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SA-β-Galactosidase-Based Screening Assay for the Identification of Senotherapeutic Drugs
Published on: June 28, 2019
Nano-encapsulated senolytic cocktail attenuates germ cell senescence in female mice
Yiting Guan1, Shuyue Deng2, Xiaopeng Zou1
1Zhanjiang Institute of Clinical Medicine, Central People's Hospital of Zhanjiang, Guangdong Medical University, Zhanjiang, 524045, People's Republic of China.
Abstract:
Low-quality oocytes directly affect fertilization and embryonic development, contributing to infertility in women, while germ cell senescence leads to reduced germ cell numbers and decreased egg quality. Dasatinib and quercetin (D and Q), as senolytic drugs, have been extensively explored in different age-related diseases. However, their effects on in vitro cultured senescent oocytes and the molecular mechanisms underpinning ovarian aging remain elusive. Here, we report that a nano-encapsulated senolytic D + Q cocktail efficiently improves the quality of post-ovulatory aging oocyte in vitro and follicle quantity in ovaries in a cyclophosphamide (Cy)-induced premature ovarian failure (POF) mouse model. Cocktail supplementation to cultured oocytes potently reduces reactive oxygen species (ROS) levels, maintains spindle integrity, decreases fragmented oocyte frequencies, rescues mislocalized cortical granules (CGs) and mitochondrial membrane potential (MMP), and alleviates DNA damage and apoptosis. Importantly, the cocktail effectively ameliorates fertility deficits in the model. Transcriptome analysis shows cocktail administration to fertility-deficient mice not only up-regulates developmental gene expression but also reduces senescence-associated secretory phenotype (SASP) accumulation. Therefore, our nano-encapsulated D + Q cocktail is a promising reagent for assisted reproductive technology and improving reproductive outcomes in POF.
Insights
A new nano-encapsulated senolytic drug cocktail of dasatinib and quercetin (D+Q) improves egg quality and ovarian function in a mouse model of premature ovarian failure (POF). This senolytic therapy offers potential for assisted reproductive technology and enhanced fertility outcomes.
Area of Science:
- Reproductive Biology
- Gerontology
- Pharmacology
Background:
- Low oocyte quality and germ cell senescence contribute to female infertility and ovarian aging.
- Senolytic drugs, dasatinib and quercetin (D+Q), target senescent cells but their impact on oocyte aging is not well understood.
- Premature Ovarian Failure (POF) is a condition characterized by loss of ovarian function.
Purpose of the Study:
- To investigate the efficacy of a nano-encapsulated D+Q senolytic cocktail on in vitro cultured senescent oocytes and in a mouse model of POF.
- To elucidate the molecular mechanisms by which the D+Q cocktail affects ovarian aging and oocyte quality.
Main Methods:
- Utilized a cyclophosphamide (Cy)-induced POF mouse model.
- Administered nano-encapsulated D+Q cocktail to mice and cultured oocytes.
- Assessed oocyte quality markers including ROS, spindle integrity, DNA damage, apoptosis, and mitochondrial membrane potential (MMP).
- Performed transcriptome analysis to evaluate gene expression changes and senescence-associated secretory phenotype (SASP).
Main Results:
- The D+Q cocktail improved in vitro post-ovulatory aging oocyte quality and in vivo follicle quantity.
- Supplementation reduced ROS, maintained spindle integrity, decreased oocyte fragmentation, and rescued CG and MMP abnormalities.
- The treatment alleviated DNA damage and apoptosis in oocytes.
- Fertility deficits were ameliorated in the POF model, with upregulated developmental genes and reduced SASP observed.
- The cocktail improved follicle quantity in ovaries.
Conclusions:
- Nano-encapsulated D+Q cocktail is effective in improving senescent oocyte quality and ovarian function in a POF mouse model.
- The D+Q cocktail demonstrates potential as a therapeutic agent for assisted reproductive technology.
- This senolytic approach may enhance reproductive outcomes in conditions associated with ovarian aging and POF.
