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Theranostics 2024; 14(8):3385-3403. doi:10.7150/thno.94943 This issue Cite
Research Paper
1. Fujian Key Laboratory of Developmental and Neural Biology & Southern Center for Biomedical Research, College of Life Sciences, Fujian Normal University, Fuzhou, Fujian 350117, China.
2. Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong 510055, China.
3. Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, China.
4. Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong 510055, China.
5. Research and Development Center for Tissue Engineering, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
6. Research Center for Computer-aided Drug Discovery, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
7. Reproductive Medicine Research Center, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510055, China.
8. Department of Neurology, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570013, China.
9. International Center for Aging and Cancer (ICAC), Hainan Medical University. Haikou, Hainan 570013, China.
10. Key Laboratory of Brain Science Research & Transformation in Tropical Environment of Hainan Province. Haikou, Hainan 570013, China.
#These authors contributed equally to this work.
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 (Fasmut) and Fas ligand mutant (FasLmut) 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; Axin1fl/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 Fasmut and FasLmut mice. Mechanistically, transcriptome analysis results revealed that MSC-apoVs downregulated a number of aberrant gene expression in Fasmut 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 NPPC/cGMP/PDE3A/cAMP cascade. When WNT/β-catenin was specially activated in theca cells of CYP17A1-Cre; Axin1fl/fl mice, the same ovarian impairment phenotypes observed in apoptosis-deficient mice were established, confirming that aberrant activation of WNT/β-catenin in theca cells caused the impairment of ovarian folliculogenesis. We firstly revealed that apoVs delivered WNT membrane receptor inhibitor protein RNF43 to ovarian theca cells to balance follicle homeostasis through vesicle-cell membrane integration. Systemically infused RNF43-apoVs down-regulated aberrantly activated WNT/β-catenin signaling in theca cells, contributing to ovarian functional maintenance. Since aging mice have down-regulated expression of WNT/β-catenin in oocytes, we used MSC-apoVs to treat 15-month-old mice and found that MSC-apoVs effectively ameliorated the ovarian function and fertility capacity of these aging mice through rescuing WNT/β-catenin expression in oocytes.
Conclusion: Our studies reveal a previously unknown association between apoVs and ovarian folliculogenesis and suggest an apoV-based therapeutic approach to improve oocyte function and birth rates in PCOS and aging.
Keywords: Apoptosis, Apoptotic vesicles, Ovarian homeostasis, Polycystic ovary syndrome (PCOS), Reproductive aging