Single-cell RNA sequencing reveals common interactions between follicle immune cells and granulosa cells in premature ovarian insufficiency patients.

Objective: To investigate the follicle microenvironment of individuals with premature ovarian insufficiency (POI), normal ovarian reserve (normal) and advanced maternal age (AMA), and identify potential therapeutic targets.

Methods: A total of 9 women, including 3 POI, 3 normal and 3 AMA women, underwent in vitro fertilization or intracytoplasmic sperm injection were included in this study. For each participant, the first punctured follicle not containing cumulus cells were submitted to single-cell RNA sequencing to explore the characteristics of the follicle microenvironment of POI, normal and AMA individuals.

Result(s): A total of 87,323 cells were isolated and grouped into six clusters: T cells, B cells, neutrophils, basophils, mononuclear phagocytes, and granulosa cells. Further analysis demonstrated that the population of granulosa cells in cluster 6 was increased in AMA and POI patients, whereas the population of gamma delta T (GDT)-cells was decreased. We also found that the genes that were differentially expressed between GDT cells and monocytes were enriched in ribosome- and endoplasmic reticulum (ER)-related pathways. In addition, it showed that VEGFA-FLT1 interaction between the monocytes and granulosa cells may be lost in the AMA and POI patients as compared with the normal group.

Conclusion(s): Loss of the VEGFA-FLT1 interaction in monocytes and granulosa cells, along with enriched ER- and ribosome-related pathways, may drive excess inflammation, accelerating granulosa cell senility and contributing to infertility. This study provides new insights into the pathogenesis of POI and aging and highlights the VEGFA/FLT1 interaction may be a potential therapeutic target for reducing inflammation and treating POI.