(1057) Healthy Placental or Umbilical Cord Stem Cell Extracellular Vesicles Restore Preeclamptic Cells to Normal Function

Preeclampsia (PE) contributes to pregnancy-related morbidity and mortality, with inflammation a critical factor in PE pathophysiology. Healthy placenta mesenchymal stem cells (P-MSC) mitigate inflammation. Our group reported on PE P-MSC dysfunction, characterized by decreased anti-inflammatory licensing, cell cycle dysregulation, and reduced immune suppressive cytokine production. Aspirin (ASA) treatment remedied these via epigenetic reprogramming. This study hypothesized extracellular vesicles (EV) from healthy P-MSCs or umbilical cord (UC) blood could reset PE P-MSCs to a healthy phenotype, improving cell cycle dysregulation and anti-inflammatory capacity.

Study Design:

P- and UC-MSCs were isolated from healthy and PE pregnancies at delivery. EVs from healthy MSCs were isolated by differential ultracentrifugation and quantified. PE P-MSCs were exposed to EVs or treated with 1mM ASA for 48h. P-MSCs were added as third-party cells in mixed lymphocyte reaction (MLR) to assess anti-inflammatory capacity. Treated P-MSCs were analyzed for the epigene regulator TDG and cell cycle linked CDK4, p21, and p53 proteins.

Results:

EV- and ASA-treated PE P-MSC suppressed MLR to levels of healthy P-MSCs. While ASA increased p21, p53, and TDG, and decreased CDK4, EV treatment decreased their expression. Of note, p53 and TDG remained elevated as compared to healthy P-MSCs while p21 was decreased.

Conclusion:

PE P-MSC can be restored towards healthy anti-inflammatory function. The healthy EVs reduced PE-MSC cell cycle with evidence of changes in DNA methylation regulation. These findings are consistent with MSCs exhibiting tissue maintenance during insult. In total, healthy P-MSC EVs may restore the function of PE P-MSCs, as well as other insults during pregnancy.  These findings suggest off-the-shelf availability of EVs to treat PE. Combined with prior data on ASA restoring MSC function, this study furthers our understanding of possible methods to reduce PE via anti-inflammatory modality.