Abstract
Simple SummaryIn this study, we examined the anti-oxidative effect of human adipose stem cell conditioned medium (ASC-CM) on the ovary and uterus of mice in advanced maternal age (AMA) and the optimal conditions of intravenous injection for ASC-CM administration. Human ASC-CM upregulated expression of antioxidant genes, restored the quality of oocytes derived from aged ovaries and resulted in improved in vitro and in vivo embryo development. The anti-oxidative effect human ASC-CM was optimized with high frequency of administration. Comprehensively, our study successfully introduced the potential of ASC-CM as an antioxidant intervention against age-related infertility in AMA.Advanced maternal age (AMA) has become prevalent globally. With aging, weakened antioxidant defense causes loss of normal function in the ovary and uterus due to oxidative stress. Here, we aimed to improve embryo development in AMA mice by intravenous injection (IV) of human adipose stem cell conditioned medium (ASC-CM) at various frequencies and intervals as an antioxidant intervention. Four- and six-month-old female ICR (Institute of Cancer Research) mice were randomly divided into groups IV treated with human ASC-CM under different conditions, and in vitro and in vivo embryo development were evaluated. Consequently, compared to the control group, blastocyst formation rate of parthenotes was significantly promoted in 4-month-old mice and the mean number of implanted fetuses after natural mating was significantly increased by approximately two-fold in 6-month-old mice. Through gene analysis, the anti-apoptotic and anti-oxidative effects of human ASC-CMs were confirmed in the ovaries and uterus of pregnant mice at both ages. In particular, ovarian expression of gpx1 and catalase drastically increased in 6-month-old mice. Furthermore, the levels of gpx1 and catalase were further increased, with a high frequency of injection regardless of age. Thus, we demonstrated for the first time the anti-oxidative effect of human ASC-CM administration against ovarian aging and the optimal injection condition.
Highlights
During the past decades, the average child-bearing age of women has increased to over 30 and fertility rates in those aged over 35 years, regarded as advanced maternal age (AMA), have risen in most member countries of the organization for economic co-operation and development countries [1].Fertility normally declines with increasing age and there is a growing risk of pregnancy failure in AMA; this has generated the need to develop and employ assisted reproductive technology (ART) [2]
The expression of cell surface markers in adipose stem cells (ASCs) isolated from a healthy female donor was analyzed analyzed by flow cytometry
Considering that the developmental competence of oocytes is determined during ovary maturation [34], it is thought that the anti-oxidative effect of human adipose-derived stem cell conditioned medium (ASC-Conditioned medium (CM)) improved the quality of oocytes in the aged ovaries and subsequently affected parthenote development during the blastocyst stage based on the results obtained, which indicated that the blastocyst formation rate of parthenotes was significantly increased in human ASC-CM-injected 4 month-old mice, but not at 6 months of age
Summary
Fertility normally declines with increasing age and there is a growing risk of pregnancy failure in AMA; this has generated the need to develop and employ assisted reproductive technology (ART) [2]. The quality of oocytes and uterus receptivity are critical factors that affect successful embryo development and maintenance of pregnancy in ART; these factors degenerate as maternal age increases [4]. Deterioration of oocyte quality may result in adverse outcomes including impaired embryo development, implantation failure, and miscarriage [6]. Reduction of endometrial receptivity in AMA, which is associated with a decrease in uterine blood flow and progesterone sensitivity [7], increases the chance of implantation failure [8]. Fetuses in AMA are exposed to a higher risk of premature growth and intrauterine death [9]
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