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Mesenchymal-to-epithelial transition of perivascular cells contributes to endometrial re-epithelialization

Author

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  • Shu-Yun Li

    (Cincinnati Children’s Hospital Medical Center, Reproductive Sciences Center, Division of Developmental Biology
    National Institute of Environmental Health Sciences, Reproductive & Developmental Biology Laboratory)

  • Sarah Whiteside

    (Cincinnati Children’s Hospital Medical Center, Reproductive Sciences Center, Division of Developmental Biology)

  • Bo Li

    (Cincinnati Children’s Hospital Medical Center, Reproductive Sciences Center, Division of Developmental Biology)

  • Xiaofei Sun

    (Cincinnati Children’s Hospital Medical Center, Reproductive Sciences Center, Division of Developmental Biology
    University of Cincinnati College of Medicine, Department of Pediatrics)

  • Tony DeFalco

    (Cincinnati Children’s Hospital Medical Center, Reproductive Sciences Center, Division of Developmental Biology
    University of Cincinnati College of Medicine, Department of Pediatrics)

Abstract

Endometrial regeneration is essential for reproductive cycles and pregnancies, allowing the endometrium to undergo estrogen-driven repair, growth, and renewal after menstruation and parturition. Epithelial cells lining the uterine cavity undergo apoptosis during estrous cycles, and remnant cells can quickly restore this lining through a process known as re-epithelialization. It is presumed that adult stem/progenitor cells in the uterine stroma also contribute to re-epithelialization. However, the specific cell type(s) and the underlying mechanisms have not been determined. Herein, we use genetic lineage tracing assays in mice to identify Nestin+ perivascular cells as active contributors to re-epithelialization. Notch signaling maintains Nestin+ perivascular cells in a quiescent state, but these cells re-enter the cell cycle and differentiate into epithelial cells via estrogen-stimulated suppression of Notch signaling dependent on estrogen receptor alpha (ESR1). These findings demonstrate that perivascular cells support re-epithelialization and reveal a mechanism regulating the quiescence and activation of uterine perivascular cells.

Suggested Citation

  • Shu-Yun Li & Sarah Whiteside & Bo Li & Xiaofei Sun & Tony DeFalco, 2025. "Mesenchymal-to-epithelial transition of perivascular cells contributes to endometrial re-epithelialization," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65139-7
    DOI: 10.1038/s41467-025-65139-7
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    References listed on IDEAS

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    1. Ryo Seishima & Carly Leung & Swathi Yada & Katzrin Bte Ahmed Murad & Liang Thing Tan & Amin Hajamohideen & Si Hui Tan & Hideki Itoh & Kazuhiro Murakami & Yoshihiro Ishida & Satoshi Nakamizo & Yusuke Y, 2019. "Neonatal Wnt-dependent Lgr5 positive stem cells are essential for uterine gland development," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
    2. Rong Li & Tianyuan Wang & Ryan M. Marquardt & John P. Lydon & San-Pin Wu & Francesco J. DeMayo, 2023. "TRIM28 modulates nuclear receptor signaling to regulate uterine function," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    3. Deepti L. Kumar & Tony DeFalco, 2018. "A perivascular niche for multipotent progenitors in the fetal testis," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
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