Impact of Metabolic Stress on BeWo Syncytiotrophoblast Function

During placental formation, cytotrophoblasts (CTBs) fuse into multinucleate, microvilli‐coated syncytiotrophoblasts (STBs), which contact maternal blood, mediating nutrient, metabolite, and gas exchange between mother and fetus, and providing a barrier against fetal infection. Trophoblasts remodel the surrounding extracellular matrix through the secretion of matrix metalloproteinases (MMPs). Maternal obesity and diabetes mellitus can negatively impact fetal development and may impair trophoblast function. We sought to model the impact of metabolic stress on STB function by examining MMP and hormone secretion. The BeWo CTB cell line was syncytialized to STB‐like cells with forskolin. Cell morphology was examined by electron microscopy and immunofluorescence; phenotype was further assessed by ELISA and RT‐qPCR. STBs were exposed to a metabolic stress cocktail (MetaC: 30 mM glucose, 10 nM insulin, and 0.1 mM palmitic acid). BeWo syncytialization was demonstrated by increased secretion of HCGβ and progesterone, elevated syncytin gene expression (ERVW‐1 and ERVFRD‐1), loss of tight junctions, and increased surface microvilli. MetaC strongly suppressed syncytin gene expression (ERVW‐1 and ERVFRD‐1), suppressed HCGβ and progesterone secretion, and altered both MMP‐9 and MMP‐2 production. Metabolic stress modeling diabetes and obesity altered BeWo STB hormone and MMP production in vitro. Multi‐nucleated syncytiotrophoblast cells exhibit enhanced expression of syncytan 1 (ERVW‐1) and syncytin 2 (ERVFRD‐1) as well as secretion of progesterone, human chorionic gonadotropin beta (HCGβ), matrix metalloproteinase 2 (MMP‐2), and matrix metalloproteinase 9 (MMP‐9). Metabolic stress (such as insulin, glucose, and palmitate) inhibits secretion of progesterone, HCGβ, MMP‐2, and MMP‐9 by syncytiotrophoblast cells. Created with BioRender.