Abstract
BackgroundThe 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.MethodsIn 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).ResultsThe 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.ConclusionsThese 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.
Highlights
The development of the human placenta is tightly coordinated by a multitude of placental cell types, including human chorionic villi mesenchymal stromal cells
Human placental MSCs have been isolated from different regions of the placenta, such as human basal decidua mesenchymal stromal cells [7], human chorionic mesenchymal stromal cells [8], human chorionic villi mesenchymal stromal cells [9], chorionic cotyledons, intervillous space mesenchymal stromal cells (CIVMSCs) [10], and human chorionic plate mesenchymal stromal cells [11]
Placenta chorionic villous stroma cells are ciliated, the population of ciliated cells and their cilium lengths decrease during gestation As we studied primary cilia in placental trophoblasts, we observed that stromal cells within the villi showed positive staining for primary cilium markers Arl13b and acetylated tubulin [17]
Summary
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). The placenta plays an essential role in supporting the development of the fetus It represents an important reservoir of stem cells and transient progenitors including hCV-MSCs. Emerging evidence demonstrates that hCVMSCs have multiple key roles in generating a functional microenvironment critical to a successful pregnancy. Human placental villous cytotrophoblasts (hVCTBs) are able to differentiate into the human syncytiotrophoblast (hSTB) or extravillous trophoblasts (hEVTs) [2, 3] Other cell types, such as Hofbauer cells, fibroblasts, vascular endothelial cells, and human chorionic villi mesenchymal stem/stromal cells (hCV-MSCs) are required for vascular engineering, angiogenesis, immunomodulation, and tissue homeostasis [4, 5]. Accumulating evidence indicates that hCV-MSCs are of key importance in generating a functional microenvironment, within diverse villus types of the human placenta They are critical for successful pregnancies and defective in placenta-related diseases like preeclampsia (PE) [12]. It is not well understood how these cells are regulated during placental development and why they are defective in preeclamptic placentas
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