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

Wnt-egrating developmental insights: an atlas of cross-species Wnt/WNT signalling in placental development and preeclampsia (128159)

Georgia P Wong 1 2 , Tu'uhevaha J Kaitu'u-Lino 1 2 , Natasha de Alwis 1 2 , Sunhild Hartmann 1 2 3 4 5 , Olivia Nonn 3 4 5 6 , Natalie J Hannan 1 2 , David G Simmons 7
  1. Department of Obstetrics, Gynaecology and Newborn Health, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia
  2. Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia
  3. Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität, Belrin, Germany
  4. Experimental and Clinical Research Center (ECRC), Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association and Charité Campus Buch, Berlin, Germany
  5. DZHK (German Center for Cardiovascular Research), Berlin, Germany
  6. Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
  7. School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia

Wingless-related integration site (WNT) signalling regulates cell fate, proliferation and differentiation in embryonic development. However, its component temporospatial expression in early placental development remain incompletely characterised, limiting understanding of WNT-related contributions to placental insufficiency, including preeclampsia. We sought to characterise Wnt expression dynamics across mouse placental development and dysregulation in human placentas with preeclampsia. Wnt-related components were proposed to localise to defined placental compartments during normal placental development, with dysregulations in preeclampsia.

To generate an atlas, 59 Wnt-related genes were profiled by qRT-PCR /in situ hybridisation across key developmental stages in wild-type C57BL/6 mouse placentas (n≥3 litters across 7 timepoints, E8.5-E18.5). Public spatial transcriptomic datasets access provided comparison/validation (E7.5-E14.5) (1-3). In human placentas, qRT-PCR assessed orthologous genes in <34-week preterm controls (n=17) versus preeclampsia (n=83); and across gestation in first trimester (n=11), early preterm (n=9) and term (n=11), with validation using an independent transcriptomic database (4).

In mice, 36 Wnt genes increased, 14 were stable, and 9 decreased across gestation. In situ hybridisation revealed distinct stage-/compartment-specific patterns. Axin1, Lgr5, Ror2, Tcf7l1 were enriched in labyrinth trophoblast progenitor populations. 21 genes exhibited broader localisation across trophoblasts, the junctional zone, vasculature and stroma. Most patterns validated with public datasets, although discrepancies existed for low abundance genes.

In human placentas, across gestation, FZD10 and GSK3a  increased from first trimester to term (p<0.0159, p=0.0005), sFRP1 displayed a U-shaped pattern (p<0.0420), and WNT3 declined (p=0.0058).  FZD10, GSK3a and sFRP1 were significantly upregulated with preeclampsia (p=0.0029, p=0.0137, p=0.0157). DKK2, DVL3, GPR177, WNT2, WNT3 and WNT7A were downregulated (p=0.0002, p=0.0398, p=0.0001, p=0.0470, p=0.0129). In human snRNA-seq data, many dysregulated genes also mapped to broader roles than trophoblasts in regulating placental progenitor niches.

These findings underscore the value of temporospatial profiling to define Wnt-related molecules coordination of placental morphogenesis and identify conserved genes susceptible to disruption in preeclampsia.

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