Work

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

Year: 2026

Type: article

Abstract: 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.

Source: Communications Biology

DOI: 10.1038/s42003-026-09798-2