Human trophoblast models recapitulate accelerated cellular ageing at late-term gestation — ASN Events
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Human trophoblast models recapitulate accelerated cellular ageing at late-term gestation (#514)

Dulce L Medina Garcia 1 , Georgia Kafer 2 , Joshua Fisher 3 , Gustavo Bracho 1 , Claire T Roberts 1 , Anya L Arthurs 1
  1. FLINDERS UNIVERSITY, ADELAIDE, SA, Australia
  2. University of the Sunshine Coast, QLD
  3. University of Newcastle, NSW

Background: The human placenta undergoes progressive physiological ageing throughout gestation, characterized by increased cellular senescence, activation of DNA damage responses, and reduced proliferative capacity1-4. While these changes are part of normal placental maturation, accelerated placental ageing has been associated with adverse pregnancy outcomes, including stillbirth at term1,3. However, current complex cell models often evaluate isolated aspects of placental ageing,  without actually recapitulating the biological phenomenon.

Aim: To investigate gestational age-associated placental senescence in primary human trophoblast stem cells (TSCs) and trophoblast organoids.

Methods: Placental tissue was collected from uncomplicated pregnancies delivered at 37 and 41 weeks’ gestation. TSCs were isolated and cultured for 7 days prior to fixation (4% paraformaldehyde). Cellular senescence was assessed by immunofluorescence microscopy (p16 and p21), while activation of the DNA damage response was evaluated by 53BP1 staining. Cell proliferation and DNA replication were analysed using IdU/CldU assays. Expression of senescence-associated genes was quantified by qPCR. In parallel, TSC-derived organoids were established to evaluate senescence markers in a three-dimensional model. (n = 4 patient samples per gestational age group).

Results: Markers p16, p21 and 53BP1 are significantly increased (p<0.05) expression in TSCs and organoids from 41 weeks’ compared with 37 weeks’, consistent with enhanced senescence and activation of the DNA damage response at later gestational ages. IdU/CldU assays determined decreased cell cycling and DNA replication in TSCs and organoids from 41 weeks’ compared with 37 weeks’.

Conclusions: TSCs and trophoblast organoids established from 41 week placentas exhibit increased signs of placental ageing compared with those from 37 week placentas. These results suggest that the 37 week placenta “early term” is still high-functioning, capable of supporting fetal development. However, the 41 week placenta “late term” appears to be compromised in its ability to support the fetus, consistent with the increased risk of stillbirth at later gestations.

 

  1. Arthurs, A. L. et al. Circular RNAs accumulate in aging human placental tissue and in stillbirth, leading to DNA damage and cellular senescence. American Journal of Obstetrics & Gynecology 234, 210-229 (2026). https://doi.org/https://doi.org/10.1016/j.ajog.2025.08.030
  2. Kajdy, A. et al. Molecular pathways of cellular senescence and placental aging in late fetal growth restriction and stillbirth. International journal of molecular sciences 22, 4186 (2021).
  3. Maiti, K. et al. Evidence that fetal death is associated with placental aging. Am J Obstet Gynecol 217, 441 (2017).
  4. Qi, H., Xiong, L. & Tong, C. Aging of the placenta. Aging (Albany NY) 14, 5294 (2022).