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

Selective fetal growth restriction (sFGR) in monochorionic twins reflects placental dysfunction, but trophoblast adaptation mechanisms remain unclear. Using single-cell RNA sequencing of three MCDA twin pairs, we reveal villous cytotrophoblasts (VCT) in growth-restricted placentas shift from TP63/SOX6-expressing barrier phenotypes to metabolically stressed YY1/RELA-activated states, with upregulated glycolysis/mitochondrial dysfunction and downregulated adhesion pathways. Trajectory analysis shows diminished syncytial precursors, suggesting impaired fusion capacity. Immune profiling identifies depleted TREM2+ Hofbauer macrophages and expanded interferon-responsive NK cells. Cell-cell interaction mapping demonstrates enhanced IFNG-IFNGR1-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. Overall design: We conducted single-cell RNA sequencing (scRNA-seq) of three pairs of MCDA twin pregnancies discordant for fetal growth (sFGR_Smaller and sFGR_Larger placental territories). A total of six placental samples were processed using the 10x Genomics Chromium platform to characterize cellular heterogeneity and microenvironmental remodeling.