Seminal Plasma and Seminal Plasma Exosomes of Aged Male Mice Affect Early Embryo Implantation via Immunomodulation

Abstract

Seminal plasma (SP), particularly SP exosomes (sExos), alters with age and can affect female mouse uterine immune microenvironment. However, the relationship between fertility decline in reproductively older males, and SP and sExos age-related changes, which may compromise the uterine immune microenvironment, remains unclear. The present study demonstrated that the implantation rate of female mice treated with SP from reproductively older male mice (aged-SP group) was lower than that of those treated with SP from younger male mice (young-SP group). RNA-sequencing analysis revealed altered levels of dendritic cell (DC)-related cytokines and chemokines in the uteri of the former group compared with those of the latter group. In vivo and in vitro experiments demonstrated a weaker inhibitory effect of aged SP on DC maturation than of young SP upon stimulation. After isolating and characterizing sExos from young and advanced-age male mice, we discovered that insemination of a subset of the aged-SP group with sExos from young male mice partially recovered the implantation rate decline. Additional in vivo and in vitro experiments revealed that sExos extracted from age male mice exerted a similar effect on DC maturation as SP of aged mice, indicating an age-related sExos inhibitory effect. In conclusion, our study demonstrated that age-related alterations of sExos may be partially responsible for lower implantation rates in the aged-SP group compared with those in the young-SP group, which were mediated by uterine immunomodulation. These findings provide new insights for clinical seminal adjuvant therapy.

Extracellular vesicles would be involved in the release and delivery of seminal TGF-β isoforms in pigs

“…Both locations of TGFβ isoforms, inside the EVs and outside in the molecular corona, ensure a long functional half-life for the active forms of TGFβ isoforms, since in both locations they remain protected from environmental degradation preserving signaling competence for days (72). The presence of active forms of TGF-β isoforms for days in sEVs would support the immunoregulatory properties attributed to sEVs in humans (36)(37)(38)(39), porcine (35), and murine (73) species. This functional immunoregulatory activity would be mediated by the TGF-β isoforms localized in the molecular corona, which would bind to TGF-β receptors on the surface of EV target cells, triggering the intracellular signaling events that would elicit the immunoregulatory response (74).…”

Messenger roles of extracellular vesicles during fertilization of gametes, development and implantation: Recent advances

“…Seminal plasma, on the other hand, causes immune rejection or tolerance in the maternal endometrium, which is closely related to the balance of immune-related cells such as dendritic cells, macrophages, and neutrophils ( Schjenken et al, 2015 ). Mouse SP-EVs can inhibit dendritic cell maturation in endometrial tissues, which may increase embryo implantation rates by establishing immune tolerance ( Wang et al, 2021b ). It should be noted that the extent to which SP-EVs inhibited maternal dendritic cell maturation varies with age.…”

“…It should be noted that the extent to which SP-EVs inhibited maternal dendritic cell maturation varies with age. SP-EVs from old mice have weaker inhibition of dendritic cells in the endometrium, higher levels of IL-6, TNF-α, and IL-1β in the uterine cavity, lower levels of IL-10 and TGF-β, and a lower implantation rate of embryos ( Wang et al, 2021b ). This suggests that the pro-embryo transfer effect of SP-EVs may vary with age.…”

“…Furthermore, EO-EVs can improve endometrial receptivity and regulate maternal immunity, facilitating implantation ( Atay et al, 2011 ; Su et al, 2022 ). Although the role of seminal plasma in IVF is frequently overlooked, numerous studies have found that SP-EVs can regulate the maternal uterine immune system and create favorable conditions for embryo implantation ( Paktinat et al, 2019 ; Wang et al, 2021b ; Paktinat et al, 2021 ).…”

Extracellular vesicle-coupled miRNA profiles of chicken seminal plasma and their potential interaction with recipient cells

“…The extracellular vesicles in seminal plasma of human ( Candenas and Chianese, 2020 ), mouse ( Wang et al, 2021 ), and fish ( Zhang et al, 2020 ) were reported to be of epididymal or sexual accessory gland origin, which is underdeveloped in poultry species. However, the presence of seminal plasma extracellular vesicles ( SPEVs ) has been recently demonstrated in chickens and actively involved in sperm viability and motility regulations ( Cordeiro et al, 2021a ).…”