Extracellular vesicles-derived microRNA-145-5p is upregulated in the uterine fluid of women with endometriosis and impedes mouse and human blastocyst development

Abstract

Abstract Background Previous work indicated that the implantation and pregnancy rates of women with endometriosis are lower than those of healthy women during in-vitro fertilisation and embryonic transfer. And there are numerous miRNAs in human uterine luminal fluid (ULF), some of which are associated with early preimplantation development of embryos. In our study, we sought to determine whether microRNAs (miRNAs) in the ULF are differentially expressed between women with and without endometriosis and to uncover the association of miRNAs with the development potential of blastocysts. Methods In this case-controlled study, 30 ULF samples were collected each from women with and without endometriosis between March 2018 and May 2019, respectively. TaqMan human miRNA cards and quantitative reverse transcription polymerase chain reaction were used to identify differentially expressed ULF microRNAs between the two groups. Furthermore, the role of miR-145-5p-enriched EVs in mouse and human early embryos was investigated by co-incubation with or without corresponding microRNA-mimic oligonucleotide-enriched EVs, and the effect of miR-145-5p upregulation was investigated on Notch/NOTCH signalling genes. Results The implantation and clinical pregnancy rates significantly decreased in women with endometriosis than in those without endometriosis. Notably, hsa-miR-145-5p was upregulated in ULF samples from women with endometriosis (fold change > 2, false discovery rate < 0.001). Moreover, the ratios of mouse/human early embryos that developed into blastocyst-staged embryos (P = 0.0037 and P = 0.0079, respectively) were significantly affected via miR-145-5p upregulation in mouse/human early embryos. Notch signalling pathway components had abnormal expression levels in the mouse/human blastocyst-stage embryos in the miR-145-5p mimic-enriched EVs group. Conclusions Our study revealed that human extracellular vesicle-derived microRNAs in ULF impacted the developmental potential of blastocysts in women with endometriosis. Moreover, the upregulation of miR-145-5p-enriched EVs in mouse and human embryos negatively affected blastocyst development by suppressing the expression of components of the NOTCH signalling pathway, which may contribute to elucidate the cause of infertility in women with endometriosis.