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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月17日

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  • Yan Bi,
  • Jiawen Yang,
  • Xiaoyu Li,
  • Yuhong Lin,
  • Yucheng Hu,
  • Xiang Ying,
  • Li Gao,
  • Yanlin Wang

摘要

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.