Macrophage‐derived extracellular vesicles regulate follicular activation and improve ovarian function in old mice by modulating local environment

Abstract

In mammals, ovarian function is dependent on the primordial follicle pool and the rate of primordial follicle activation determines a female's reproductive lifespan. Ovarian ageing is characterised by chronic low‐grade inflammation with accelerated depletion of primordial follicles and deterioration of oocyte quality. Macrophages (Mφs) play critical roles in multiple aspects of ovarian functions; however, it remains unclear whether Mφs modulate the primordial follicle pool and what is their role in ovarian ageing. Here, by using super‐ or naturally ovulated mouse models, we demonstrated for the first time that ovulation‐induced local inflammation acted as the driver for selective activation of surrounding primordial follicles in each estrous cycle. This finding was related to infiltrating Mφs in ovulatory follicles and the dynamic changes of the two polarised Mφs, M1 and M2 Mφs, during the process. Further studies on newborn ovaries cocultured with different subtypes of Mφs demonstrated the stimulatory effect of M1 Mφs on primordial follicles, whereas M2 Mφs maintained follicles in a dormant state. The underlying mechanism was associated with the differential regulation of the Phosphatidylinositol 3‐kinase/Mechanistic target of rapamycin (PI3K/mTOR) signaling pathway through secreted extracellular vesicles (EVs) and the containing specific miRNAs miR‐107 (M1 Mφs) and miR‐99a‐5p (M2 Mφs). In aged mice, the intravenous injection of M2‐EVs improved ovarian function and ameliorated the inflammatory microenvironment within the ovary. Thus, based on the anti‐ageing effects of M2 Mφs in old mice, M2‐EVs may represent a new approach to improve inflammation‐related infertility in women.

Spatiotemporal transcriptomic changes of human ovarian aging and the regulatory role of FOXP1

“…The prolonged presence of senescent cells in the tissue is problematic because they secrete SASPs that trigger local inflammation and spread the senescence phenotype 31 . Numerous studies have associated ovarian aging with a chronic low-grade inflammatory environment 12 , 32 , 33 , supported by our findings demonstrating the activation of inflammation-associated signal pathways (NF-κB, NOD-like receptor, IL-17 and FoxO) and increased expression of pro-inflammatory factors (such as IL-1α, IL-1β, IL-6, IL-8, TNF and IFNγ) in aged ovaries. This inflammatory microenvironment in the ovary may induce oocyte damage, as indicated by the activation of the DNA damage system in aged oocytes, suggesting chronic inflammation as a potential confounding factor in ovarian aging.…”

Engineered M2 macrophage-derived extracellular vesicles with platelet membrane fusion for targeted therapy of atherosclerosis

“…Recent research has demonstrated that miR-99a-5p, a specific miRNA released by M2 macrophages, plays a vital part in ameliorating the inflammatory microenvironment and combating aging [ 34 ]. Additionally, miR-99a-5p is believed to possess inhibitory effects on atherosclerosis [ 35 ].…”

miRNA profiling of granulosa cell‐derived exosomes reveals their role in promoting follicle development

“…At present, the regulation of FLT1 by miRNA‐10b‐5p is scarce in folliculogenesis, which should be researched in the future. It was found that macrophage‐derived exosomes containing miRNA‐99a‐5p and miRNA‐107 regulate the dormancy and activation of follicles through the PI3K/mTOR signaling pathway, which plays a decisive role in the opening of folliculogenesis (Xiao et al, 2022). At the same time, the expression level of miRNA‐21‐5p is highly correlated not only with blastocyst development and oocyte euploid rate, but also with follicular atresia (Bartolucci et al, 2020; Donadeu et al, 2017).…”