Human placental mesenchymal stromal cells are ciliated and their ciliation is compromised in preeclampsia

Abstract

Background The development of the human placenta is tightly coordinated by a multitude of placental cell types, including human chorionic villi mesenchymal stromal cells (hCV-MSCs). Defective hCV-MSCs have been reported in preeclampsia (PE), a gestational hypertensive disease characterized by maternal endothelial dysfunction and systemic inflammation. Our goal was to determine whether hCV-MSCs are ciliated and whether altered ciliation is responsible for defective hCV-MSCs in preeclamptic placentas, as the primary cilium is a hub for signal transduction, which is important for various cellular activities. Methods In the present work, we collected placental tissues from different gestational stages and we isolated hCV-MSCs from 1st trimester, term control, and preeclamptic placentas. We studied their ciliation, functionality, and impact on trophoblastic cell lines and organoids formed from human trophoblast stem cells (hTSCs) and from the trophoblastic cell line JEG-3 with various cellular and molecular methods, including immunofluorescence staining, gene analysis, spheroid/organoid formation, motility, and cellular network formation assay. The statistical evaluation was performed using a Student’s t test (two-tailed and paired or homoscedastic) or an unpaired Mann–Whitney U test (two-tailed). Results The results show that primary cilia appeared abundantly in normal hCV-MSCs, especially in the early development of the placenta. Compared to control hCV-MSCs, the primary cilia were truncated, and there were fewer ciliated hCV-MSCs derived from preeclamptic placentas with impaired hedgehog signaling. Primary cilia are necessary for hCV-MSCs’ proper signal transduction, motility, homing, and differentiation, which are impaired in preeclamptic hCV-MSCs. Moreover, hCV-MSCs derived from preeclamptic placentas are significantly less capable of promoting growth and differentiation of placental organoids, as well as cellular network formation. Conclusions These data suggest that the primary cilium is required for the functionality of hCV-MSCs and primary cilia are impaired in hCV-MSCs from preeclamptic placentas.

Maternal blood pressure associates with placental DNA methylation both directly and through alterations in cell-type composition

“…On the one side, our results show that BP is associated with alterations in DNAm which may be partly explained by changes in placental cell-type composition, especially in the ratio of stromal to syncytiotrophoblast cells. This compares with recent observations showing that preeclampsia, a pregnancy disorder characterized by gestational hypertension, is associated with a lower amount and an altered structure and activity of mesenchymal stromal cells in term placental tissues [86,87]. Interestingly, gestational age has also been associated with a decrease in the quantity of mesenchymal stromal cells and an increase in syncytiotrophoblasts, suggesting that elevated maternal blood pressure could be associated with an acceleration of placental cellular maturation [14,20].…”

Case Report:Pregnancy and birth in a mild phenotype of Alström syndrome

“…Studies on ciliopathies suggest a potential role of primary cilium dysfunction in eclampsia. The primary cilium is required for the functionality of human chorionic villi mesenchymal stromal cells, and the primary cilia are also impaired on human chorionic villi mesenchymal stromal cells from preeclamptic placentas ( Romberg et al, 2022 ).…”

Significance of Placental Mesenchymal Stem Cell in Placenta Development and Implications for Preeclampsia

“…Therefore, a restriction in multipotentiality of PMSCs is imposed via gestational age, thereinto, first trimester-derived PMSCs show more plasticity than term PMSCs counterparts concerning fate acquisition. Even though the physiological senescence exists in the DBMSCs as pregnancy advances to term ( Khanabdali et al, 2021 ), preeclamptic PMSCs exhibit abnormal proliferation, inhibited migration, and accelerated senescence ( Wang et al, 2012 ; Rolfo et al, 2013 ; Ji et al, 2017 ; Nuzzo et al, 2017 ; Romberg et al, 2022 ). Senescent PMSCs in PE are further characterized by abnormal paracrine actions.…”