Multifunctional N6-methyladenosine (m6A) has been revealed to be an important epigenetic component in various physiological and pathological processes, but its role in female ovarian aging remains unclear. Thus, we demonstrated m6A demethylase FTO downregulation and the ensuing increased m6A in granulosa cells (GCs) of human aged ovaries, while FTO-knockdown GCs showed faster aging-related phenotypes mediated. Using the m6A-RNA-sequence technique (m6A-seq), increased m6A was found in the FOS-mRNA-3′UTR, which is suggested to be an erasing target of FTO that slows the degradation of FOS-mRNA to upregulate FOS expression in GCs, eventually resulting in GC-mediated ovarian aging. FTO acts as a senescence-retarding protein via m6A, and FOS knockdown significantly alleviates the aging of FTO-knockdown GCs. Altogether, the abovementioned results indicate that FTO in GCs retards FOS-dependent ovarian aging, which is a potential diagnostic and therapeutic target against ovarian aging and age-related reproductive diseases.

Endothelial and fibroblast niches are crucial for epithelial organs. How these heterotypic cells interact is of great interest. In this study, we reveal an axis of signaling in which fibroblasts relay Wnt signals from the endothelial niche to organize epithelial patterning. We generate an Axin2-membrane GFP (mGFP) reporter mouse and observe robust Wnt/β-catenin signaling activities in fibroblasts surrounding the mammary epithelium. To enable cell-type-specific gene manipulation in vitro, we establish an organoid system via coculture of endothelial cells (ECs), fibroblasts, and mammary epithelial cells. Deletion of β-catenin in fibroblasts impedes epithelium branching, and ECs are responsible for the activation of Wnt/β-catenin signaling in fibroblasts. In vivo, EC deletion of Wntless inhibits Wnt/β-catenin signaling activity in fibroblasts, rendering a reduction in epithelial branches. These findings highlight the significance of the endothelial niche in tissue patterning, shedding light on the interactive mechanisms in which distinct niche components orchestrate epithelial organogenesis and tissue homeostasis.

Intrauterine adhesions caused by damage to the basal layer of the endometrium have a serious impact on women's fertility. Currently, there is no effective treatment to promote the regeneration of the endometrium. Urinary bladder matrix (UBM) is a derivative extracellular matrix biomaterial that has a complete basement membrane and provides a basis for the body to achieve complete self-functional repair. In this study, UBM was transplanted into the uterine horns of intrauterine adhesions in Sprague-Dawley rats to test whether UBM could improve endometrial regeneration in rats with intrauterine adhesions. Thicker endometria, increased numbers of glands, fewer fibrotic areas and increased proliferation of cells and blood vessels were found in the UBM group compared to the injury group. Transplantation of UBM reduced the mRNA levels of proinflammatory cytokines (tumor necrosis factor α) and increased those of anti-inflammatory cytokines (basic fibroblast growth factor) compared to the injury group. In the UBM group, the mRNA expression of endometrial receptivity factors (leukemia inhibitory factor and integrin αVβ₃) was higher than that in the injury group, but it was lower than that in the normal group and the sham-operated group. More embryos were seen in the UBM group than in the injury group, although the UBM group had fewer embryos than the normal and sham-operated groups. Therefore, UBM may contribute to endometrial regeneration and may improve endometrial receptivity and fertility.

The microbiota in the human body play critical roles in many physiological and pathological processes. However, the diversity and dynamics of the female genital tract (FGT) microbiota have not been fully unveiled. In this study, we characterized the microbiome variations in reproductive-aged Chinese women, and we revealed that the cervicovaginal microbiota were dominated by Lactobacillus. Overall, the composition of microbiota in the uterine cavity was more diverse than that in the vagina and cervix. A positive correlation between Lactobacillus iners and Lactobacillus crispatus was observed in both the vagina and the cervix, suggesting that these two species might have a symbiotic relationship in the cervicovaginal microbiota. Moreover, we, for the first time, stratified the reproductive-aged Chinese women into subgroups, based on their microbiome profiles. Furthermore, we identified the bacteria whose abundance changed in the uterine cavity of infertile patients when compared with healthy controls, such as L. iners and L. crispatus. Functionally, the metabolism-related pathways, neurotrophin signaling pathway, and adipocytokine signaling pathway were predominantly dysregulated in the uterine cavity of infertile patients. In conclusion, we characterized a comprehensive microbial landscape in FGT, as well as their functional roles in female infertility of the Chinese population.