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Background <p>The global incidence of advanced maternal age (AMA) has risen substantially over the past two decades, accompanied by elevated risks of adverse perinatal outcomes. This phenomenon has been linked to premature placental aging, yet the precise molecular pathways have yet to be fully elucidated. Our study aims to delineate the impact of Gremlin1 (GREM1) aberrant expression in AMA pregnancies and elucidate its underlying molecular mechanisms.</p> Methods <p>This study employed a multi-level approach to investigate GREM1’s role in AMA-associated placental aging. Analysis of 42 human placental samples quantified GREM1 expression patterns. In vitro functional validation was performed using the HTR-8/SVneo trophoblast cell through GREM1 overexpression/knockdown interventions, assessing proliferation, migration, and invasion capabilities, as well as senescence through the expression of key markers and senescence-associated β-galactosidase staining. Mechanistic studies examined GREM1-BMP4 interactions and SMAD1/5/9 phosphorylation via Western blotting, supplemented by rescue experiments with exogenous BMP4 and BMP-SMAD pathway activator sb4. In vivo validation utilized AAV9-mediated GREM1 overexpression in pregnant mice, with placental aging phenotypes evaluated following sb4 intervention.</p> Results <p>First-time identification revealed significant GREM1 upregulation in human AMA placentas. Cellular experiments demonstrated GREM1 overexpression suppressed trophoblast proliferation, migration, and invasion while inducing senescence, effects that were ameliorated by GREM1 knockdown. Mechanistically, GREM1 promoted senescence by antagonizing BMP4 and inhibiting SMAD1/5/9 phosphorylation. Both BMP4 and sb4 partially rescued senescence phenotypes in vitro. Animal studies confirmed AAV9-GREM1 induced premature placental aging and reduced placental efficiency in mice, phenotypes significantly alleviated by sb4 treatment. In naturally aged AMA mice, sb4 treatment mitigated molecular senescence markers but did not significantly improve macroscopic pregnancy outcomes.</p> Conclusion <p>This work elucidates GREM1/BMP4 imbalance-driven trophoblast senescence as one of the mechanisms underlying AMA-related placental dysfunction, mediated through impaired BMP-SMAD signaling. While targeting this axis effectively mitigates molecular aging markers, the multifaceted nature of clinical AMA suggests that fully reversing macroscopic outcomes may require integrated, multi-pathway interventions. Nevertheless, targeted modulation of the BMP-SMAD pathway or anti-GREM1 strategies holds significant clinical intervention potential.</p>

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Aberrant expression of Gremlin1 induces trophoblast senescence in the placenta of advanced maternal age pregnancy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月27日

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  • Haojun Tian,
  • Yingying Wei,
  • Lu Zhang,
  • Xuancheng Wei,
  • Mengtian Wei,
  • Ruixue Wang,
  • Qizhi He,
  • Tao Duan,
  • Xiaojie Huang,
  • Kai Wang

摘要

Background

The global incidence of advanced maternal age (AMA) has risen substantially over the past two decades, accompanied by elevated risks of adverse perinatal outcomes. This phenomenon has been linked to premature placental aging, yet the precise molecular pathways have yet to be fully elucidated. Our study aims to delineate the impact of Gremlin1 (GREM1) aberrant expression in AMA pregnancies and elucidate its underlying molecular mechanisms.

Methods

This study employed a multi-level approach to investigate GREM1’s role in AMA-associated placental aging. Analysis of 42 human placental samples quantified GREM1 expression patterns. In vitro functional validation was performed using the HTR-8/SVneo trophoblast cell through GREM1 overexpression/knockdown interventions, assessing proliferation, migration, and invasion capabilities, as well as senescence through the expression of key markers and senescence-associated β-galactosidase staining. Mechanistic studies examined GREM1-BMP4 interactions and SMAD1/5/9 phosphorylation via Western blotting, supplemented by rescue experiments with exogenous BMP4 and BMP-SMAD pathway activator sb4. In vivo validation utilized AAV9-mediated GREM1 overexpression in pregnant mice, with placental aging phenotypes evaluated following sb4 intervention.

Results

First-time identification revealed significant GREM1 upregulation in human AMA placentas. Cellular experiments demonstrated GREM1 overexpression suppressed trophoblast proliferation, migration, and invasion while inducing senescence, effects that were ameliorated by GREM1 knockdown. Mechanistically, GREM1 promoted senescence by antagonizing BMP4 and inhibiting SMAD1/5/9 phosphorylation. Both BMP4 and sb4 partially rescued senescence phenotypes in vitro. Animal studies confirmed AAV9-GREM1 induced premature placental aging and reduced placental efficiency in mice, phenotypes significantly alleviated by sb4 treatment. In naturally aged AMA mice, sb4 treatment mitigated molecular senescence markers but did not significantly improve macroscopic pregnancy outcomes.

Conclusion

This work elucidates GREM1/BMP4 imbalance-driven trophoblast senescence as one of the mechanisms underlying AMA-related placental dysfunction, mediated through impaired BMP-SMAD signaling. While targeting this axis effectively mitigates molecular aging markers, the multifaceted nature of clinical AMA suggests that fully reversing macroscopic outcomes may require integrated, multi-pathway interventions. Nevertheless, targeted modulation of the BMP-SMAD pathway or anti-GREM1 strategies holds significant clinical intervention potential.