Endometriosis-associated infertility alters the microRNA signatures of cumulus cells with a particularly pronounced effect in oocytes that failed fertilization.

Abstract

Background: Endometriosis (E) is multifactorial disease affecting around 10% of women worldwide. The association between E and infertility is clinically well recognized. For E patients to achieve a successful pregnancy, assisted reproductive technologies (ART) are considered as a treatment option. However, the impact of E on oocyte quality, its potential to be fertilized as well as pregnancy rates, is still under debate and with very few molecular clues explaining the clinical data. Alterations in protein-coding RNAs in cumulus cells (CCs), cells surrounding the oocytes and contributing to oocyte maturation, have been reported in E patients. But there is a lack of information regarding microRNAs (miRNAs), which control protein translation. Thus, we aimed: (1) to identify altered miRNA expression in CCs of E patients versus patients without the disease (control, C); and (2) to unveil if in E patients, CCs from fertilized oocytes display a different miRNA profile versus oocytes that failed fertilization. Small RNA-sequencing was performed on CCs from patients undergoing ART.

Results: A total of 85 differentially expressed (DE) miRNAs were identified in E versus C patients (FDR < 0.05). In E patients, 25 DE miRNAs were found between fertilized oocytes and oocytes that failed fertilization, while 13 DE miRNAs in C patients (FDR < 0.05). Comparisons among DE miRNAs highlighted three notable miRNA sets: Set (1) 35 DE miRNAs specific to E; Set (2) 27 DE miRNAs affected by both E and the potential to be fertilized; and Set (3) 6 DE miRNAs characteristic of a competent oocyte successfully fertilized despite the disease. Target gene analysis of DE miRNAs unveiled genes involved in oocyte meiosis, progesterone-mediated oocyte maturation pathway, embryo development, mitochondria and spindle alterations, calcium signaling, and oxidative stress.

Conclusion: This study identified for the first time an altered miRNA signature in CCs of E patients, pointing towards compromised oocyte competence. Besides, in E patients, a characteristic CCs miRNA footprint for oocytes that can be successfully fertilized despite the disease has been revealed. The study charts new territory for non-invasive diagnosis and personalized treatments based on miRNAs to improve oocyte competence in E patients under ART treatments.