Single-cell insights into trophoblast heterogeneity and adaptive dysfunction in selective fetal growth restriction

Selective fetal growth restriction (sFGR) in monochorionic diamniotic twins (MCDA) reflects placental dysfunction, but trophoblast adaptation mechanisms remain unclear. Using single-cell RNA sequencing on placental tissues from three paired sFGR, we demonstrate that villous cytotrophoblasts (VCT) in growth-restricted placentas undergo a transition from VCT_TP63, which expresses barrier-associated TP63/SOX6 and maintains cytoskeletal integrity, to VCT_LDHA, a metabolically reprogrammed phenotype marked by LDHA/YY1/RELA activation. Trajectory analysis shows diminished syncytial precursors, suggesting impaired fusion capacity. Immune profiling identifies depleted TREM2+ Hofbauer macrophages and expanded interferon-responsive natural killer (NK) cells. Cell-cell interaction mapping demonstrates enhanced Interferon Gamma (IFNG)-Interferon Gamma Receptor 1 (IFNGR1)-Signal Transducer and Activator of Transcription 1 (STAT1) signaling between VCT_LDHA and immune cells, alongside weakened VCT_TP63-stromal crosstalk. This study defines a maladaptive triad of metabolic stress, inflammation, and structural disintegration in sFGR, contributing to sFGR pathogenesis. Single-cell analysis of placentas from growth-discordant twins reveals a shift from structural to metabolically stressed trophoblasts, with pro-inflammatory immune remodelling, defining a maladaptive triad driving selective fetal growth restriction.