Abstract
BackgroundAge-related diminished ovarian reserve (AR-DOR) reduced the quality of oocytes, resulting in decreased female fertility. Aging is tightly related to abnormal distribution and function of mitochondria, while mitophagy is a major process to maintain normal quality and quantity of mitochondria in cells, especially in oocytes which containing a large number of mitochondria to meet the demand of energy production during oocyte maturation and subsequent embryonic development. Ampk/FoxO3a signaling is crucial in the regulation of mitophagy. It is reported mesenchymal stem cells (MSCs) can improve ovarian function. Here we aim to explore if human amnion-derived mesenchymal stem cells (hAMSCs) are effective in improving ovarian function in AR-DOR mice and whether Ampk/FoxO3a signaling is involved.MethodsThe AR-DOR model mice were established by 32-week-old mice with 3–8 litters, significantly low serum sex hormone levels and follicle counts. The old mice were divided into 5 treatment groups: normal saline (NS, control), 1% human serum albumin (HSA, resolver), low dose (LD, 5.0 × 106cells/kg), middle dose (MD, 7.5 × 106cells/kg), and high dose (HD, 10.0 × 106cells/kg). The prepared hAMSCs were injected through tail vein. Serum sex hormone level, follicle counts, fertilization rate, gestation rate, little size, apoptosis of granulosa and stromal cells, expression level of Sod2, Ampk, and ratio of phosphorylated FoxO3a to total FoxO3a in ovaries were examined.ResultsOur results show that after hAMSC transplantation, the ovarian function in AR-DOR mice was significantly improved, meanwhile the apoptosis of granulosa and stromal cells in the ovaries was significantly repressed, the expression level of Ampk and the ratio of phosphorylated FoxO3a to total FoxO3a both were significantly increased, meanwhile increased Sod2 expression was also observed.ConclusionOur results demonstrate hAMSC transplantation via tail-injection can improve ovarian function of AR-DOR mice through Ampk/FoxO3a signaling pathway.
Highlights
Age-related diminished ovarian reserve (AR-Diminished ovarian reserve (DOR)) reduced the quality of oocytes, resulting in decreased female fertility
Our results demonstrate that middle (7.5 × 106 cells/kg) and high (10.0 × 106 cells/kg) dose of Human amnion-derived mesenchymal stem cell (hAMSC) transplantation improved the ovarian function by Ampk/FoxO3a signaling mediated mitophagy in oocytes in Age-related diminished ovarian reserve (AR-DOR) mice
The expression of FSHR located in the granulosa cell surface showed the same trend. These results indicated that the hAMSC transplantation could increase the expression of protein involved in reproductive hormone signaling in ovarian cells to improve the ovarian function (Figure S3)
Summary
Age-related diminished ovarian reserve (AR-DOR) reduced the quality of oocytes, resulting in decreased female fertility. Ampk/FoxO3a signaling is crucial in the regulation of mitophagy It is reported mesenchymal stem cells (MSCs) can improve ovarian function. We aim to explore if human amnion-derived mesenchymal stem cells (hAMSCs) are effective in improving ovarian function in AR-DOR mice and whether Ampk/FoxO3a signaling is involved. Diminished ovarian reserve (DOR) in female refers to the decline in the quality and quantity of oocytes in the ovaries, accompanied by menstrual abnormalities, ovulation disorders, infertility, and organ and systemic decline related to hypoestrogen [1,2,3]. The age over 35 years old of women who have fertility requirements is defined as advanced reproductive age, which can lead to AR-DOR, showing physiological ovarian degeneration [4]
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