PRIN 2022 Scorrimento - Prot. 2022PR33RS

In normal human placentation, uterine invasion by trophoblast cells and subsequent spiral artery remodeling depend on the cooperation between fetal trophoblasts and maternal decidual, myometrial, immune, and vascular cells of the uterine wall. Aberrant function of one or several of these cell-types could theoretically impair placentation leading to the development of preeclampsia (PE). The pathogenesis of PE is traditionally described with a two-stage model. In the first pre-clinical stage, the abnormal remodeling of maternal spiral arteries leads to placental ischemia and structural damage. In the second one, the damaged placenta releases factors into the maternal circulation and causes diffuse maternal endothelial damage and an exaggerated systemic inflammatory response, that eventually manifest as hypertension and end-organ injury, both clinical manifestations of PE. Although the shallow invasion of cytotrophoblast cells (CTB) into the spiral arteries has been recognized in the pathogenesis of PE, the cause of this defective invasion remains unknown. Recently the contribution of maternal uterine factors regulating the preparation of the endometrium to implantation in the pathogenesis of PE is receiving increasing attention. Aim of this project is to test the hypothesis that decidualization failure contributes to the pathogenesis of PE and investigate which dysregulated molecular pathways are involved in the development of decidualization resistance. Since this pathogenetic cascade and a clear placental pathology is associated with early-onset preeclampsia (EO-PE), we have chosen to investigate only this form of disease. The role of maternal endometrium in decidualization failure will be investigated using endometrial stromal cells isolated from non-pregnant women with either a previous history of EO-PE or experiencing recurrent pregnancy loss (RPL) and compared with control women with previous uncomplicated pregnancy. The use of endometrial tissue from both EO-PE and RPL is justified by the fact that women experiencing RPL have a higher risk of developing PE, suggesting that PE and RPL share pathogenic factors. Moreover, we plan to use undifferentiated human trophoblast stem cells, which can differentiate into all trophoblast lineages, to investigate factors regulating decidual invasion. Finally, samples of placental decidua (basalis and parietalis) will be collected at the time of delivery from women with PE and women with uncomplicated pregnancy and used to confirm whether alterations observed in the non-pregnant decidual tissue persist and progress during pregnancy. Research on the underlying mechanisms that lead to deficient decidualization would be especially valuable since these studies could enable identification of women at increased risk for developing PE and aid the development of therapies focused on improving decidualization, which perhaps may contribute to the prevention of PE.

Working group:

• Rosanna Apa - Responsabile scientifico UCSC

Partners:

• Università degli Studi di Roma Tor Vergata
• Università degli Studi di Roma La Sapienza