Mesenchymal stem cell-derived apoptotic vesicles ameliorate impaired ovarian folliculogenesis in polycystic ovary syndrome and ovarian aging by targeting WNT signaling

Rationale: It has been emergingly recognized that apoptosis generates plenty of heterogeneous apoptotic vesicles (apoVs), which play a pivotal role in the maintenance of organ and tissue homeostasis.However, it is unknown whether apoVs influence postnatal ovarian folliculogenesis.Methods: Apoptotic pathway deficient mice including Fas mutant (Fas mut ) and Fas ligand mutant (FasL mut ) mice were used with apoV replenishment to evaluate the biological function of apoVs during ovarian folliculogenesis.Ovarian function was characterized by morphological analysis, biochemical examination and cellular assays.Mechanistical studies were assessed by combinations of transcriptomic and proteomic analysis as well as molecular assays.CYP17A1-Cre; Axin1 fl/fl mice was established to verify the role of WNT signaling during ovarian folliculogenesis.Polycystic ovarian syndrome (PCOS) mice and 15-month-old mice were used with apoV replenishment to further validate the therapeutic effects of apoVs based on WNT signaling regulation.Results: We show that systemic administration of mesenchymal stem cell (MSC)-derived apoptotic vesicles (MSC-apoVs) can ameliorate impaired ovarian folliculogenesis, PCOS phenotype, and reduced birth rate in Fas mut and FasL mut mice.Mechanistically, transcriptome analysis results revealed that MSC-apoVs downregulated a number of aberrant gene expression in Fas mut mice, which were enriched by kyoto encyclopedia of genes and genomes (KEGG) pathway analysis in WNT signaling and sex hormone biosynthesis.Furthermore, we found that apoptotic deficiency resulted in aberrant WNT/β-catenin activation in theca and mural granulosa cells, leading to responsive action of dickkopf1 (DKK1) in the cumulus cell and oocyte zone, which downregulated WNT/β-catenin expression in oocytes and, therefore, impaired ovarian folliculogenesis via Ivyspring International