Foxa2-dependent uterine glandular cell differentiation is essential for successful implantation

Zhaoyu Jia, Bo Li, Mitsunori Matsuo, Amanda Dewar, Anxhela Mustafaraj, Sudhansu K. Dey (), Jia Yuan () and Xiaofei Sun ()
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Zhaoyu Jia: Shandong University
Bo Li: Cincinnati Children’s Hospital Medical Center
Mitsunori Matsuo: Cincinnati Children’s Hospital Medical Center
Amanda Dewar: Cincinnati Children’s Hospital Medical Center
Anxhela Mustafaraj: Cincinnati Children’s Hospital Medical Center
Sudhansu K. Dey: Cincinnati Children’s Hospital Medical Center
Jia Yuan: Shandong University
Xiaofei Sun: Cincinnati Children’s Hospital Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Uterine receptivity is essential for successful implantation. In mice, uterine receptivity begins with the secretion of LIF from uterine glands stimulated by estrogen on the morning of day 4 pregnancy. We hypothesize that gland readiness for estrogen stimulation is indispensable for uterine receptivity. The current study reveals that uterine glands undergo a differentiation process with expanded branching during the preimplantation period. The single-cell RNA profiling of glandular cells identifies that LIF is expressed exclusively in a Prss29+ subgroup of glandular cells on day 4 of pregnancy. Interestingly, Foxa2-deficient glands lacking LIF production fail to develop branches and the functional Prss29+ subgroup. This Prss29+ subgroup develops prior to estrogen secretion. Collectively, our findings show that uterine glands undergo a FOXA2-dependent maturation process to acquire the competence, named “transitional phase”, for entering the receptive phase. The “transitional phase”, predicting uterine receptivity one day before implantation, is a landmark concept in uterine receptivity.

Date: 2025
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DOI: 10.1038/s41467-025-57848-w

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