SFRP3 negatively regulates placental extravillous trophoblast cell migration mediated by the GCM1-WNT10B-FZD7 axis

Migration of placental extravillous trophoblast (EVT) cells into uterine decidua facilitates the establishment of blood circulation betweenmother and fetus and is modulated by EVT-decidual cell interaction. Poor or excessive EVTmigration is associatedwith pregnancy complications such as preeclampsia or placenta accreta.Glial cellsmissing 1 (GCM1) transcription factor is essential for placental development, and decreasedGCM1 activity is detected inpreeclampsia.To study whetherGCM1regulates trophoblast cellmigration,herewe showedthatGCM1 promotes BeWo and JAR trophoblast cell migration through a novel target gene, WNT10B. Moreover, WNT10B signaling stimulated cytoskeletal remodeling via Rac1 and frizzled 7 (FZD7) was identified as the cognate receptor for WNT10B to up-regulate cell migration. We further showed that secreted frizzled-related protein 3 (SFRP3) is expressedinuterine decidual cellsby immunohistochemistry and that SFRP3expressionintelomerase-transformed human endometrial stromal cells (T-HESCs) is elevated under decidualization stimuli and further enhanced by bone morphogenetic protein 2 via SMAD1. SFRP3 blocked the interaction between FZD7 andWNT10B to decrease BeWo cellmigration,which corroborated the elevated BeWo cellmigrationwhen coculturedwith decidualized and SFRP3-knockdown T-HESC monolayer. Our results suggest that GCM1 up-regulates EVT cell migration through WNT10B and FZD7, which is negativelymodulated by decidual SFRP3.