium of women with endometriosis. We also observed downregulation of Prap1, which is an indicator of uterine receptivity and successful implantation in mice. In the mice where immune tolerance was induced, the endometriosis associated transcriptomic changes were partially reversed. In immune cells, endometriosis leads to an inflammation-associated signature. Additionally, the interferon gamma response is reduced in NK cells, which has been shown to be crucial for spiral artery remodelling and decidual integrity, which may be involved in the observed increased resorption rate. Overall, our findings provide new insights into endometriosis-associated infertility and pregnancy complications in a mouse model that can be partially corrected by immune modulation. These results suggest that targeting the immune system should be considered in future studies to improve pregnancy outcomes in patients with endometriosis.