Identification of TMIGD1, a novel cell adhesion molecule involved in human trophoblast cell migration

Transmembrane and immunoglobulin domain-containing 1 (TMIGD1) is a newly identified cell adhesion molecule that mediates cell-cell interactions and is mainly expressed in kidney and colon epithelial cells. In renal epithelial cells, TMIGD1 regulates cell proliferation and migration. Human tissue panels showed expression of TMIGD1 in placenta; however, the potential function of TMIGD1 in placenta is not known. We elected to study the expression and function of TMIGD1 during placentation. This is of interest because dysregulation of placental invasion is linked to obstetrical complications such as preeclampsia and intrauterine growth restriction (IUGR). We hypothesized that TMIGD1 is expressed in trophoblast cells and regulates cell migration during placental invasion. Placental tissues were subjected to immunofluorescence (IF) staining using anti-TMIGD1 antibody and TMIGD1 localization in trophoblast was visualized using a fluorescence microscope. Additionally, we overexpressed TMIGD1 in the immortalized trophoblast cell line, HTR8/SVneo, via a retroviral system. Transduction was verified using IF, Western blot, and qPCR to compare the modified and original cell lines. Migration of TMIGD1-overexpressing HTR8/SVneo cells was assessed using wound-healing and transwell migration assays. We observed TMIGD1 localization in the apical region of syncytiotrophoblasts. TMIGD1 mRNA expression in the transduced HTR8/SVneo cells was 3-fold greater than that in the control line, and 400-fold greater in first trimester whole placenta. TMIGD1-overexpressing HTR8/SVneo cells exhibited a 30±5% decrease in migration in the wound-healing assay, compared to the untransduced cells. Similarly, TMIGD1 overexpression in HTR8/SVneo suppressed migration by 36%, compared to control cells in transwell assays. Fluorescent staining showed that increased TMIGD1 expression modifies actin cytoskeleton by redistributing filaments to the peripheries. Additionally, cells overexpressing TMIGD1 exhibit a distinct morphology that lacks filopodia or other motility structures. Our study demonstrates for the first time that TMIGD1 is expressed in trophoblast cells and acts to inhibit cell migration. The evidence presented in this study supports the idea that TMIGD1 expression in trophoblast may play an important function in regulating placental invasion, and that perturbations in its activity may be associated with obstetrical complications such as preeclampsia and intrauterine growth restriction