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Background <p>Decidualization of endometrial mesenchymal stem cells (ESCs) is crucial for the implantation of the embryo. Thin endometrium (TE) can impair endometrial receptivity by affecting the decidualization of ESCs. However, how TE affects the decidualization of ESCs remains unclear.</p> Methods <p>Through multiple transcriptome analyses, we found that <i>LGR5</i> plays a crucial role in the decidualization of ESCs. In vitro, siRNA was used to knock down <i>LGR5</i> in ESCs, and decidualization was assessed via morphology, qRT-PCR, Western blot, and ELISA for decidualization marker (PRL, IGFBP-1). Colony forming assay, EdU, CFSE, and tube formation were used to evaluate proliferation and secretion. Signaling pathway components (<i>β-catenin</i>,<i> AXIN2</i>,<i> PGR</i>) were analyzed. In vivo, an adeno-associated virus (AAV) delivered shRNA to knock down <i>Lgr5</i> in mouse uterine to assess endometrial receptivity and pregnancy rates. A TE mouse model was established and treated with decidualized endometrial mesenchymal stem cells (DSCs) or <i>LGR5</i>-knockdown DSCs to evaluate therapeutic efficacy.</p> Results <p><i>LGR5</i> was significantly upregulated during decidualization and downregulated in TE tissues. In vitro, <i>LGR5</i> knockdown impaired DSCs’ morphological transformation, reduced decidualization, restored proliferation, but diminished secretory function and angiogenic potential. Mechanistically, <i>LGR5</i> knockdown suppressed the β-catenin pathway and downregulated progesterone receptor (PGR). In vivo, <i>Lgr5</i> knockdown reduced endometrial thickness, receptivity markers (<i>Lif</i>,<i> Hoxa10</i>,<i> Pgr</i>), and embryo implantation numbers. Crucially, transplanting <i>LGR5</i>-knockdown DSCs into TE mice resulted in inferior restoration of endometrial structure, reduced angiogenesis, and lower pregnancy rates compared to DSCs.</p> Conclusion <p><i>LGR5</i> plays an important role in ESCs decidualization and may contribute to the therapeutic efficacy of DSCs for TE repair, potentially through regulation of PGR via the β-catenin pathway. These results indicate that <i>LGR5</i> represents a candidate target worthy of further investigation for developing function-restoring therapies in TE.</p>

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LGR5 as a therapeutic target for decidualization-based endometrial mesenchymal stem cells therapy in thin endometrium

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月8日

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  • Kai Chen,
  • Xueqing Ning,
  • Huiru Wang,
  • Jingxin Wang,
  • Xin Zhao,
  • Lu Zong,
  • Shengxia Zheng

摘要

Background

Decidualization of endometrial mesenchymal stem cells (ESCs) is crucial for the implantation of the embryo. Thin endometrium (TE) can impair endometrial receptivity by affecting the decidualization of ESCs. However, how TE affects the decidualization of ESCs remains unclear.

Methods

Through multiple transcriptome analyses, we found that LGR5 plays a crucial role in the decidualization of ESCs. In vitro, siRNA was used to knock down LGR5 in ESCs, and decidualization was assessed via morphology, qRT-PCR, Western blot, and ELISA for decidualization marker (PRL, IGFBP-1). Colony forming assay, EdU, CFSE, and tube formation were used to evaluate proliferation and secretion. Signaling pathway components (β-catenin, AXIN2, PGR) were analyzed. In vivo, an adeno-associated virus (AAV) delivered shRNA to knock down Lgr5 in mouse uterine to assess endometrial receptivity and pregnancy rates. A TE mouse model was established and treated with decidualized endometrial mesenchymal stem cells (DSCs) or LGR5-knockdown DSCs to evaluate therapeutic efficacy.

Results

LGR5 was significantly upregulated during decidualization and downregulated in TE tissues. In vitro, LGR5 knockdown impaired DSCs’ morphological transformation, reduced decidualization, restored proliferation, but diminished secretory function and angiogenic potential. Mechanistically, LGR5 knockdown suppressed the β-catenin pathway and downregulated progesterone receptor (PGR). In vivo, Lgr5 knockdown reduced endometrial thickness, receptivity markers (Lif, Hoxa10, Pgr), and embryo implantation numbers. Crucially, transplanting LGR5-knockdown DSCs into TE mice resulted in inferior restoration of endometrial structure, reduced angiogenesis, and lower pregnancy rates compared to DSCs.

Conclusion

LGR5 plays an important role in ESCs decidualization and may contribute to the therapeutic efficacy of DSCs for TE repair, potentially through regulation of PGR via the β-catenin pathway. These results indicate that LGR5 represents a candidate target worthy of further investigation for developing function-restoring therapies in TE.