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<p>The vaginal epithelium, a hormone-sensitive barrier critical for reproductive health, lacks robust in vitro models due to primary tissue scarcity and existing systems’ limitations. Here, we established the first long-term, genetically stable human vaginal epithelial organoids (VEOs) using a tailored Matrigel-based culture medium that preserves the native stratified squamous architecture. Through transcriptomic and functional profiling, we identified progesterone as a key suppressor of immune defense and keratinization. Modeling <i>Chlamydia trachomatis</i> (CT) infection in VEOs recapitulated infection-induced reactive oxygen species (ROS) overproduction, senescence, and inflammation. Progesterone pretreatment significantly reduced ROS and cellular damage, suggesting hormonal modulation of cellular homeostasis. By integrating air-liquid interface (ALI) culture technique and exploring different proportions of Matrigel and collagen composition, we resolved the polarity limitations of three-dimensional (3D) organoids, enabling physiological modeling of infection-induced barrier dysfunction. This study establishes VEOs as a transformative model for dissecting hormone-microbe crosstalk in reproductive health and for accelerating therapeutic development against vaginal infections.</p> Graphical Abstract <p></p>

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Sex hormone-responsive human vaginal epithelial organoids: a novel in vitro platform for studying Chlamydia trachomatis infection

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月24日

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  • Biya Zeng,
  • Fanxuan Zhao,
  • Feng Zhou,
  • Weijia Gu,
  • Fangying Sun,
  • Wen Lv,
  • Guangxiao Li,
  • Yi Zhang,
  • Xinyu Wang,
  • Xiang Lin,
  • Na Liu,
  • Yulu Wang,
  • Jianhua Yang,
  • Songying Zhang,
  • Yongdong Dai

摘要

The vaginal epithelium, a hormone-sensitive barrier critical for reproductive health, lacks robust in vitro models due to primary tissue scarcity and existing systems’ limitations. Here, we established the first long-term, genetically stable human vaginal epithelial organoids (VEOs) using a tailored Matrigel-based culture medium that preserves the native stratified squamous architecture. Through transcriptomic and functional profiling, we identified progesterone as a key suppressor of immune defense and keratinization. Modeling Chlamydia trachomatis (CT) infection in VEOs recapitulated infection-induced reactive oxygen species (ROS) overproduction, senescence, and inflammation. Progesterone pretreatment significantly reduced ROS and cellular damage, suggesting hormonal modulation of cellular homeostasis. By integrating air-liquid interface (ALI) culture technique and exploring different proportions of Matrigel and collagen composition, we resolved the polarity limitations of three-dimensional (3D) organoids, enabling physiological modeling of infection-induced barrier dysfunction. This study establishes VEOs as a transformative model for dissecting hormone-microbe crosstalk in reproductive health and for accelerating therapeutic development against vaginal infections.

Graphical Abstract