Time-series single-cell transcriptomic profiling of luteal-phase endometrium uncovers dynamic characteristics and its dysregulation in recurrent implantation failures

Dandan Cao, Yijun Liu, Yanfei Cheng, Jue Wang, Bolun Zhang, Yanhui Zhai, Kongfu Zhu, Ye Liu, Ye Shang, Xiao Xiao, Yi Chang, Yin Lau Lee, William Shu Biu Yeung (), Yuanhua Huang () and Yuanqing Yao ()
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Dandan Cao: the University of Hong Kong-Shenzhen Hospital
Yijun Liu: the University of Hong Kong
Yanfei Cheng: the University of Hong Kong-Shenzhen Hospital
Jue Wang: the University of Hong Kong-Shenzhen Hospital
Bolun Zhang: the University of Hong Kong-Shenzhen Hospital
Yanhui Zhai: the University of Hong Kong-Shenzhen Hospital
Kongfu Zhu: the University of Hong Kong-Shenzhen Hospital
Ye Liu: the University of Hong Kong-Shenzhen Hospital
Ye Shang: the University of Hong Kong-Shenzhen Hospital
Xiao Xiao: Geneplus-Shenzhen
Yi Chang: Jilin University
Yin Lau Lee: the University of Hong Kong-Shenzhen Hospital
William Shu Biu Yeung: the University of Hong Kong-Shenzhen Hospital
Yuanhua Huang: the University of Hong Kong
Yuanqing Yao: the University of Hong Kong-Shenzhen Hospital

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Understanding human endometrial dynamics in the establishment of endometrial receptivity remains a challenge, which limits early diagnosis and treatment of endometrial-factor infertility. Here, we decode the endometrial dynamics of fertile women across the window of implantation and characterize the endometrial deficiency in women with recurrent implantation failure. A computational model capable of both temporal prediction and pattern discovery is used to analyze single-cell transcriptomic data from over 220,000 endometrial cells. The time-series atlas highlights a two-stage stromal decidualization process and a gradual transitional process of the luminal epithelial cells across the window of implantation. In addition, a time-varying gene set regulating epithelium receptivity is identified, based on which the recurrent implantation failure endometria are stratified into two classes of deficiencies. Further investigation uncovers a hyper-inflammatory microenvironment for the dysfunctional endometrial epithelial cells of recurrent implantation failure. The holistic characterization of the physiological and pathophysiological window of implantation and a computational tool trained on this temporal atlas provide a platform for future therapeutic developments.

Date: 2025
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DOI: 10.1038/s41467-024-55419-z

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