Abstract Body: Preeclampsia (PE), a pregnancy-related complication, is a major cause of maternal and fetal morbidity and mortality. The pathophysiology is not fully elucidated.
Activin A and GDF15 are part of the TGFβ superfamily and markers for trophoblast differentiation. Both are senescence associated secretory phenotype (SASP) factors that have been associated with cardiovascular disease. Mitochondrial dysfunction is associated with SASP and both have been described in PE. Serum levels of GDF15 and Activin A, were elevated in the maternal blood prior to the onset of PE and found to be elevated in placental tissue of women with PE.

BeWo cells were metabolically reprogrammed to a physiological glucose-environment by cultivating them for 10-15 passages in a cell culture medium with 5.5 mM glucose as opposed to the standard high-glucose environment at 17.1mM. Next, BeWo cells were differentiated into multinucleated syncytiotrophoblasts with Forskolin, and with DMSO as solvent control to model cytotrophoblasts. Subsequently, these two trophoblast differentiation states were treated with GDF15 (20 ng/ml) and Activin A (20ng/ml) and the cell metabolic profile was analyzed.
Additionally, a single cell human trophoblast organoid transcriptomics dataset from Shannon et al. was investigated for expression patterns of GDF15 and INHBA (Activin A) together with the overall metabolic profile of trophoblast cells.

Treating BeWo cells with Activin A and GDF15 leads to an increase in mitochondrial activity, shown by elevated ATP levels in syncytiotrophoblast and an increase in mitochondrial membrane potential in cytotrophoblasts. Additionally, the oxygen consumption rate is significantly higher in syncytiotrophoblasts after Activin A and GDF15 treatment.
In human trophoblast organoids, syncytiotrophoblasts showed the lowest metabolic activity measured by the expression of genes related to glycolysis and mitochondrial respiratory chain. Furthermore, GDF15 and INHBA (Activin A) were strongly expressed in syncytiotrophoblasts.

Together, Activin A and GDF15 stimulation increases the metabolic activity in BeWo cells. As preeclampsia is associated with mitochondrial dysfunction as well as with senescence, our data indicate a potential role of Activin A and GDF15 in preeclampsia development.