Role Of Junctional Adhesion Molecule C Research Articles

The role of junctional adhesion molecule-C in trophoblast differentiation and function during normal pregnancy and preeclampsia.

Junctional adhesion molecule-C (JAM-C) is an important regulator of many physiological processes, ranging from maintenance of tight junction integrity of epithelia to regulation of cell migration, homing and proliferation. Preeclampsia (PE) is a trophoblast-related syndrome with abnormal placentation and insufficient trophoblast invasion. However, the role of JAM-C in normal pregnancy and PE pathogenesis is unknown. The expression and location of JAM-C in placentas were determined by quantitative real-time PCR (qRT-PCR), western blot and immunohistochemistry. The expression of differentiation and invasion markers were detected by qRT-PCR or western blot. The effects of JAM-C on migration and invasion of trophoblasts were examined using wound-healing and invasion assays. Additionally, a mouse model was established by injection of JAM-C-positive adenovirus to explore the effects of JAM-C in vivo. In normal pregnancy, JAM-C was preferentially expressed on cytotrophoblast (CTB) progenitors and progressively decreased when acquiring invasion properties with gestation advance. However, in PE patients, the expression of JAM-C was upregulated in extravillous trophoblasts (EVTs) and syncytiotrophoblasts (SynTs) of placentas. It was also demonstrated that JAM-C suppressed the differentiation of CTBs into EVTs in vitro. Consistently, JAM-C inhibited the migration and invasion capacities of EVTs through GSK3β/β-catenin signaling pathway. Importantly, Ad-JAMC-infected mouse model mimicked the phenotype of human PE. JAM-C plays an important role in normal placentation and upregulated JAM-C in placentas contributes to PE development.

Role of Junctional Adhesion Molecule-C in the Regulation of Inner Endothelial Blood-Retinal Barrier Function.

Although JAM-C is abundantly expressed in the retinae and upregulated in choroidal neovascularization (CNV), it remains thus far poorly understood whether it plays a role in the blood-retinal barrier, which is critical to maintain the normal functions of the eye. Here, we report that JAM-C is highly expressed in retinal capillary endothelial cells (RCECs), and VEGF or PDGF-C treatment induced JAM-C translocation from the cytoplasm to the cytomembrane. Moreover, JAM-C knockdown in RCECs inhibited the adhesion and transmigration of macrophages from wet age-related macular degeneration (wAMD) patients to and through RCECs, whereas JAM-C overexpression in RCECs increased the adhesion and transmigration of macrophages from both wAMD patients and healthy controls. Importantly, the JAM-C overexpression-induced transmigration of macrophages from wAMD patients was abolished by the administration of the protein kinase C (PKC) inhibitor GF109203X. Of note, we found that the serum levels of soluble JAM-C were more than twofold higher in wAMD patients than in healthy controls. Mechanistically, we show that JAM-C overexpression or knockdown in RCECs decreased or increased cytosolic Ca2+ concentrations, respectively. Our findings suggest that the dynamic translocation of JAM-C induced by vasoactive molecules might be one of the mechanisms underlying inner endothelial BRB malfunction, and inhibition of JAM-C or PKC in RCECs may help maintain the normal function of the inner BRB. In addition, increased serum soluble JAM-C levels might serve as a molecular marker for wAMD, and modulating JAM-C activity may have potential therapeutic value for the treatment of BRB malfunction-related ocular diseases.

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.

Expression of Junctional Adhesion Molecule-C on the Surface of Platelets Supports Adhesion, but not Differentiation, of Human CD34+ Cells in Vitro

Background: CD34⁺ progenitor cells play an important role in haematopoiesis and vascular homeostasis. The aim of the present study was to investigate the role of platelet-derived junctional adhesion molecule-C (JAM-C) in adhesion and differentiation of human CD34⁺ cells in vitro, as well as its association with platelet-derived P-selectin in patients with coronary artery disease. Methods and Results: Using flow cytometry we observed that JAM-C expression on the surface of washed platelets is increased after activation with thrombin receptor activating peptide-6 in vitro and correlated with platelet-derived P-selectin expression in patients with coronary artery disease (r=0.326, P=0.007). The role of JAM-C and its counter receptor Mac-1 in adhesion of human CD34⁺ cells over immobilized platelets was investigated by using a neutralizing soluble protein (sJAM-C-Fc) and a monoclonal antibody against JAM-C or integrin Mac-1 (CD11b/CD18). Treatment with soluble JAM-C-Fc or anti-JAM-C or anti-Mac-1, but not with control-Fc or IgG1, resulted in a significantly decreased adhesion of human CD34⁺ cells to platelets under static conditions (P<0.05). In order to validate our findings under high shear stress we performed flow chamber experiments. In a similar manner, inhibiting JAM-C interaction with Mac-1 resulted in a significantly decreased adhesion of CD34⁺ cells over immobilized platelets under high shear stress (P<0.05). Colony forming unit assays and coculture assays revealed that inhibition of JAM-C/Mac-1 axis did not influence the platelet-mediated differentiation of CD34⁺ cells to endothelial cells or to macrophages/foam cells. Conclusions: Taken together a platelet-derived JAM-C supports CD34⁺ cell adhesion, a mechanism potentially involved in homing as well as domiciliation of human CD34⁺ cells.

The role of junctional adhesion molecule-C (JAM-C) in angiogenesis and inflammation

The role of junctional adhesion molecule-C (JAM-C) in angiogenesis and inflammation