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The Role of Junctional Adhesion Molecule-C in Trophoblast Differentiation and Function During Pregnancy and Preeclampsia

Background: Junctional adhesion molecule-C (JAM-C) is an important regulator of many physiological processes, ranging from the maintenance of tight junction integrity of epithelia to regulation of cell migration, homing and proliferation. Preeclampsia (PE) is a trophoblast-related syndrome with abnormal implantation and insufficient trophoblast invasion of spiral arteries. What’s the role of JAM-C in trophoblasts differentiation and migration in normal pregnancy and PE pathogenesis? 
 
Methods: The expression and location of JAM-C in the placental tissues were determined by qRT-PCR, western blot and immunohistochemistry. RNA-sequencing was used to characterize the role of JAM-C in primary CTBs. The effects of JAM-C on migration and invasion of trophoblasts were determined using wound-healing and Matrigel invasion assays. The expression of differentiated and invasion markers were detected by qRT-PCR or western blot. Additionally, twenty pregnant mice were included. Fetal resorption rate, systolic blood pressure (SBP) and urinary protein level were measured and smooth muscle cell (SMC) coverage were analyzed by immunostaining. 
 
Findings: In normal pregnancy, JAM-C was preferentially expressed on cytotrophoblast (CTB) progenitors and progressively decreased when acquiring invasion properties with gestational advance. As RNA-seq analysis demonstrated that JAM-C inhibited the differentiation, migration and invasion of trophoblasts. However, in PE patients, the expression of JAM-C is up-regulated in extravillous trophoblasts (EVTs) and syncytiotrophoblasts (SynTs) of placentas. Over-expression of JAM-C in human trophoblast stem cells (hTSCs) negatively regulated the differentiation potentiality. In HTR-8/SV neo cells, JAM-C inhibits migration and invasion through GSK3β/β-catenin signaling pathway . Importantly, the mouse model induced by JAM-C mimics the human PE phenomenon and impaired spiral arteries remodeling. 
 
Interpretation: JAM-C plays an important role in normal placentation and that its abnormal increase in placentas contributes to PE development. 
 
Funding Statement: This study was funded by grants from National Key R&D Program of China (2018YFC1004404), Jiangsu Provincial Key Medical Center (YXZXB2016004), National Natural Science Foundation of China (82071666, 81701474, 81701475, 81801470), and Jiangsu Biobank of Clinical Resources (BM2015004). 
 
Declaration of Interests: The authors have no conflicts of interest to declare. 
 
Ethics Approval Statement: This study was reviewed and approved by the Ethics Committee (2018-034-01) of Affiliated Drum Tower Hospital, Nanjing University Medical School. Written informed consent was obtained from all participants before surgery.