Tim1 Deficiency Mediates Gestational Hyperglycemia-Related Syncytiotrophoblast Dysfunction and Fetal Growth Restriction

Gestational hyperglycemia (GHG) causes fetal growth restriction (FGR), while its mechanism remains incompletely understood. Defects in the syncytiotrophoblast, which is pivotal for maternal-fetal substance exchange, adversely affect fetal development. Whether dysfunction in syncytiotrophoblast is involved in GHG-related FGR remains unclear. In this study, we used an STZ-induced GHG mouse model and found that GHG-induced FGR (44.5% reduction in fetal weight) was associated with a 28.3% decrease in placental efficiency. Immunofluorescence and transmission electron microscopy examinations revealed defective formation of the syncytiotrophoblast layer in GHG placenta, resulting from impaired fusion of trophoblast cells. Gene expression profiling and staining analysis of the placenta revealed that Tim1, a phosphatidylserine-binding protein, was 43.5% downregulated in GHG placenta. In vitro studies confirmed that hyperglycemia decreased Tim1 and led to trophoblast fusion defects. Tim1 silence alone recapitulated the effects of hyperglycemia on trophoblast fusion, while Tim1 overexpression rescued the anti-fusion effects of hyperglycemia. Moreover, we generated a Tim1 knockout mouse strain, and observed that Tim1 deficiency alone induced defective formation of syncytiotrophoblast and FGR during pregnancy. Further analysis revealed that Tim1 was downregulated by hyperglycemia-related oxidative stress. Antioxidant treatment during pregnancy reversed Tim1 downregulation, promoted syncytiotrophoblast formation and improved FGR. Finally, the reduction of TIM1 expression was confirmed in human placenta with pre-gestational diabetes and FGR. These findings suggest that Tim1 downregulation in GHG inhibits placental syncytiotrophoblast formation and contributes to FGR.