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Updated: Jun 12, 2025
Isolation of Human Endometrial Stromal Cells for In Vitro Decidualization
Published on: September 1, 2018
Aberrant TCF21 upregulation in adenomyosis impairs endometrial decidualization by increasing PDE4C expression
Ruoer Yu1, Chenxuan Wei1, Guojing Li1
1International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Shanghai Key Laboratory of Embryo Original Diseases, Shanghai 200030, China; Municipal Key Clinical Specialty, Shanghai 200030, China.
Background:
Impaired decidualization is a major cause of infertility in patients with adenomyosis (AM). However, the effect of transcription factor 21 (TCF21) on AM and the underlying mechanism of associated-impaired decidualization remain unclear. The aim of this study was to investigate the expression of TCF21 in endometrial tissues of AM patients and the specific mechanisms by which it impairs the decidualization of human endometrial stromal cells (HESCs), with a view to improving the reproductive outcome of AM infertile patients.
Methods:
We compared gene expressions via transcriptomics between the control and AM-associated recurrent implantation failure (RIF) groups. qRT-PCR, western blot, and IHC were performed to confirm the expression and location of TCF21 in the endometrium. Furthermore, we confirmed that high expression of TCF21 impairs decidualization by qRT-PCR, immunofluorescence, and western blot. RNA-seq following overexpression of TCF21 in HESCs was conducted to identify TCF21-related molecular changes during in vitro decidualization. Then we performed ChIP-seq/qPCR and dual-luciferase reporter assay to explore the exact interaction between TCF21 and PDE4C. The related downstream mechanisms were further proved using IHC, qRT-PCR, western blot, and ELISA.
Results:
According to the RNA-seq analysis, TCF21 expression was remarkably higher in the endometrium of the AM-related RIF group compared to the control group. We confirmed the same results using samples from patients with AM and controls. TCF21 overexpression in HESCs impaired decidualization through suppression of decidual markers and cytoskeleton alterations. The mechanistic analysis revealed that TCF21 inhibited intracellular cAMP levels by directly increasing PDE4C expression and suppressing FOXO1 expression.
Conclusions:
TCF21 compromises decidualization in patients with AM via the PDE4C/cAMP-FOXO1 axis, which offers valuable insights on the pathology of decidualization-related infertility and indicates a potential treatment to improve endometrial receptivity in AM.
Insights
Transcription factor 21 (TCF21) is elevated in adenomyosis (AM) patients, impairing decidualization. TCF21 disrupts the PDE4C/cAMP-FOXO1 pathway, offering a target for improving fertility in AM.
Area of Science:
- Reproductive biology and endocrinology
- Molecular genetics and cell signaling
- Infertility research
Background:
- Impaired decidualization is a primary cause of infertility in adenomyosis (AM).
- The role of transcription factor 21 (TCF21) in AM and its impact on decidualization remain largely unknown.
- Understanding TCF21's mechanism is crucial for improving reproductive outcomes in AM patients.
Purpose of the Study:
- To investigate TCF21 expression in endometrial tissues of AM patients.
- To elucidate the mechanisms by which TCF21 impairs human endometrial stromal cell (HESC) decidualization.
- To identify potential therapeutic targets for enhancing endometrial receptivity in AM-related infertility.
Main Methods:
- Transcriptomic analysis to compare gene expression between control and AM-associated recurrent implantation failure (RIF) groups.
- Quantitative real-time PCR (qRT-PCR), Western blot, and immunohistochemistry (IHC) to confirm TCF21 expression and localization.
- RNA-sequencing (RNA-seq), chromatin immunoprecipitation sequencing (ChIP-seq)/qPCR, and dual-luciferase reporter assays to identify molecular changes and TCF21-PDE4C interactions.
Main Results:
- TCF21 expression was significantly higher in the endometrium of AM-RIF patients compared to controls.
- Overexpression of TCF21 in HESCs suppressed decidual markers and altered cytoskeleton, impairing decidualization.
- Mechanistically, TCF21 inhibited intracellular cAMP levels by upregulating PDE4C and downregulating FOXO1 expression.
Conclusions:
- TCF21 compromises decidualization in AM patients through the PDE4C/cAMP-FOXO1 signaling axis.
- This pathway provides critical insights into the pathology of decidualization-related infertility in AM.
- Targeting the TCF21-mediated pathway presents a potential therapeutic strategy to improve endometrial receptivity.
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