Transplacental communication via extracellular vesicles in gestational diabetes mellitus

Gestational diabetes mellitus (GDM) is one of the most common complications in pregnancy. In gestation, pancreatic beta cells undergo a tremendous adaptation to the pregnancy. A failure to meet the adaptations may result in the development of GDM. Next to soluble factors, it was postulated that extracellular vesicles (EVs) contribute to the maternal-fetal interaction. Evidence on the communication between the placenta and the pancreas via EVs is still lacking. This project aimed to evaluate the influence of blood and placental small EVs (sEVs) on pancreatic beta cell functions. sEVs from three different sources were obtained and enriched using ultracentrifugation. The impact of sEVs on pancreatic beta cell glucose consumption, lactate production, proliferation, apoptosis, insulin content and secretion as well as mRNA and miRNA gene expression was analysed. The influence of GDM on sEV protein content was evaluated by proteomics. Our results demonstrated that maternal blood sEVs significantly alter beta cell proliferation and metabolism. These changes were greater in beta cells treated with maternal blood sEVs from GDM patients. Furthermore, HTR-8/SVneo sEVs from low glucose and high glucose cultures changed beta cell glucose and lactate metabolism as well as proliferation significantly. Placenta perfusate sEVs led to significant changes in beta cell proliferation, insulin content and secretion and gene expression of genes related to insulin synthesis and beta cell functions, glucose transport and inflammation. Finally, we demonstrated that placental perfusate sEVs from GDM contain proteins that are differentially expressed compared to healthy sEVs. Our results show that placental and maternal blood sEVs play a role in beta cell adaptation during pregnancy. A GDM condition may influence the content of such EVs and contribute to a failed intercellular communication which may lead to an impairment of beta cell adjustment during pregnancy.