Project description:Pre-exposure chemoprophylaxis using antiretroviral agents is a promising strategy for the prevention of sexual HIV transmission in women. Molecular transporters in the human vaginal tract may play a pivotal role in determining drug disposition and, consequently, pharmacodynamic outcomes in these efforts. Little is known, however, on the expression of these transporters in vaginal tissues, representing a critical knowledge gap. Our study analyzed the genome-wide transcriptome in 44 vaginal tissue samples from 6 reproductive-age women undergoing gynecologic surgeries.
Project description:While the vaginal epithelium is essential for female reproductive health, a mechanistic understanding of its homeostasis and diseases has remained elusive, in part because of the lack of model systems that recapitulate the stem cell niche of the native tissue. Here, we establish human vaginal epithelial organoids (hVEOs) and infect hVEOs with Candida demonstrated the model's capacity to recapitulate specific inflammatory responses, confirming its utility for host-pathogen research. In summary, this study provides a robust, physiologically relevant model for dissecting the molecular pathways of human vaginal homeostasis and disease, enabling the definition of pathogenic mechanisms and the screening of novel therapeutic strategies.
Project description:Pelvic organ prolapse (POP) is a group of diseases caused by extracellular matrix (ECM) degradation in the pelvic supportive tissues. Cysteine and serine rich nuclear protein 1 (CSRNP1) is involved in cell proliferation and survival regulation, and reportedly facilitates collagen breakdown in human chondrocytes. We here uncovered CSRNP1 as a key driver on collagen degradation in human-derived vaginal fibroblasts. Apoptosis of POP patient-derived vaginal fibroblasts was suppressed after knocking down CSRNP1. Silencing of CSRNP1 inhibited hydrogen peroxide (H2O2)-triggered apoptosis, ROS generation and collagen loss in normal vaginal fibroblasts. In line with this, CSRNP1 overexpression led to proliferation inhibition, apoptosis and collagen degradation in normal subject-derived vaginal fibroblasts. Silencing of CSRNP1 also reduced the expression of cell senescence markers p21 and γ-H2Ax (the histone H2Ax phosphorylated at Ser139), as well as curbed collagen breakdown in normal vaginal fibroblasts caused by a DNA damage agent etoposide. Transcriptomic analysis showed that differentially expressed genes affected by CSRNP1 overexpression in normal vaginal fibroblasts were mainly enriched in the Wnt signaling pathway, which was crucial for the onset and progression of POP. Silencing of CSRNP1 upregulated the expression of nuclear β-catenin and induced nuclear translocation of β-catenin in H2O2-induced normal vaginal fibroblast. Furthermore, collagen deposition caused by CSRNP1 knockdown was curbed after treatment with a Wnt pathway inhibitor DKK1. Our study indicates that the CSRNP1 may be involved in POP progression through the Wnt signaling, which provides a potential therapeutic strategy for POP.
