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Theranostics 2022; 12(15):6527-6547. doi:10.7150/thno.74053 This issue Cite

Research Paper

Single-cell transcriptome profiling of the human endometrium of patients with recurrent implantation failure

Zhen-Zhen Lai^1,2#, Yun Wang^3#, Wen-Jie Zhou^4#, Zhou Liang^3#, Jia-Wei Shi^1,5, Hui-Li Yang¹, Feng Xie⁶, Wei-Dong Chen⁷, Rui Zhu^8,9, Ce Zhang^8,9, Jie Mei¹⁰, Jian-Yuan Zhao^11,12, Jiang-Feng Ye¹³, Tao Zhang¹⁴, Ming-Qing Li^1,2,5✉

1. Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, People's Republic of China.
2. NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai 201203, People's Republic of China.
3. Department of Assisted Reproduction, Shanghai Ninth People's Hospital Affiliated Shanghai JiaoTong University School of Medicine, Shanghai 200011, People's Republic of China.
4. Center of Reproductive Medicine of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China
5. Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, People's Republic of China.
6. Center for Diagnosis and Treatment of Cervical and Uterine Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, People's Republic of China.
7. NovelBio Bio-Pharm Technology Co., Ltd, Shanghai 201112, People's Republic of China.
8. Center for Human Reproduction and Genetics, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215002, People's Republic of China.
9. State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, People's Republic of China.
10. Reproductive Medicine Center, Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medicine School, Nanjing, 210000, People's Republic of China.
11. State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200433, People's Republic of China.
12. Institute of Metabolism and Integrative Biology (IMIB), School of Life Sciences, Fudan University, Shanghai, 200433, People's Republic of China.
13. Division of Obstetrics and Gynecology, KK Women's and Children's Hospital, 229899, Singapore.
14. Assisted Reproductive Technology Unit, Department of Obstetrics and Gynecology, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, People's Republic of China.
#These authors contributed equally to this work.

✉ Corresponding author: Ming-Qing Li, E-mail: mqliedu.cn.

Abstract

Introduction: Despite great advances in assisted reproductive technology (ART), recurrent implantation failure (RIF) cannot be effectively avoided. Notably, cellular characteristics and communication that regulate endometrial receptivity and differentiation, and its disorders in RIF at window of implantation (WOI) remain rudimentary.

Objectives: In this study, we profiled the endometrial cells present at the WOI timing in RIF patients and healthy controls using single-cell RNA sequencing (scRNA-seq) and provided a detailed molecular and cellular map of a healthy and RIF endometrium at the WOI.

Method: In the current study, the endometrium from RIF patient (n = 6; age range, 32 - 35 years) and control (Ctrl) (n = 3; age range, 29 - 35 years) groups were studied at a single-cell resolution. single-cell RNA-seq and analysis were performed on the endometrium of patients with RIF and Ctrl. Immunofluorescence, flow cytometry assays, and quantitative real-time polymerase chain reaction (qRT-PCR) were performed to verify cellular identity and function.

Results: We profiled the transcriptomes of 60222 primary human endometrial cells isolated from control and RIF patients at a single-cell resolution. We discovered dramatic differential expression of endometrial receptivity-related genes in four major endometrial fibroblast-like cells from RIF patients compared to the control endometrium. We observed that CD49a⁺CXCR4⁺NK cells were diminished in proportion with RIF. The decrease in subset of CD63^highPGR^high endometrial epithelial cells with high levels of progesterone receptor, autophagy and exosomes should contribute to the decrease in subset of NK cells. Additionally, we characterized aberrant molecular and cellular characteristics and endometrial cell-cell communication disorders in RIF patients.

Conclusion: Our study provides deeper insights into endometrial microenvironment disorder of RIF that are potentially applicable to improving the etiological diagnosis and therapeutics of unexplained RIF.

Keywords: recurrent implantation failure, endometrial receptivity, endometrial fibroblast-like cell, epithelial cell, NK cell

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