Oral Presentation ESA-SRB-ANZOS 2025 in conjunction with ENSA

Purinergic Receptor Inhibition Impairs Trophoblast and Trophectoderm Outgrowth During Early Placentation   (128652)

Christine Farah 1 2 , Natasha de Alwis 1 2 , Rose Freemantle 1 2 , Natalie K Binder 1 2 , Sally Beard 1 2 , Sunhild Hartmann 3 4 5 6 7 8 9 , Stefan Botha 3 4 5 6 7 8 9 , Olivia Nonn 4 5 6 8 , Tu’uhevaha J. Kaitu’u-Lino 3 , Lisa Hui Lisa Hui 2 , Natalie J Hannan 1 2
  1. Therapeutic Discovery & Vascular Function in Pregnancy Group, Department of Obstetrics, Gynecology and Newborn Health, University of Melbourne, Melbourne, Australia
  2. Northern Centre Health, Education & Research Northern Hospital, Melbourne, Vic
  3. Translational Obstetrics Group, Department of Obstetrics & Gynaecology, University of Melbourne, Heidelberg, Melbourne, VIC, Australia
  4. Charité - Universitätsmedizin, a cooperation between the Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association and the Charité - Universitätsmedizin , Berlin, Germany
  5. Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin , Germany
  6. DZHK (German Center for Cardiovascular Research), Berlin, Germany
  7. HELIOS Clinic, Department of Cardiology and Nephrology, Berlin, Germany
  8. Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
  9. Freie Universität Berlin, Institute for Chemistry and Biochemistry, Berlin, Germany

 

Early placentation relies on tightly coordinated trophoblast differentiation, adhesion, migration and invasion. Purinergic signalling is an understudied but exciting area due to the ability of extracellular nucleotides, including ATP and UTP to act as rapid messengers, enabling swift cellular responses to environmental cues via surface purinergic receptors. Thus, purinergic signalling offers a novel avenue to explore mechanisms driving early placentation. However, specific purinergic signalling function during early placentation remain unclear. This study aimed to determine functional actions of purinergic receptors P1A1 and P2Y6 on trophectoderm and trophoblast migration, invasion and expansion.  

 

Spatial transcriptomics on human placentas (n=13; 5–13 and ≥38 weeks) was undertaken to assess the purinome across gestation. First trimester placental tissue (7–12 weeks) was cultured on collagen and treated with antagonists to P1A1 (DPCPX) or P2Y6 (MRS2578) for 48 hours. Outgrowth area was measured to assess trophoblast migration and expansion. Mouse blastocysts were also cultured on fibronectin with the same antagonists for 96 hours to evaluate trophectoderm/trophoblast outgrowth.   

 

Spatial transcriptomic analysis revealed low expression of P1A1 across samples assessed. P2YR6 expression was abundantly detected in cytotrophoblasts and syncytiotrophoblasts, suggesting a trophoblast specific function. Inhibiting both receptors significantly reduced first trimester placental outgrowth, suggesting their effects in early trophoblast expansion. P2Y6 inhibition also caused altered differentiation and increased cell death in placental explants, indicating a potential disruption in trophoblast function. Preliminary findings suggest that mouse blastocysts treated with both P1A1 and P2Y6 antagonists showed reduced trophectoderm outgrowth compared to control, suggesting these receptors may play a critical role in early trophoblast function.  

  

Collectively, these findings suggest that dysregulation of P1A1 and P2Y6 in early trophectoderm and trophoblast may disrupt placental development. Therefore this may contribute to placental dysfunction in major pregnancy complications, including preeclampsia and fetal growth restriction.