Increased expression of HMGB1 in the implantation phase endometrium is related to recurrent implantation failure.

Mi Han,Bufang Xu,Yi Cao,Mingjuan Zhou,Aijun Zhang,Dan Zhang,Wenjie Zhou,Xiaowei Zhou

doi:10.1007/s11033-021-06979-6

Abstract

Impaired endometrial receptivity was the main cause of recurrent implantation failure (RIF); however, its underlying mechanisms had not been elucidated. This study aimed to determine the expression level of high-mobility group box protein 1 (HMGB1) in the endometrium with RIF and its effect on endometrial receptivity. Genome-wide expression profiling, real-time reverse transcription PCR, immunohistochemical staining, western blot, and in vitro assays were performed in this study. We found that HMGB1 expression was significantly decreased in the implantation phase endometrium in the control group (patients with tubal infertility and successfully achieve conception after the first embryo transfer) (P = 0.006). However, the expression levels of HMGB1 mRNA and protein were significantly upregulated during the implantation phase in endometrial tissues obtained from patients with RIF compared to that in the control group (P = 0.001), consistent with the results of the genome-wide expression profiling. Moreover, in vitro assays showed that increased expression of HMGB1 in human endometrial epithelial cells dramatically displayed a marked deficiency in supporting blastocysts and human embryonic JAR cells adhesion, which mimic the process of embryo adhesion. These findings strongly indicated that increased HMGB1 levels suppressed the epithelial cell adhesion capability, therefore contributing to impaired endometrial receptivity in patients with recurrent implantation failure, which can be used as a target for the recognition and treatment of recurrent implantation failure in clinical practice.

Highlights

Recurrent implantation failure (RIF), defined as the absence of clinical pregnancy following more than three in vitro fertilization-embryo transfer (IVF-ET) or intracytoplasmic sperm injection (ICSI) treatments with a total of at least four good-quality embryos [1], accounts for approximately 10% of cases of sterility in women during IVF-ET treatment [2]
There were no significant differences between groups in average age, body mass index (BMI), follicle-stimulating hormone (FSH), luteinizing hormone (LH), or estradiol (E2), the number of embryo transfers differed significantly (P < 0.001)
IHC staining showed that High-mobility group box protein 1 (HMGB1) expression in the implantation phase endometrium of the RIF group was increased compared to in the control group (Fig. 2e,f), in line with the above-mentioned findings

Summary

Introduction

Recurrent implantation failure (RIF), defined as the absence of clinical pregnancy following more than three in vitro fertilization-embryo transfer (IVF-ET) or intracytoplasmic sperm injection (ICSI) treatments with a total of at least four good-quality embryos (score ≥ 7 or grade of 3BB or better) [1], accounts for approximately 10% of cases of sterility in women during IVF-ET treatment [2]. RIF etiologies are complex and include maternal endocrine abnormality, hydrosalpinx, intrauterine adhesions, etc. Endometrial receptivity and embryo quality are the main factors influencing the embryo implantation rate; it was reported that impaired endometrial receptivity is the major cause of RIF [7]. Factors that may affect endometrial receptivity include uterine fibroids [9], intrauterine adhesions [10], endometriosis [11], and hydrosalpinx [12], among others. Establishment of stable adhesion between the embryo and maternal tissue is crucial for endometrial receptivity acquisition [13]. The mechanism of impaired endometrial receptivity is not well-understood. Few effective treatments have been developed for patients with infertility showing low endometrial receptivity in clinical practice [15]

Methods

Results

Discussion

Conclusion