Human Amnion-Derived Mesenchymal Stem Cells Improved the Reproductive Function of Age-Related Diminished Ovarian Reserve in Mice Through Ampk/Foxo3a Signaling Pathway
Human Amnion-Derived Mesenchymal Stem Cells Improved the Reproductive Function of Age-Related Diminished Ovarian Reserve in Mice Through Ampk/Foxo3a Signaling Pathway
复制标题
人羊膜间充质干细胞通过 Ampk/Foxo3a 信号通路改善小鼠与年龄相关的卵巢储备功能下降的生殖功能
DOI：
10.21203/rs.3.rs-177213/v1
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发表时间：
2021
影响因子：
7.5
通讯作者：
Lianju Qin
中科院分区：
文献类型：
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作者：
Hanwen Liu;Chunyan Jiang;Meng Cao;Boya La;Song Ning;Jing Zhou;Zhengjie Yan;Chuyu Li;Yugui Cui;Xiang Ma;Meilian Wang;Li Chen;Yuexin Zhang;Huimin Wu;Jiayin Liu;Lianju Qin
背景与卵巢储备减少（AR-DOR）降低了卵母细胞的质量，导致女性生育力下降。衰老与线粒体的分布和功能异常密切相关，而线粒体自噬是维持细胞内线粒体数量和质量正常的主要过程，尤其是在含有大量线粒体的卵母细胞中，线粒体自噬是维持卵母细胞成熟和随后胚胎发育过程中能量产生的主要过程。Ampk/FoxO 3a信号通路在线粒体自噬的调控中起重要作用。有报道称间充质干细胞（Mesenchymal stem cells，MSCs）可以改善卵巢功能。在这里，我们的目的是探索人类胚胎来源的间充质干细胞（hAMSC）是否能有效改善AR-DOR小鼠的卵巢功能，以及Ampk/FoxO 3a信号转导是否参与其中。方法采用32周龄3-8窝、血清性激素水平和卵泡数明显降低的小鼠建立AR-DOR模型。将老龄小鼠分为5个处理组：生理盐水（NS，control）、1%人血清白蛋白（HSA，resolver）、低剂量（LD，5.0× 106 cells/kg）、中剂量（MD，7.5× 106 cells/kg）和高剂量（HD，10.0× 106 cells/kg）。将制备的hAMSC经尾静脉注射。检测血清性激素水平、卵泡数、受精率、妊娠率、小卵泡数、卵巢颗粒细胞和间质细胞凋亡、卵巢组织中Sod 2、Ampk表达水平及磷酸化FoxO 3a/总FoxO 3a比值。结果hAMSC移植后AR-DOR小鼠卵巢功能明显改善，卵巢颗粒细胞和基质细胞凋亡明显减少，Ampk表达水平和磷酸化FoxO 3a/总FoxO 3a比值均明显升高，结论尾部注射hAMSCs移植可通过Ampk/Sod 2途径改善AR-DOR小鼠的卵巢功能。FoxO 3a信号通路
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 hAMSCs transplantation via tail-injection can improve ovarian function of AR-DOR mice through Ampk/FoxO3a signaling pathway.