Zhang Yulin, Ouyang Xiaolan, You Shuang, Zou Heng, Shao Xiaoyan, Zhang Guanghui, Zhang Chanyu, Hu Lina
The Center for Reproductive Medicine, Obstetrics and Gynecology Department, The Second Affiliated Hospital, Chongqing Medical University Chongqing, China.
Reproduction and Stem Cell Therapy Research Center of Chongqing China.
Am J Transl Res. 2020 Jul 15;12(7):3234-3254. eCollection 2020.
Human amniotic epithelial cells (hAECs) show similar features to stem cells and have low immunogenicity. This study aims to investigate the therapeutic effect of hAEC transplantation on cyclophosphamide-induced primary ovarian insufficiency (POI) rats and evaluate the underlying mechanisms by mRNA sequencing of ovarian samples. Notably, hAECs mainly located in the interstitial area of the ovaries rather than follicles. hAEC transplantation led to a slight increase in body and ovary weight, normalized irregular estrous cycles, decreased serum follicle stimulating hormone (FSH) and increased anti-Mullerian hormone (AMH) level and restored follicle pools in POI rats. Ovarian expression of AMH, follicle stimulating hormone receptor (FSHR) and klotho in POI rats was also significantly upregulated following hAEC transplantation. Fetus number was higher in the hAEC transplantation group than the POI group. The mRNA sequencing results showed that hAEC transplantation led to the upregulation of several angiogenesis and inflammation molecules including interferon regulatory factor 7 (IRF7), Mx dynamin-like GTPase 1 (Mx1), vascular endothelial growth factor receptor (VEGFR)1 and VEGFR2. Moreover, hAEC therapy had an effect on ribosomes, protein digestion, protein absorption, neuroactive ligand-receptor interaction, cAMP signaling pathway and steroid biosynthesis pathways. The expression of several steroid biosynthesis proteins was significantly upregulated as measured by quantitative real-time polymerase chain reaction (RT-qPCR), immunohistochemical staining and Western blot analysis. In summary, hAECs can significantly restore ovarian function, and improve both ovarian reserve and fertility. This may be due to the paracrine effect of hAECs in regulating steroid biosynthesis, modulating follicle development from initiation to ovulation, promoting angiogenesis and reducing inflammation.
人羊膜上皮细胞（hAECs）具有与干细胞相似的特征，且免疫原性低。本研究旨在探讨hAEC移植对环磷酰胺诱导的原发性卵巢功能不全（POI）大鼠的治疗效果，并通过对卵巢样本进行mRNA测序来评估其潜在机制。值得注意的是，hAECs主要位于卵巢的间质区域而非卵泡内。hAEC移植使POI大鼠的体重和卵巢重量略有增加，使不规则的发情周期恢复正常，降低血清卵泡刺激素（FSH）水平，提高抗苗勒管激素（AMH）水平，并恢复卵泡池。hAEC移植后，POI大鼠卵巢中AMH、卵泡刺激素受体（FSHR）和klotho的表达也显著上调。hAEC移植组的胎儿数量高于POI组。mRNA测序结果表明，hAEC移植导致包括干扰素调节因子7（IRF7）、Mx动力蛋白样GTP酶1（Mx1）、血管内皮生长因子受体（VEGFR）1和VEGFR2在内的几种血管生成和炎症分子上调。此外，hAEC疗法对核糖体、蛋白质消化、蛋白质吸收、神经活性配体-受体相互作用、cAMP信号通路和类固醇生物合成途径有影响。通过定量实时聚合酶链反应（RT-qPCR）、免疫组织化学染色和蛋白质印迹分析测量，几种类固醇生物合成蛋白的表达显著上调。总之，hAECs可显著恢复卵巢功能，改善卵巢储备和生育能力。这可能是由于hAECs的旁分泌作用，调节类固醇生物合成，从起始到排卵调节卵泡发育，促进血管生成并减轻炎症。
