Late Onset Preeclampsia (LOPE) is a serious condition affecting ~6% of Australian pregnancies, accounting for ~85% of all preeclampsia cases1. It develops after 34 weeks’ gestation and remains incurable, threatening the health of mother and baby, until delivery. Placentae from LOPE pregnancies show histopathological signs of ageing2, however the mechanism by which this occurs remains unknown.
Placental tissue (n=3/LOPE or healthy pregnancy, per gestational week 36,37,38,39,40,41; total n=36) was assessed for telomere length using TESLA assay and markers of ageing (gH2AX, 8-OHdG) using immunofluorescence. Trophoblast stem cells were isolated from placenta biopsies (n=3/LOPE or healthy, per gestational week 37/40; total n=12) and grown as placental organoids for 4 weeks, with or without treatment using antioxidant superoxide dismutase, anti-inflammatory compound JNUTS013 or antisense oligonucleotides to sequester Telomeric Repeat-containing RNAs (TERRAs; non-coding RNAs that protect from telomere degradation). Telomere, senescence (senescence-associated b-Galactosidase assays), damage and morphometric analyses were performed along with appropriate statistical tests.
Placentae from LOPE had shortened telomere length (p=0.0253) and increased expression of ageing markers (p=0.0021, p=0.0050) significantly earlier in gestation compared with healthy controls. Placental organoids were confirmed to age in culture at a similar rate to placentae in vivo. Treatment with superoxide dismutase and JNUTS013 delayed, and treatment with antisense oligonucleotides expedited, telomere shortening, senescence and DNA damage (results shortened for brevity; all p<0.05) with no significant change in organoid morphometry. Treatment with antisense oligonucleotides had the largest effect on placental organoid ageing, with treated organoids ageing ~2 weeks faster than untreated.
In summary, the LOPE placenta experiences premature placental ageing, likely due to multiple biological mechanisms. Our investigation into 3 proposed mechanisms confirmed that all contributed to premature placental ageing, with inflammation contributing the least and TERRA depletion contributing the most. These findings highlight potential therapeutic targets to delay placental ageing in LOPE, improving pregnancy outcomes.