Unfolding the Role of Endoplasmic Reticulum Stress and IRE1 Signaling in Trophoblast Differentiation
Abstract
Impaired formation of a placental cell lineage called syncytiotrophoblast is associated with preeclampsia, a serious pregnancy complication. While endoplasmic reticulum stress and unfolded protein response (UPR) activation occur during healthy placentation, these processes are disrupted in preeclampsia. I hypothesize that activation of specific UPR branches is required for syncytialization and impaired UPR signaling disrupts syncytialization. I found that genes associated with UPR activation were upregulated during differentiation of BeWo cells, a model for studying syncytialization. I also found that inositol requiring enzyme 1 (IRE1) inactivation resulted in >50% reduction of cell fusion and human chorionic gonadotropin subunit β production. This impaired syncytialization was independent of classical spliced X-box binding protein 1 (XBP1s) and non-canonical c-jun NH2 terminal kinase (JNK) signaling pathways. My findings suggest that IRE1 branch signaling is required for syncytialization and could inform therapeutic approaches for preeclampsia through the modulation of UPR signaling.