Extracellular vesicles miRNA-21: a potential therapeutic tool in premature ovarian dysfunction

Abstract

Chemotherapy induces an irreversible premature ovarian dysfunction (POD). Amniotic fluid mesenchymal stem cells (AFMSCs) can rescue fertility; however, the notion that stem cells can rejuvenate follicles is highly controversial due tthe predetermined ovarian reserve. This study aims to isolate AFMSC-derived extracellular vesicles (EVs) and investigate their abundancy for the anti-apoptotic miRNA-21 as a means of ovarian restoration. Female rats were divided into healthy controls and POD-induced groups. The POD induced groups were subdivided into three groups according to the therapies they received: placebo-treated POD, AFMSC and EVs groups. Rats were assessed for serum anti-Müllerian hormone (AMH) levels, ovarian caspase 3 and PTEN protein levels in the ovarian lysate. Total follicular counts (TFC) were estimated from stained ovarian sections. Functional recovery was investigated through daily vaginal smears and mating trials. In-vitro chemical transfection of the AFMSCs with selective miRNA-21 mimics/inhibitors followed by isolation of EVs for therapy was conducted in two additional groups. At the interval points studied, treatment with AFMSCs and EVs equally restored TFC, AMH levels, regular estrous cycles and fruitful conception, while it both diminished caspase 3 and PTEN levels. EVs carrying miRNA-21 mimics recapitulated the short-term effects. Placebo-treated POD or EVs carrying miRNA-21 inhibitors showed augmented ovarian follicular damage demonstrated the low AMH levels, TFC and high levels of PTEN and caspase 3. miRNA-21 allowed regeneration by modulating PTEN and caspase 3 apoptotic pathways. Our findings exemplify that EVs could serve as an innovative cell-free therapeutic tool functioning through their miRNA content and that miRNA-21 has a chief regenerative role through modulating PTEN and caspase 3 apoptotic pathways.

Human mesenchymal stem cell treatment of premature ovarian failure: new challenges and opportunities

“…In 2012, Liu et al [119] proved that CD44 + / CD105 + hAFMSCs transplanted into the ovaries of mice with POF survived for at least 3 weeks, and CD44 + / CD105 + hAFMSCs underwent normal cycles of cell proliferation and self-renewal in ovarian tissues of mice with POF. HAFMSC-derived exosomes (hAFMSCs-EXOs) enhanced follicular regeneration, regular estrous cycles, and AMH level through the miRNA 21/PTEN/caspase 3 signaling pathway [120]. Compared with hBMMSCs, hAFMSCs secreted higher levels of exosomes.…”

Therapeutic Role of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Female Reproductive Diseases

“…And then a study in mice revealed higher level of AKT, P-AKT, VEGF, and IGF in UCMSC-MVs-treated groups compared to non-treated POI group, implying that UCMSC-MVs might induce angiogenesis and activate the PI3K/AKT signaling pathway in ovaries ( 38 ). Notably, PTEN, which regulated PI3K/AKT pathway negatively, was downregulated after injected BMSC-EVs or AFMSC-EVs in POI rat models ( 40 , 46 ), suggesting that MSC-EVs might ameliorate GCs apoptosis in POI via PTEN-PI3K pathway. Moreover, MSC-EVs could suppress SIRT families (including SIRT4 or SIRT7) and P53 to reduce cisplatin or cyclophosphamide (CTX)-induced GCs apoptosis ( 36 , 41 , 44 ).…”

Application of Perinatal Derivatives in Ovarian Diseases

“…Functionality of the ovaries through the production of hormones and gametes guarantees the health of the female reproductive system ( Kim et al, 2018 ). In the ovarian follicle, the oocyte is surrounded by granulosa cells and cumulus cells that allow oocytes to survive, grow and mature through molecular and intercellular communications ( Thabet et al, 2020 ). Proliferation and differentiation of granulosa cells is essential for the continuous development of follicles from primary, secondary, tertiary antral follicles up to ovulation ( Li et al, 2019 ).…”